Chronic hyponatremia and association with osteoporosis among a large racially/ethnically diverse population.

Chronic hyponatremia may contribute to decreased bone density. We studied 341,003 men and women who underwent DXA testing and observed that individuals with chronic hyponatremia (sodium < 135 mEq/L) had an 11% greater likelihood of having osteoporosis. There was a dose-dependent effect with lower sodium and stronger association with osteoporosis. INTRODUCTION: Chronic hyponatremia has been associated with both neurologic deficits and increased risk of gait abnormalities leading to falls and resultant bone fractures. Whether chronic hyponatremia contributes to decreased bone density is uncertain. We evaluated whether chronic, mild hyponatremia based on serial sodium measurements was associated with increased risk of osteoporosis within a large, ethnically diverse population. METHODS: This is a retrospective cohort study between January 1, 1998 and December 31, 2014 within Kaiser Permanente Southern California, an integrated healthcare delivery system. Men and women were aged ≥ 55 years with ≥ 2 serum sodium measurements prior to dual-energy X-ray absorptiometry (DXA) testing. Time-weighted (TW) mean sodium values were calculated by using the proportion of time (weight) elapsed between sodium measurements and defined as < 135 mEq/L. Osteoporosis defined as any T-score value ≤ - 2.5 of lumbar spine, femoral neck, or hip. RESULTS: Among 341,003 individuals with 3,330,903 sodium measurements, 11,539 (3.4%) had chronic hyponatremia and 151,505 (44.4%) had osteoporosis. Chronic hyponatremic individuals had an osteoporosis RR (95% CI) of 1.11 (1.09, 1.13) compared to those with normonatremia. A TW mean sodium increase of 3 mEq/L was associated with a lower risk of osteoporosis [adjusted RR (95% CI) 0.95 (0.93, 0.96)]. A similar association was observed when the arithmetic mean sodium value was used for comparison. CONCLUSIONS: We observed a modest increase in risk for osteoporosis in people with chronic hyponatremia. There was also a graded association between higher TW mean sodium values and lower risk of osteoporosis. Our findings underscore the premise that chronic hyponatremia may lead to adverse physiological effects and responses which deserves better understanding.

Sensitivity and specificity of radiographic characteristics in atypical femoral fractures.

Using the American Society for Bone and Mineral Research Task Force case definition for atypical femoral fractures, sensitivity and specificity of radiographic fracture characteristics were calculated. Fracture pattern was the most sensitive and specific characteristic. This suggests that some characteristics should be weighted more heavily when identifying these fractures. INTRODUCTION: To estimate the sensitivity and specificity of each radiographic criterion in the 2013 ASBMR atypical femoral fracture (AFF) case definition for distinguishing AFF from other subtrochanteric/diaphyseal fractures (non-AFF) among women enrolled in a large integrated health care organization. METHODS: Radiographs from 55 physician-confirmed AFFs and a sample of 39 non-AFFs were reviewed by four independent expert reviewers representing four medical specialties. One image per fracture was selected for review. Using a standardized data collection tool, based on the 2013 AFF case definition, reviewers indicated the presence or absence of the following characteristics viewable on radiograph: fracture pattern, comminution, periosteal and/or endosteal thickening, and cortical thickening. Sensitivity and specificity for each characteristic was calculated for each reviewer and summarized across reviewers with the mean and range. Agreement across reviewers was quantified using Fleiss's kappa (FK) statistic. RESULTS: The most sensitive factors distinguishing AFF from non-AFF were lateral cortex transverse fracture pattern (mean 93.6 %, range 85.5-98.2 %), medial cortex transverse or oblique fracture pattern (mean 84.1 %, range 72.7-98.2 %), and minimal/non-comminution (mean 93.2 %, range 89.1-98.2 %). Specificity was the greatest for lateral cortex transverse fracture pattern (mean 95.5 %, range 92.3-97.4 %). Agreement across reviewers was the highest for lateral cortex transverse fracture pattern (FK 0.83) and incomplete fracture through the lateral cortex only (FK 0.80). CONCLUSION: Lateral cortex transverse fracture pattern was the most sensitive and specific characteristic and the most highly agreed upon across reviewers. Other characteristics were less readily agreed upon across reviewers. Measurement of discrete combinations of individual characteristics may enhance sensitivity and/or specificity.

