Medical Education Column, Creating a High-Yield Guide to Lifestyle Medicine for Medical Students and Healthcare Professionals.

Despite their inclusion as first-line therapy for many chronic diseases, lifestyle interventions are often de-emphasized in medical education and fail to make it into the repertoire of non-lifestyle medicine trained clinicians. We sought to address this gap in medical education by creating a concise pocket guide to lifestyle medicine that lends itself to use in the face-to-face clinical setting. With input from lifestyle medicine experts, the guide was created by medical students for medical students as well as other healthcare professionals for use in a variety of clinical settings. In this article we share our process of creating the guide, initial feedback, and future directions.

Heterogeneity of obstructive sleep apnea phenotypes after ischemic stroke: Outcome variation by cluster analysis.

INTRODUCTION: Obstructive sleep apnea (OSA) is common but under-recognized after stroke. The aim of this study was to determine whether post-stroke phenotypic OSA subtypes are associated with stroke outcome in a population-based observational cohort. METHODS: Ischemic stroke patients (n = 804) diagnosed with OSA (respiratory event index ≥10) soon after ischemic stroke were identified from the Brain Attack Surveillance in Corpus Christi (BASIC) project. Functional, cognitive, and quality of life outcomes were assessed at 90 days post-stroke and long-term stroke recurrence was ascertained. Latent profile analysis was performed based on demographic and clinical features, pre-stroke sleep characteristics, OSA severity, and vascular risk factors. Regression models were used to assess the association between phenotypic clusters and outcomes. RESULTS: Four distinct phenotypic clusters provided the best fit. Cluster 1 was characterized by more severe stroke; cluster 2 by severe OSA and higher prevalence of medical comorbidities; cluster 3 by mild stroke and mild OSA; and cluster 4 by moderate OSA and mild stroke. Compared to cluster 3 and after adjustment for baseline stroke severity, cluster 1 and cluster 2 had worse 90-day functional outcome and cluster 1 also had worse quality of life. No difference in cognitive outcome or stroke recurrence rate was noted by cluster. CONCLUSION: Post-stroke OSA is a heterogeneous disorder with different clinical phenotypes associated with stroke outcomes, including both daily function and quality of life. The unique presentations of OSA after stroke may have important implications for stroke prognosis and personalized treatment strategies.

Breast conservation therapy versus mastectomy in the surgical management of invasive lobular carcinoma measuring 4 cm or greater.

BACKGROUND: The safety of breast conservation therapy (BCT) has not been demonstrated in large ILC tumors, potentially contributing to the higher mastectomy rates seen in ILC. METHODS: We queried a prospectively maintained database to identify patients with ILC measuring ≥4 cm and evaluated difference in recurrence free survival (RFS) between those treated with BCT versus mastectomy using a multivariate model. RESULTS: Of 180 patients, 30 (16.7%) underwent BCT and 150 (83.3%) underwent mastectomy. Patients undergoing mastectomy were younger (56.6 vs. 64.3 years, p = 0.003) and had larger tumors (7.2 vs. 5.4 cm, p < 0.001). While tumor size, nodal stage, receptor subtype, and margin status were significantly associated with RFS, there was no difference in RFS at 5 (p = 0.88) or 10 (p = 0.65) years for individuals undergoing BCT versus mastectomy. CONCLUSIONS: For patients with ILC ≥4 cm, BCT provides similar tumor control as mastectomy, provided that negative margins are achieved.

Weibull modulus and fracture strength of highly porous hydroxyapatite.

Porous hydroxyapatite (HA) is used in a variety of applications including biomedical materials such as engineered bone materials and microbe filters. Despite the utility of the Weibull modulus, m, as a gauge of the mechanical reliability of brittle solids, there have been very few studies of m for porous HA. A recent study of porous HA that included the current authors (Fan, X., Case, E.D., Ren, F., Shu, Y., Baumann, M.J., 2012a. Journal of the Mechanical Behavior of Biomedical Materials. 8, 21-36) showed increases in m for porosity, P, approaching PG, the porosity of the green (unfired) specimen. In this paper, 18 groups of highly porous HA specimens (12 groups fabricated in this study and 6 groups from Fan et al., 2012a) were analyzed with P values from 0.59 to 0.62, where PG=0.62. The partially sintered HA specimens were fractured in biaxial flexure using a ring-on-ring test fixture. The fracture strength decreased monotonically with decreasing sintering temperature, Tsinter, from 4.8MPa for specimens sintered at 1025°C-0.66MPa for specimens sintered at 350°C. However, the Weibull modulus remained surprisingly high, ranging from 6.6 to 15.5. In comparison, for HA specimens with intermediate values of P, from about 0.1-0.55, the Weibull modulus tended to be lower (ranging from about 4 to 11) than the highly porous specimens included in this study.

