The primary stability of two dental implant systems in low-density bone.

Primary stability in low-density bone is crucial for the long-term success of implants. Tapered implants have shown particularly favourable properties under such conditions. The aim of this study was to compare the primary stability of tapered titanium and novel cylindrical zirconia dental implant systems in low-density bone. Fifty implants (25 tapered, 25 cylindrical) were placed in the anterior maxillary bone of cadavers meeting the criteria of low-density bone. The maximum insertion (ITV) and removal (RTV) torque values were recorded, and the implant stability quotients (ISQ) determined. To establish the isolated influence of cancellous bone on primary stability, the implantation procedure was performed in standardized low-density polyurethane foam bone blocks (cancellous bone model) using the same procedure. The primary stability parameters of both implant types showed significant positive correlations with bone density (Hounsfield units) and cortical thickness. In the cadaver, the cylindrical zirconia implants showed a significantly higher mean ISQ when compared to the tapered titanium implants (50.58 vs 37.26; P < 0.001). Pearson analysis showed significant positive correlations between ITV and ISQ (P = 0.016) and between RTV and ISQ (P = 0.035) for the cylindrical zirconia implants; no such correlations were observed for the tapered titanium implants. Within the limitations of this study, the results indicate that cylindrical zirconia implants represent a comparable viable treatment option to tapered titanium implants in terms of primary implant stability in low-density human bone.

Safe and Ethical Artificial Intelligence in Radiotherapy - Lessons Learned From the Aviation Industry.

Ethical artificial intelligence (AI) frameworks can be the catalyst in improving the safety and wellbeing of people when developing AI systems. In 2020 Rolls-Royce released its ethical and trustworthiness toolkit, The Aletheia FrameworkTM, which helps guide organisations as they consider the ethics around the use of AI. It covers three facets: social impact, accuracy and trust, and governance - which apply across all uses of AI. By adopting AI ethics and trust frameworks, oncologists can ensure the ratio between the benefit and harms of AI can be maximised. With AI transforming every sector, collaboration across industries to share ideas and learn from each other - even unlikely partnerships between engineering and oncology - could help optimise that transition.

Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell transplantation in patients with newly diagnosed multiple myeloma on the ECOG-ACRIN E4A03 randomized clinical trial: long-term follow-up.

In Eastern Cooperative Oncology Group-ACRIN E4A03, on completion of four cycles of therapy, newly diagnosed multiple myeloma patients had the option of proceeding to autologous peripheral blood stem cell transplant (ASCT) or continuing on their assigned therapy lenalidomide plus low-dose dexamethasone (Ld) or lenalidomide plus high-dose dexamethasone (LD). This landmark analysis compared the outcome of 431 patients surviving their first four cycles of therapy pursuing early ASCT to those continuing on their assigned therapy. Survival distributions were estimated using the Kaplan-Meier method and compared with log-rank test. Ninety patients (21%) opted for early ASCT. The 1-, 2-, 3-, 4- and 5-year survival probability estimates were higher for early ASCT versus no early ASCT at 99, 93, 91, 85 and 80% versus 94, 84, 75, 65 and 57%, respectively. The median overall survival (OS) in the early versus no early ASCT group was not reached (NR) versus 5.78 years. In patients <65 years of age, median OS in the early versus no early ASCT groups was NR in both, hazard ratio 0.79, 95% confidence interval: (0.50, 0.25). In patients ⩾65 years of age, median OS in the early versus no early ASCT was NR versus 5.11 years. ASCT dropped out of statistical significance (P=0.080). Patients opting for ASCT after induction Ld/LD had a higher survival probability and improvement in OS regardless of dexamethasone dose density.

Oral antibiotic prophylaxis of early infection in multiple myeloma: a URCC/ECOG randomized phase III study.