Ten-year hip fracture incidence rate trends in a large California population, 1997-2006.

UNLABELLED: Hip fractures are a large public health problem with significant negative impact on an individual's overall health and survival. But while the total numbers of persons affected by hip fractures may be anticipated to increase, incidence rates appear to be declining. INTRODUCTION: To describe annual hip fracture incidence rate trends in an integrated health-care organization over 1997-2006, during which a proactive bone health program was initiated program-wide and other secular trends occurred in the population. METHODS: For this ecologic trend study, we identified all men and women ≥45 years old as of January 1 of each year. Incident fractures for each year were identified using ICD-9 diagnosis codes 820-820.9, excluding all subjects who had fractures in prior years. Annual person-time at risk for hip fracture was determined from enrollment data. Sex- and age-specific and adjusted annual incidence rates were calculated. RESULTS: The overall annual hip fracture incidence rate for men declined from 1.52/1,000 person-years in 1997 to 1.29/1,000 person-years in 2006, a 15.3% (95% confidence interval [CI]=6.2-24.5) decrease. For women, incidence declined from 2.65/1,000 person-years in 1997 to 2.24/1,000 person-years in 2006, a 15.3% (95% CI=8.7-21.9) decrease. Among subjects aged 85 years or older, incidence rates for men declined from 27.0/1,000 to 18.9/1,000 person-years, and for women they declined from 32.7/1,000 to 27.1/1,000 person-years. CONCLUSION: Hip fracture incidence has been declining in all age groups over the past 10 years. While many factors may contribute to this decline, the results are consistent with a potential benefit of the active bone health intervention.

Altered pre-pulse inhibition in adult rats treated neonatally with domoic acid.

Altered functioning of the glutamate system during critical periods of development is believed to play a role in various neurodevelopmental disorders, such as schizophrenia. Prepulse inhibition (PPI) of the acoustic startle response is deficient in people with schizophrenia. This study investigated the theory that neonatal treatment with domoic acid (DOM), a glutamate agonist, leads to deficient PPI. Results indicate that neonatal treatment with DOM leads to lowered PPI in adult males and an increased startle response in adult females.

Data Management for Applications of Patient Reported Outcomes.

CONTEXT: Patient reported outcomes (PROs) are one means of systematically gathering meaningful subjective information for patient care, population health, and patient centered outcomes research. However, optimal data management for effective PRO applications is unclear. CASE DESCRIPTION: Delivery systems associated with the Health Care Systems Research Network (HCSRN) have implemented PRO data collection as part of the Medicare annual Health Risk Assessment (HRA). A questionnaire assessed data content, collection, storage, and extractability in HCSRN delivery systems. FINDINGS: Responses were received from 15 (83.3 percent) of 18 sites. The proportion of Medicare beneficiaries completing an HRA ranged from less than 10 to 42 percent. Most sites collected core HRA elements and 10 collected information on additional domains such as social support. Measures for core domains varied across sites. Data were collected at and prior to visits. Modes included paper, clinician entry, patient portals, and interactive voice response. Data were stored in the electronic health record (EHR) in scanned documents, free text, and discrete fields, and in summary databases. MAJOR THEMES: PRO implementation requires effectively collecting, storing, extracting, and applying patient-reported data. Standardizing PRO measures and storing data in extractable formats can facilitate multi-site uses for PRO data, while access to individual PROs in the EHR may be sufficient for use at the point of care. CONCLUSION: Collecting comparable PRO data elements, storing data in extractable fields, and collecting data from a higher proportion of eligible respondents represents an optimal approach to support multi-site applications of PRO information.