Part I: porosity dependence of the Weibull modulus for hydroxyapatite and other brittle materials.

Porous brittle materials are used as filters, catalyst supports, solid oxide fuel cells and biomedical materials. However the literature on the Weibull modulus, m, versus volume fraction porosity, P, is extremely limited despite the importance of m as a gauge of mechanical reliability. In Part I of this study, m is determined for 441 sintered hydroxyapatite (HA) specimens fractured in biaxial flexure for 0.08 ≤ P ≤ 0.62. In this study, we analyze a combined data set collected from the literature that represents work from a total of 17 different research groups (including the present authors), eight different materials and more than 1560 oxide and non-oxide specimens, the m versus P plot is "U-shaped" with a wide band of m values for P<0.1 (Region I) and P>0.55 (Region III), and a narrower band of m values in the intermediate porosity region of 0.1, and the Young's modulus E for the HA specimens tested in Part I along with literature data for other brittle materials. Both <σ(f)> and E are power law functions of the degree of densification, ϕ, where ϕ=1-P/P(G) and P(G) is the green (unfired) porosity.

Part II: fracture strength and elastic modulus as a function of porosity for hydroxyapatite and other brittle materials.

Part I of this paper discussed the Weibull modulus m, versus porosity P behavior of brittle materials, including HA. While the Weibull modulus m deals with the scatter in fracture strength data, this paper (Part II) focuses on two additional key mechanical properties of porous materials, namely the average fracture strength <σ(f)>, and Young's modulus E, for P in the interval from P≈ zero to P≈P(G) (the porosity of the unfired compacts). The <σ(f)> versus P data for HA from this study and the literature data for alumina, yttria stabilized zirconia (YSZ) and silicon nitride are described well by functions of ϕ, where ϕ=1-P/P(G)= the degree of densification. A similar function of ϕ applies to the versus P behavior of HA from this study and data from the literature for alumina, titanium and YSZ. All of the data analyzed in this study (Part II) are based on partially and fully sintered powder compacts (excluding green powder compacts), thus the <σ(f)>/σ(0) versus ϕ and /E(0) versus ϕ relationships may apply only to such specimens.

Supplementation of fibrin gels with sodium chloride enhances physical properties and ensuing osteogenic response.

Modifying the relative concentrations of fibrinogen and thrombin can control the physical properties of fibrin gels, while the viability of associated cells has been linked to the gel's final network structure. It was hypothesized that increasing the gel ionic strength during fabrication through supplementation with sodium chloride (NaCl) would provide an improved approach for tailoring the physical properties of fibrin gels and maintaining the viability and osteogenic potential of entrapped cells. Fibrin gels were formed by mixing fibrinogen, thrombin and calcium chloride with varying masses of NaCl (0-4.40% w/v), and the osteogenic potential of entrapped human mesenchymal stem cells (MSC) was examined over 14 days. Physical properties including gelation time, compressive modulus and fiber diameter were dependent upon NaCl content, with gels containing 2.60% NaCl possessing compressive moduli threefold higher than gels without NaCl. Alkaline phosphatase activity was highest for MSC entrapped in gels containing 2.15-2.60% NaCl after 14 days, and all gels exhibited increased calcium incorporation over the culture period. These data confirm that varying the salt concentration of the pre-gel solution can modulate the material properties of fibrin constructs without additional fibrinogen or thrombin, thereby offering a new approach for generating improved cell transplantation vehicles for use in bone tissue regeneration.

Self-joining of zirconia/hydroxyapatite composites using plastic deformation process.

A plastic deformation process was demonstrated to self-join 3 mol.% yttria partially stabilized zirconia (3Y-TZP)/hydroxyapatite (HA) composites. The 3Y-TZP/40 vol.% HA composites were fabricated by conventional ceramic processing by cold pressing premixed 3Y-TZP and HA powders into pellets. Densification ( approximately 90%) of composites was achieved by sintering composite powder compacts at 1450 degrees C for 5h. Optimum self-joining of 3Y-TZP/40 vol.% HA composites was obtained at 1300 degrees C for a strain rate of 5 x 10(-5)/s. The flow stress during joining was 40 MPa. Microstructural and mechanical characterizations of the joint interface demonstrated that there were no discernible differences between the joint and the composite material away from the interface.

Confocal laser scanning microscopy as a tool for imaging cancellous bone.