Multiple myeloma (MM) is a malignancy of clonal plasma cells, resulting in an increased production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. Patients with MM are at increased risk of infectious complications, particularly streptococcal and staphylococcal infections. This study evaluated the impact of prophylactic antibiotics on the incidence of serious bacterial infections (SBIs) during the first 2 months of treatment in patients with newly diagnosed MM. Patients with MM receiving initial chemotherapy were randomized on a 1:1:1 basis to daily ciprofloxacin (C; 500 mg twice daily), trimethoprim-sulfamethoxazole (T; DS twice daily) or observation (O) and evaluated for SBI (Eastern Cooperative Oncology Group ≥grade 3) for the first 2 months of treatment. From July 1998 to January 2008, 212 MM patients were randomized to C (n=69), T (n=76) or O (n=67). The incidence of SBI was comparable among groups: C=12.5%, T=6.8% and O=15.9%; P=0.218. Further, any infection during the first 2 months was also comparable (20% vs 23% vs 22%, respectively, P=0.954). We demonstrate that prophylactic antibiotics did not decrease the incidence of SBI (≥grade 3) within the first 2 months of treatment. We conclude that routine use of prophylactic antibiotics should not be mandated for patients receiving induction chemotherapy.

Cellular signals underlying ß-adrenergic receptor mediated salivary gland enlargement.

We examined the cellular signaling pathways involved in parotid gland enlargement induced by repeated isoproterenol administration in rats. Immunoblot analysis revealed early (1h) activation of the mitogen activated protein kinase (MAPK) ERK1/2, and progressive activation of epidermal growth factor receptor (EGFR), p38MAPK and p70S6 kinase (p70S6K) during 72h of isoproterenol treatment. Expression of ß-adrenergic receptors (ARs) of the ß2, but not ß1, subtype increased over time in parallel with increases in the proliferation marker PCNA and parotid gland weight. Levels of ß2-AR mRNA, assessed by quantitative RT-PCR and Northern blot analysis, were upregulated in parotid glands of isoproterenol treated rats. cAMP response element binding protein (CREB), a positive regulator of ß2-AR transcription, was activated at 1h after isoproterenol administration, as evidenced by increased nuclear translocation and DNA binding using immunohistochemical staining and electrophoretic mobility shift assay. ELISA of NF-κB, also a ß2-AR transcriptional regulator, revealed an increase in p65 and p50 subunits in nuclear protein extracts from parotid glands of isoproterenol treated rats. Together, these results demonstrate that ß-adrenergic stimulation activates diverse cell survival and progrowth signaling pathways, including cAMP and EGFR linked activation of ERK1/2, p38MAPK, and p70S6K, and also induction of ß2-ARs, possibly mediated by CREB and NF-κB, resulting in salivary gland enlargement. We propose that during isoproterenol treatment activation of the ß1-AR, the predominant ß-AR subtype in unstimulated salivary glands, initiates proliferative signaling cascades, and that upregulation of the ß2-AR plays an essential role in later stages of salivary gland growth.

Genetic polymorphisms of EPHX1, Gsk3beta, TNFSF8 and myeloma cell DKK-1 expression linked to bone disease in myeloma.

Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. A custom-built DNA single nucleotide polymorphism (SNP) chip containing 3404 SNPs was used to test genomic DNA from myeloma patients classified by the extent of bone disease. Correlations identified with a Total Therapy 2 (TT2) (Arkansas) data set were validated with Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) data sets. Univariate correlates with bone disease included: EPHX1, IGF1R, IL-4 and Gsk3beta. SNP signatures were linked to the number of bone lesions, log(2) DKK-1 myeloma cell expression levels and patient survival. Using stepwise multivariate regression analysis, the following SNPs: EPHX1 (P=0.0026); log(2) DKK-1 expression (P=0.0046); serum lactic dehydrogenase (LDH) (P=0.0074); Gsk3beta (P=0.02) and TNFSF8 (P=0.04) were linked to bone disease. This assessment of genetic polymorphisms identifies SNPs with both potential biological relevance and utility in prognostic models of myeloma bone disease.

Translational regulation is a control point in RUNX2/Cbfa1 gene expression.