Phase I trial of multiple cycles of high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell support as front-line therapy.

PURPOSE: To determine the safety and feasibility of delivering multiple cycles of front-line high-dose carboplatin, paclitaxel, and topotecan with peripheral-blood stem-cell (PBSC) support. PATIENTS AND METHODS: Patients were required to have a malignant solid tumor for which they had received no prior chemotherapy. Mobilization of PBSC was achieved with either filgrastim alone or in combination with cyclophosphamide and paclitaxel. Patients then received three or four cycles of high-dose carboplatin (area under the concentration-time curve [AUC] 16), paclitaxel (250 mg/m(2)), and topotecan (10-15 mg/m(2)), with the latter two agents administered as 24-hour infusions and supported with PBSC and filgrastim. Cycles were repeated every 28 days. RESULTS: Twenty patients were enrolled onto the trial and were assessable for toxicity and clinical outcome. Dose-limiting toxicities were stomatitis and prolonged hematopoietic recovery. The maximum-tolerated dose of topotecan was 12.5 mg/m(2) when given with high-dose carboplatin and paclitaxel for three cycles. Four cycles were able to be given with a dose of topotecan of 10 mg/m(2). The pharmacokinetics of each compound were not affected by the other agents. Eleven (85%) of 13 patients with assessable disease responded. CONCLUSION: Multiple cycles of high-dose carboplatin, paclitaxel, and topotecan can be safely administered with filgrastim and PBSC support. The recommended doses for phase II study are carboplatin AUC 16, paclitaxel 250 mg/m(2), and topotecan 10 mg/m(2). Trials are currently being conducted with this regimen as front-line treatment in patients with advanced ovarian cancer and extensive small-cell carcinoma. This approach remains experimental and should be used only in the context of a clinical trial.

Rapid identification of proteins on flat surfaces, using antibody-coated metal oxide suspensions.

Suspensions of Fe3O4 (black), Fe2O3 (red), and Cr2O3 (green) were exposed to solutions of protein A, and then each to a different antiserum to one of the following human proteins: fibrinogen, high molecular weight kininogen (HMK), albumin or immunoglobulins (IgG). Test surfaces were patterns of human proteins adsorbed out of solutions or out of plasma, onto glass as well as onto polyvinylchloride slides. They were exposed to single or mixed suspensions of the treated oxides for about 30 s and rinsed. Adhesion of each oxide onto each matching protein of these patterned test surfaces resulted, thus identifying each protein by color.

Targeted delivery of a peripheral benzodiazepine receptor ligand-gemcitabine conjugate to brain tumors in a xenograft model.