Understanding the bimodal structure of cancellous bone is important for tissue engineering in order to more accurately fabricate scaffolds to promote bone ingrowth and vascularization in newly forming bone. In this study, confocal laser scanning microscopy (CLSM) was used to create detailed images of the bimodally porous intertrabecular space of defatted and deproteinized cancellous canine bone taken from the epiphysis of the humerus. The bimodal pore structure was imaged using both reflective and fluorescent modes in CLSM, resulting in four different, but complementary image types: (1) a Z-stack overlay, (2) a phi-Z scan, (3) a topographical map, and (4) a contour map. Submerging the bone in rhodamine B dye prior to fluorescent imaging enhanced the pore surface details, giving a more accurate pore size measurement. The average macropore diameter was found to be 260 +/- 97 microm while the average micropore diameter was 13 +/- 10 microm. When compared with common techniques, including microcomputed tomography, magnetic resonance imaging, scanning electron microscopy, and environmental scanning electron microscopy, for imaging cancellous bone, CLSM was found to be an effective tool, given its ability to nondestructively image the surface and near-surface pore structure.

TQI in the Albuquerque Veterans Affairs Medical Center's long-term oxygen therapy program.

BACKGROUND: Long-term oxygen therapy (LTOT) is the only treatment demonstrated to prolong the life of patients with chronic obstructive pulmonary disease. In November 1994, a multidisciplinary total quality improvement (TQI) team composed of the involved hospital services was established to reorganize and improve the LTOT program at the Albuquerque Veterans Affairs Medical Center (AVAMC), Albuquerque. FROM THE OLD TO THE NEW PROCESS: The LTOT team used a process map to analyze the current process and gather information from patients and staff regarding their satisfaction with the program. It then began working on the identified problems and streamlining the LTOT referral process. A respiratory therapy position with the specific responsibility of serving as the home oxygen (O2) coordinator (HOC) was established and filled. The evaluation process was to be initiated by the AVAMC physicians, following which the HOC would perform a newly standardized evaluation that would establish the patient's need for O2 and result in a specific prescription. RESULTS: Quality indicators were selected to monitor changes in the program. Data from chart reviews, the Veterans Affairs National Cost Containment Center, and patient surveys were used to evaluate the indicators. Timeliness of referral to the program before inpatient discharge improved, O2 prescriptions in the new program more frequently addressed activity, and the cost per patient was reduced by 37.1%. Patient satisfaction rates also improved. DISCUSSION: A motivated team with representatives of the services involved was able to analyze and dramatically improve an important but complicated program.

Genetic alterations on chromosome 17 distinguish different types of epithelial ovarian tumors.

Epithelial tumors of the ovary are the most common ovarian tumors of adult women. They exist in several different histological patterns and exhibit varying degrees of aggressiveness. Molecular genetic studies in epithelial ovarian cancer have shown that loss of heterozygosity (LOH) for regions of chromosome 17 is a common event, probably reflecting the inactivation of one or more tumor suppressor genes present on this chromosome. We examined 87 sporadic epithelial ovarian tumors of different grade and histological type at 16 loci on this chromosome and found that 35% of them showed LOH for chromosome 17. Of these, 84% showed LOH for all informative markers, suggesting that loss of the entire chromosome 17 homologue may have occurred. Interestingly, chromosome 17 loss was observed frequently in serous tumors (49%), was less common in endometrioid tumors (15%), and was rare in mucinous tumors (4%) (P = .01 and P = .0002, respectively). Our findings support the concept that the histological subtypes of epithelial ovarian cancer may be the result of different molecular genetic events.

Hypermethylation at a chromosome 17 "hot spot" is a common event in ovarian cancer.

Alterations of normal DNA methylation patterns have been reported in various types of human tumors. These alterations are represented by genome wide hypomethylation and by region specific hypermethylation. One commonly hypermethylated region is 17p13.3 (D17S5), the putative site of a tumor suppressor gene. In this study we report that hypermethylation at this locus occurs frequently (33%) in ovarian tumors. We reported previously that loss of chromosome 17 is a common event in serous epithelial ovarian tumors. A correlation of the methylation event and chromosome 17 loss suggests that hypermethylation at D17S5 precedes chromosome 17 loss.

Molecular genetic changes in human epithelial ovarian malignancies.

The frequent finding of loss of heterozygosity (LOH) for a specific chromosomal marker in tumor DNA compared to normal DNA suggests the presence of a closely linked tumor-suppressor gene. Using Southern blot analysis, 34 primary ovarian epithelial tumors were examined for the presence of tumor-specific allelic losses, using six probes for chromosomes 6q, 11p, 13q, 16q, and 17p. A high incidence of LOH was observed on 11p, 13q, and 17p. LOH for 17p was present in 3 of 4 (75%) informative benign ovarian tumors, 1 of 5 (20%) borderline tumors, and 16 of 24 (67%) invasive ovarian cancers. Allelic loss with the H-ras1 probe on 11p was present in 10 of 19 (53%) invasive tumors but was not identified in 6 benign or borderline tumors. LOH on 13q was present in 18 of 31 (58%) informative cases including 8 of 10 (80%) Stage 1 tumors. This preliminary study suggests that loss of tumor-suppressor genes on chromosomes 13q and 17p may be early events in ovarian tumorigenesis and that changes on chromosome 11p are later events.