Runt-related transcription factor-2 (RUNX2)/core binding factor a1 (Cbfa1) is implicated in the regulation of osteoblast differentiation and osteoblast-specific gene expression. Mutations in RUNX2 cause the bone disease cleidocranial dysplasia, which is characterized by multiple skeletal defects. RUNX2 is expressed as two isoforms (type-I and type-II) encoded by two different mRNAs. We report here the detection of both mRNAs in osteoblastic cells and osteoblast precursors as well as nonosteoblastic cells. Surprisingly, however, osteoblast precursors and nonosteoblastic cells express no RUNX2 protein; mature osteoblasts express both isoforms, while less mature osteoblastic cells express only type-I protein. Northern blot analysis of RNA isolated from polysomes and ribonucleoprotein particles demonstrated that RUNX2 mRNA is polysome-associated in osteoblastic cells but polysome-free in osteoblast precursors. These results suggest that (a) RUNX2 mRNAs are expressed but dormant in osteoblast precursors and nonosteoblastic cells, (b) RUNX2 gene expression is controlled at the translational level, and (c) the expression of individual protein isoforms of RUNX2 is differentiation stage specific. Thus, differentiation of cells along the osteoblast lineage appears to be regulated at the level of RUNX2 mRNA translation.

Analysis of type-I and type-II RUNX2 protein expression in osteoblasts.

Runt-related transcription factor-2 (RUNX2) is expressed as two isoforms (type-I and type-II) differing only in their amino terminal sequences. The amino terminus of type-I contains MRIPV instead of MASNSLFSAVTPCQQSFFW in type-II. Although type-II mRNA has been considered osteoblast specific, the RUNX2 protein isoforms expressed in osteoblasts have not yet been identified. Using antisera generated against the two different amino terminal sequences of type-I and type-II RUNX2, we show the expression of both isoforms in cells with the mature osteoblast phenotype (fetal rat calvarial cells, and ROS 17/2.8, SaOS-2 and U2OS osteosarcoma cell lines), but only type-I in partially differentiated osteoblast-like cells (the UMR-106 osteosarcoma cell line). Since UMR-106 cells express both type-I and type-II mRNAs, our results suggest that the translation of type-II mRNA is repressed in these cells. No RUNX1 and RUNX3 proteins are detected in any of the osteoblastic cells tested. The antisera we have generated will be useful for studies relating expression of RUNX2 isoforms to control of osteoblast differentiation.

Succinylcholine pretreatment using gallamine or mivacurium during rapid sequence induction in children: a randomized, controlled study.

STUDY OBJECTIVE: To determine if pretreatment with either gallamine or mivacurium before succinylcholine in children is associated with reduction in fasciculations; postoperative myalgias; or serum levels of potassium, creatinine phosphokinase (CPK), and myoglobin. DESIGN: Prospective, randomized, double-blinded study. SETTING: Operating room at a children's hospital. PATIENTS: 45 ASA physical status IE children, aged 3 to 15 years, scheduled for emergency surgery. INTERVENTIONS: The children received either normal saline 0.5 mL, mivacurium chloride 0.03 mg. kg(-1), or gallamine triethiodide 0.04 mg. kg(-1)2 minutes prior to rapid sequence induction (RSI) using thiopental sodium 5 mg. kg(-1), fentanyl 2 microg. kg(-1), and succinylcholine 2 mg. kg(-1). MEASUREMENTS: Serum potassium concentration (0, 3, 5, 7.5, and 15 min), myoglobin concentration (5 and 15 min), and CPK concentration (0 min and 24 hr). Fasciculation and myalgia were rated on a 0 to 3 score. MAIN RESULTS: There was no difference between groups for fasciculation (p = 0.87) or myalgia score (p = 0.52). The mivacurium group had significantly less increase in potassium at 5 minutes (0.45 vs. 0.0, p = 0.01), myoglobin at 5 minutes (56 vs. 2, p < 0.001), myoglobin at 15 minutes (128 vs. 2.5, p < 0.001), and CPK at 24 hours (399 vs. 138, p < 0.001) following succinylcholine when compared with normal saline. Additionally, we found a significant level of association (p < 0.001) between fasciculation and myoglobin levels and fasciculation and CPK levels (p < 0.001). Gallamine was not effective in reducing the increase of potassium, myoglobin, or CPK. However, the dose of gallamine used for pretreatment was 13 times less than the dose of mivacurium. CONCLUSIONS: Administration of mivacurium 0.03 mg. kg(-1) intravenously 2 minutes before administration of succinylcholine 2 mg. kg(-1) in children is effective in reducing the increase in serum potassium at 5 minutes, the increase in myoglobin at 5 minutes and 15 minutes, and the increase in CPK at 24 hours.