PURPOSE: Peripheral benzodiazepine receptors (PBRs) are overexpressed in brain tumors compared to normal brain, and could serve as a target to selectively increase anticancer drug delivery through a PBR ligand-drug conjugate system. We have previously synthesized PBR ligand-gemcitabine conjugates based on the model PBR ligand, PK11195. The goal of the current study was to examine this new drug delivery strategy in an intracerebral xenograft model by measurement of steady-state drug distribution following administration of gemcitabine (GEM) and PK11195-GEM. METHODS: In vitro PBR receptor binding and cytotoxicity assays were used to screen three different PK11195-GEM conjugates (GG01, GG02, GG03) in human SF126 glioma cells. Based on these findings and the favorable chemical stability of GG01, here referred as PK11195-GEM, pharmacokinetic investigations of PK11195-GEM and GEM were conducted in male rats. These studies consisted of single-dose and steady-state dosing regimen studies, the latter to assess drug distribution in normal brain and brain tumors. PK11195-GEM and GEM were measured in blood and tissue samples by HPLC. RESULTS: All PBR-GEM conjugates demonstrated appreciable receptor binding affinity and cytotoxicity with mean IC50 values ranging from 248 to 376 nM and 5.6 to 29.1 nM, respectively. The cytotoxicity of GEM was comparable with a mean IC50 value of 5.9 nM. Following administration of single 8 mg/kg doses of PK11195-GEM to rats (n=4), PK11195-GEM had a mean total clearance of 126.3 +/- 29.6 ml/min per kg, and a volume of distribution at steady-state of 1,261.9 +/- 31.05 ml/kg that resulted in a very short elimination half-life of 16.1 +/- 5.8 min. In comparison GEM had a similar volume of distribution (993.8 +/- 131.6 ml/kg), reduced clearance (3.4 +/- 0.8 ml/ min per kg), and longer half-life (235.6 +/- 26.7 min). In nude rats bearing intracerebral tumors, mean steady-state tumor/plasma, tumor/right brain, and tumor/left brain PK 11195-GEM concentration ratios were 1.75 +/- 0.46, 5.49 +/- 5.2, and 9.96 +/- 3.2, respectively. The analogous values following GEM administrations were 0.81 0.5, 3.67 1.57, and 5.21 +/- 1.95, respectively. These values indicate a minimum twofold increase in tumor target selectivity for the conjugate delivery system compared to GEM treatment. CONCLUSION: Targeting intracellular PBRs is a new drug delivery strategy based on the use of low molecular weight drug conjugates that can be administered systemically. It was demonstrated under steady-state conditions that PK11195-GEM possessed a twofold enhancement in brain tumor selectivity compared to GEM alone. This type of target selectivity would allow higher tumor concentrations to be achieved in conjunction with lower drug concentrations in normal or non-target tissues.

The effect of high molecular weight kininogen on surface-adsorbed fibrinogen.

High molecular weight kininogen (HMWK) plays an important role in altering the association of plasma fibrinogen with surfaces. Plasma initially deposits fibrinogen onto most materials, but on hydrophilic surfaces within 10 min adsorbed plasma fibrinogen cannot be detected on the surface by anti-fibrinogen antisera. However, using HMWK-deficient plasma, fibrinogen remains immunologically identifiable. The interrelationship of adsorbed plasma fibrinogen with kininogen on hydrophilic surfaces is studied further using glass slides stained for protein with Coomassie Blue, and oxidized silicon crystal slices in an automated ellipsometer. On glass slides when plasma that is deficient in both low molecular weight kininogen (LMWK) and HMWK, is reconstituted with HMWK (0.04 Units/ml), fibrinogen is no longer detected on the surface. This finding is specific for HMWK, since, when the same plasma is reconstituted with LMWK (220 micrograms/ml), the amount of fibrinogen detected on the surface is unchanged. The alteration of surface-adsorbed fibrinogen by HMWK is not due to plasmin-induced fibrinolysis, since it occurs in plasminogen-free plasma. In the ellipsometer, surface adsorption of normal plasma is associated with a significantly less (p less than 0.0005) thick protein layer (1.99 +/- 0.08 degree change in azimuth) than plasmas deficient in HMWK (2.32 +/- 0.11). Using ellipsometry, HMWK in plasma is shown to shorten the time in which immunologically detectable surface-adsorbed fibrinogen was removed or altered. These studies in a whole plasma system present further evidence that HMWK specifically modifies the association of plasma fibrinogen with hydrophilic surfaces.

Operative cholangiography.

The value of operative cholangiography in the management of biliary tract disease has been questioned. To better define the role of cholangiography, we reviewed 579 consecutive cholecystectomies done by 1 group of surgeons in a small rural practice over 8 years. Cholangiography demonstrated unsuspected common bile duct disease in 5% of the procedures, while 12% of the patients were spared an unnecessary choledochotomy after a normal cholangiogram was obtained. There was no morbidity, mortality, or prolongation of the hospital stay attributed to the cholangiographic procedure. These findings bolster the argument for routine cholangiography as a safe, effective, and helpful screening examination for patients who are at risk for having common bile duct disease.

Analysis and simulation of a stochastic, discrete-individual model of STD transmission with partnership concurrency.