Nitrogen fixation by Azotobacter vinelandii in tungsten-containing medium.

Nitrogenase was isolated and purified from wild-type and a tungsten-resistant mutant (LM2) of Azotobacter vinelandii strain OP derepressed on medium containing 1-10 mM W. While the enzyme from the wild-type strain contained the polypeptides of the conventional enzyme, metal analysis of component 1 demonstrated the existence of one atom each of molybdenum and tungsten. Furthermore, the ESR spectrum of this protein contained three signals, two of which originated from S = 3/2 spin states. One of these signals is nearly identical to that of the conventional MoFe-protein while the other is hypothesized to originate from a W-containing cofactor. In spite of the presence of W, the substrate reduction pattern of this enzyme is the same as that of the conventional enzyme.

Characterization of the metal clusters in the nitrogenase molybdenum-iron and vanadium-iron proteins of Azotobacter vinelandii using magnetic circular dichroism spectroscopy.

Low-temperature magnetic circular dichroism (MCD) spectroscopy has been used to investigate the metal clusters in the conventional nitrogenase MoFe protein and alternative VFe protein from Azotobacter vinelandii. In the dithionite-reduced state, the MCD spectrum of the MoFe protein is extremely similar to that previously observed for the S = 3/2 spin state of the M clusters in the MoFe protein of Klebsiella pneumoniae. A paramagnetic cluster with an S = 3/2 ground state is also responsible for the temperature-dependent MCD transitions of dithionite-reduced VFe protein. However, the electronic and magnetic properties of this cluster are quite distinct from those of M centers in conventional nitrogenase. When these proteins are oxidized with thionine, the MoFe protein exhibits MCD spectra and magnetization characteristics identical with those observed for the P clusters in K. pneumoniae, while those of the VFe protein are only similar. However, the paramagnetism in the thionine-oxidized VFe protein, like the conventional enzyme, probably arises from an S = 5/2 spin system with near-axial symmetry and a negative zero-field splitting. Novel clusters with electronic, magnetic, and redox properties similar to those of conventional P clusters are, therefore, present in the VFe protein.

Isolation of a new vanadium-containing nitrogenase from Azotobacter vinelandii.

A new nitrogenase from Azotobacter vinelandii has been isolated and characterized. It consists of two proteins, one of which is almost identical with the Fe protein (component 2) of the conventional enzyme. The second protein (Av1'), however, has now been isolated and shown to differ completely from conventional component 1, i.e., the MoFe protein. This new protein consists of two polypeptides with a total molecular weight of around 200,000. In place of Mo and Fe it contains V and Fe with a V:Fe ratio of 1:13 +/- 3. The ESR spectrum of Av1' also differs from conventional component 1 in that lacks the g = 3.6 resonance that arises from the FeMo cofactor but contains an axial signal with gav less than 2 as well as inflections in the g = 4-6 region possibly arising from an S = 3/2 state. This new enzyme can reduce dinitrogen, protons, and acetylene but is only able to utilize 10-15% of its electrons for the reduction of acetylene.

Isolation and characterization of a second nitrogenase Fe-protein from Azotobacter vinelandii.

Wild-type Azotobacter vinelandii strain UW was transformed with plasmid pDB12 to produce a species (LS10) unable to synthesize the structural proteins of component 1 and component 2 of native nitrogenase. A spontaneous mutant of this strain was isolated (LS15) which can grow by nitrogen fixation in the presence or absence of either Mo or W. It is proposed that LS15 fixes nitrogen solely by an alternative nitrogen-fixing system which previously has been hypothesized to exist in A. vinelandii. Under nitrogen-fixing conditions, LS15 synthesizes a protein similar to component 2 (Av2) of native nitrogenase in that it can complement native component 1 (Av1) for enzymatic activity. Isolation and characterization of this second component 2 shows it to be a 4Fe-4S protein of molecular mass about 62 kDa and is antigenically similar to Av2. This protein is also similar to Av2 in that in the reduced state it possesses a rhombic ESR spectrum in the g = 2 region, which changes to an axial spectrum upon addition of MgATP. It is suggested that this second Fe-protein is associated with the alternative nitrogen-fixing system in A. vinelandii.

Epidermal growth factor antagonizes ovarian theca-interstitial cytodifferentiation.

This study was aimed at testing the hypothesis that epidermal growth factor (EGF) can modulate the gonadotropin-dependent differentiation of theca-interstitial cells in vitro. Addition of EGF to chemically defined culture medium severely antagonized the ability of hCG to transform undifferentiated theca-interstitial cells into active androgen-producing cells. The inhibitory action of EGF was dose-dependent, hormone-specific, and independent of granulosa cells. Since ovarian androgens are obligatory precursors to estrogen formation and induce atresia, a repressive action of EGF on theca-interstitial cytodifferentiation has new implications for understanding the way in which follicles develop in the ovary.