Geriatrics grand rounds: Eve's rib, or a revisionist view of osteoporosis in men.

It is widely accepted that estrogen withdrawal following menopause predisposes women to accelerated bone loss and increased risk of developing osteoporosis. Although osteoporosis is a significant public health problem for aging men as well as women, the cause of osteoporosis in men remains largely unknown. A substantial number of men with osteoporosis present with bone loss secondary to conditions associated with reduced gonadal steroid hormone levels. Although hypogonadism is related to bone loss in men, and androgen levels decline with age in men, it is not at all clear that reduced androgen levels are related to bone loss in older men. What, then, is the role of gonadal steroids in osteoporosis in men? This review focuses on recent research--including clinical investigations of men with genetic disorders of estrogen action, basic biomedical studies of estrogen receptor "knockout" mice, and population-based comparisons of bone density with gonadal steroids in older men--leading to the surprising conclusion that estrogen plays a vital role in maintenance of bone in men as well as in women. Possible mechanisms whereby reduced estrogen levels might result in bone loss in both sexes are also reviewed, as are potential therapeutic implications of a role for estrogen in osteoporosis in men.

EGF inhibits muscarinic receptor-mediated calcium signaling in a human salivary cell line.

The effects of epidermal growth factor (EGF) on intracellular calcium ([Ca(2+)](i)) responses to the muscarinic agonist carbachol were studied in a human salivary cell line (HSY). Carbachol (10(-4) M)-stimulated [Ca(2+)](i) mobilization was inhibited by 40% after 48-h treatment with 5 x 10(-10) M EGF. EGF also reduced carbachol-induced [Ca(2+)](i) in Ca(2+)-free medium and Ca(2+) influx following repletion of extracellular Ca(2+). Under Ca(2+)-free conditions, thapsigargin, an inhibitor of Ca(2+) uptake to internal stores, induced similar [Ca(2+)](i) signals in control and EGF-treated cells, indicating that internal Ca(2+) stores were unaffected by EGF; however, in cells exposed to thapsigargin, Ca(2+) influx following Ca(2+) repletion was reduced by EGF. Muscarinic receptor density, assessed by binding of the muscarinic receptor antagonist L-[benzilic-4,4'-(3)HCN]quinuclidinyl benzilate ([(3)H]QNB), was decreased by 20% after EGF treatment. Inhibition of the carbachol response by EGF was not altered by phorbol ester-induced downregulation of protein kinase C (PKC) but was enhanced upon PKC activation by a diacylglycerol analog. Phosphorylation of mitogen-activated protein kinase (MAP kinase) and inhibition of the carbachol response by EGF were both blocked by the MAP kinase pathway inhibitor PD-98059. The results suggest that EGF decreases carbachol-induced Ca(2+) release from internal stores and also exerts a direct inhibitory action on Ca(2+) influx. A decline in muscarinic receptor density may contribute to EGF inhibition of carbachol responsiveness. The inhibitory effect of EGF is mediated by the MAP kinase pathway and is potentiated by a distinct modulatory cascade involving activation of PKC. EGF may play a physiological role in regulating muscarinic receptor-stimulated salivary secretion.

Accuracy of dipyridamole SPECT imaging in identifying individual coronary stenoses and multivessel disease in women versus men.

BACKGROUND: Older women frequently undergo dipyridamole perfusion imaging and can have advanced coronary artery disease, but little data exist on the accuracy of perfusion imaging in detecting disease in individual vascular territories and multivessel disease in women, compared with men. METHODS AND RESULTS: From a database of patients undergoing myocardial single photon emission computed tomography (SPECT) perfusion imaging, 107 unselected sequential patients (58 women, 49 men) who underwent sestamibi dipyridamole stress and cardiac catheterization within 6 months of each other were identified. Data were analyzed to compare sensitivities for detection of individual coronary stenoses and multivessel disease. The concordance between perfusion image results and cardiac catheterization for individual coronary territories for women was 75%, and for men, it was 65% (P = .09). In women, the presence of disease of the left anterior descending coronary artery was detected more frequently than it was in men, 84% versus 44% (P = .004). The detection of disease in the territories of the left circumflex and right coronary arteries was similar for both groups. For women, the accuracy of perfusion imaging in identifying the presence/absence of multivessel coronary disease was 64%, compared with 71 % for men (P = not significant). CONCLUSIONS: The accuracy of dipyridamole sestamibi SPECT imaging in detecting multivessel disease was similar for men and women. The sensitivity of dipyridamole sestamibi SPECT imaging in detecting disease of the left anterior descending artery was better in women.

The potency of succinylcholine in obese adolescents.

UNLABELLED: We constructed a single-dose response curve for succinylcholine in 30 obese adolescents during thiopental-fentanyl anesthesia administration by using 100 microg/kg, 150 microg/kg, or 250 microg/kg IV. The maximal response (percent depression of neuromuscular function) of the adductor pollicis to supramaximal train-of-four stimuli was recorded by using a Datex (Helsinki, Finland) relaxograph. Linear regression and inverse prediction were used to determine doses of succinylcholine to produce 50% (ED(50)), 90% (ED(90)), and 95% (ED(95)) depression of neuromuscular function. The ED(50), ED(90), and ED(95) were 152.8 microg/kg (95% confidence interval: 77.8-299.5), 275.4 microg/kg (95% confidence interval: 142-545.7), and 344.3 microg/kg (95% confidence interval: 175.3-675. 3), respectively. This ED(50) is similar to the dose reported for similarly aged, nonobese adolescents, 147 microg/kg. The previously reported ED(95) for succinylcholine in nonobese adolescents, 270 microg/kg, is within the 95% confidence interval generated for ED(95) in our study. IMPLICATIONS: The potency estimates for succinylcholine in obese (body mass index > 30 kg/m(2)) adolescents are comparable to those in similarly aged nonobese adolescents when dosing is calculated based on total body mass and not lean body mass. When a rapid sequence induction of anesthesia is considered in an obese adolescent, the dose of succinylcholine should be based on actual (not lean) body mass.

Activation of PLC and PI 3 kinase by PDGF receptor alpha is not sufficient for mitogenesis and migration in mesangial cells.

BACKGROUND: Platelet-derived growth factor (PDGF) isoforms act through two distinct cell surface alpha and beta receptors. Glomerular mesangial cells express both receptors. PDGF BB and AB are potent mitogens for glomerular mesangial cells, and PDGF BB stimulates cell migration in a phosphatidylinositol 3 (PI 3) kinase-dependent manner. In this study, we investigated the effect of PDGF AA on cell migration, PI 3 kinase and phospholipase C (PLC) activation, and the role of these two enzymes in mediating biological responses in these cells in response to all three isoforms. METHODS: 3H-thymidine incorporation and modified Boyden chamber assay were used to determine DNA synthesis and directed migration, respectively, in response to all three PDGF isoforms. Differential activation of alpha and beta receptors was studied by immunecomplex tyrosine kinase assay of corresponding receptor immunoprecipitates. PLC gamma 1 activity was determined by measuring total inositol phosphates in response to different PDGF isoforms. PI 3 kinase activity was determined in antiphosphotyrosine or PDGF receptor immunoprecipitates. RESULTS: Both PDGF BB and AB resulted in stimulation of DNA synthesis and directed migration of mesangial cells. AA was neither chemotactic nor mitogenic. However, all three isoforms increased tyrosine phosphorylation of a 180 kD protein in antiphosphotyrosine immunoprecipitates, suggesting activation of respective receptors. Direct immunecomplex tyrosine kinase assay of alpha and beta receptors demonstrated significant activation of both of these receptors when cells are treated with PDGF BB or AB. PDGF AA increased tyrosine kinase activity of the alpha receptor but not the beta receptor. All three isoforms significantly stimulated the production of inositol phosphates with order of potency being BB > AB > AA. PDGF AA also dose dependently stimulated PI 3 kinase activity measured in antiphosphotyrosine immunoprecipitates of treated cells. A comparison of PI 3 kinase activity in antiphosphotyrosine immunoprecipitates from mesangial cells stimulated with three different PDGF isoforms showed significant activation of this enzyme with a decreasing order of activity: BB > AB > AA. CONCLUSION: Taken together, these data demonstrate that all three isoforms of PDGF significantly stimulate PLC gamma 1 and PI 3 kinase, two enzymes necessary for both DNA synthesis and directed migration. However, activation of alpha receptor by PDGF AA with a subsequent increase in PLC and PI 3 kinase activities is not sufficient to induce these biological responses in mesangial cells. These data indicate that the extent of activation of signal transduction pathways may be a major determinant of the biological activity of different PDGF isoforms in mesangial cells.

G-protein signaling abnormalities mediated by CD95 in salivary epithelial cells.

Salivary epithelial cells from patients with primary Sjögren's syndrome (SS) undergo Fas-mediated apoptosis. Bcl-2 and Bcl-xL are apoptosis suppressing oncogenes. Very little is known about the role of these oncogene molecules in salivary epithelial cells. To investigate the possible prevention of salivary glandular destruction in SS by Bcl-2 and Bcl-xL, stable transfectants expressing these molecules were made from HSY cells, a human salivary epithelial cell line. HSY cells were transfected with an expression vector for human Bcl-2 or Bcl-xL. Stable transfectants were selected and apoptosis was induced by anti-Fas antibody. Apoptosis was quantified by propidium iodide staining followed by flow cytometry. Caspase activity was detected by immunohistochemical analysis and enzyme cleavage of DEVD-AMC, a fluorescent substrate. Response to carbachol, a muscarinic receptor agonist, and EGF was measured by Ca2+ mobilization and influx. Fas-mediated apoptosis was significantly inhibited in Bcl-2 and Bcl-xL transfectants compared to wild-type and control transfectants (empty vector). Surprisingly, caspase activity was not inhibited in Bcl-2 and Bcl-xL transfectants. Activation of the Fas pathway in the Bcl-2 and Bcl-xL transfectants by antibody also inhibited carbachol and EGF responsiveness (i.e., Ca2+ mobilization and/or influx) by 50-60%. This Fas-mediated inhibition of cell activation was partially or completely restored by specific peptide interference of caspase enzyme activity. The prevention of Fas-mediated apoptosis by the overexpression of Bcl-2 and Bcl-xL in salivary gland epithelial cells results in injured cells expressing caspase activity and unable to respond normally to receptor agonists. Such damaged cells may exist in SS patients and could explain the severe dryness out of proportion to the actual number of apoptotic cells seen on salivary gland biopsy.

Patterns of recurrence and outcome for patients with clinical stage II non-small-cell lung cancer.

Forty-six patients with pathologic clinical stage II non-small-cell lung carcinoma underwent resection with or without adjuvant radiotherapy from 1989 through 1994. These patients were analyzed to determine patterns of recurrence and survival. Surgery consisted of pneumonectomy for 11 patients, bilobectomy for two patients, lobectomy for 29 patients, and wedge or segmental resection for four patients. Adjuvant radiotherapy was delivered to 29 patients, and the median total dose was 54 Gy (range, 44-60 Gy). Median follow-up time was 23 months for all patients and 25 months for surviving patients. Twenty-six of 46 patients have had recurrence. The site of first recurrence was locoregional for 9 of 46 patients (20%) and distant for 17 of 46 patients (37%). The median time to locoregional recurrence was 18 months for patients treated with radiotherapy and 13 months for patients treated without radiotherapy. An isolated locoregional recurrence (with no simultaneous distant recurrence) was seen in 2 of 28 evaluable patients (7%) treated with radiotherapy compared with 3 of 17 patients (18%) not treated with radiotherapy. For all patients, the 3-year disease-free survival rate was 52%, and the overall survival rate was 52%. Among patients treated with radiotherapy, the 3-year disease-free survival and overall survival rates were 56% and 56%, respectively, compared with 46% and 43%, respectively, for patients who did not receive radiotherapy (p values were not significant). The locoregional recurrence rate was 33% for patients with adenocarcinoma and 15% for those with squamous cell carcinoma. The distant recurrence rates by histologic characteristic were 56% and 20%, respectively. For patients with clinical stage II non-small-cell lung cancer, postoperative radiotherapy appears to improve locoregional control. However, the preponderance of recurrences remains distant. Further study is warranted with special emphasis on control of systemic disease.