Deterministic differential equation models indicate that partnership concurrency and non-homogeneous mixing patterns play an important role in the spread of sexually transmitted infections. Stochastic discrete-individual simulation studies arrive at similar conclusions, but from a very different modeling perspective. This paper presents a stochastic discrete-individual infection model that helps to unify these two approaches to infection modeling. The model allows for both partnership concurrency, as well as the infection, recovery, and reinfection of an individual from repeated contact with a partner, as occurs with many mucosal infections. The simplest form of the model is a network-valued Markov chain, where the network's nodes are individuals and arcs represent partnerships. Connections between the differential equation and discrete-individual approaches are constructed with large-population limits that approximate endemic levels and equilibrium probability distributions that describe partnership concurrency. A more general form of the discrete-individual model that allows for semi-Markovian dynamics and heterogeneous contact patterns is implemented in simulation software. Analytical and simulation results indicate that the basic reproduction number R(0) increases when reinfection is possible, and the epidemic rate of rise and endemic levels are not related by 1-1/R(0), when partnerships are not point-time processes.

Lack of exchange among plasma proteins in narrow spaces on glass, demonstrated with metal oxide coatings.

Onto 'activating' surfaces, intact normal plasma deposits an overlapping sequence of proteins, each being desorbed by the next. Ultimately, high molecular weight kininogen (HMK) is deposited unless contact was too short, or space between 2 surfaces too narrow. Thus, injected between a glass slide and a convex lens, intact plasma will leave a disk of HMK with a center of fibrinogen. We describe here how the exchange of proteins on the surface can be demonstrated by staining the adsorbate with a metal oxide suspension. Subsequent flooding of the preparation with more normal plasma causes lift-off of the oxide where underlying fibrinogen is being displaced by the HMK of the newly applied plasma. Kininogen-deficient plasma fails to remove any oxide, while normal plasma can remove nearly all of the oxide and adsorbate, left on glass by HMK-deficient plasma.

Tongue extrusion as an aid to blind nasal intubation.

Blind nasal intubation often results in esophageal placement of the tube because reflex swallowing and supralaryngeal structures direct the tube posteriorly. Extrusion of the tongue, which inhibits swallowing and shifts the supralaryngeal structures anteriorly, facilitated blind placement of a nasotracheal tube in 14 of 16 critically ill patients. The technique avoids manipulation of the neck, the use of heavy sedation or anesthesia, and requires no specialized training or equipment.

Convex-lens-on-slide: a simple system for the study of human plasma and blood in narrow spaces.

On clot-promoting surfaces, intact normal blood or plasma deposits fibrinogen and then supplants it with high molecular weight kininogen (HMWK). On glass, plasma layers of less than about 25 micron thick, while still containing enough fibrinogen to coat the surrounding surfaces, lack sufficient HMWK per surface area to remove this fibrinogen deposit. Thus normal intact citrated plasma allowed to enter the space between a glass slide and a convex lens resting belly-down on the slide will leave a disc of fibrinogen where the thickness of plasma layer was below this "critical height" H. The discs of fibrinogen left by plasma that lacks HMWK pathologically or by activation or dilution, are larger--the required H being greater. The present study shows that plasma dilution (final volume divided by original plasma volume) plotted against H yields a straight line. In preliminary series, the slope of this line increases with the atomic weight of five metals whose oxidized surfaces were used as substrates. In whole blood collected in either heparin or ACD, a circle of platelets adheres to oxidized silicon, anodized tantalum, or glass; this circle is similar in size to the one of fibrinogen left by plasma.

Effects of varying forage types on milk production responses to whole cottonseed, tallow, and yeast.

Four forage treatments (45% corn silage, 33.75% corn silage plus 11.25% alfalfa hay, 11.25% bermudagrass hay, or 11.25% cottonseed hulls on a DM basis) were arranged factorially with no added fat, 12.5% whole cottonseed, or 2.5% tallow. Different diets were fed during three 28-d periods to 20 control Holstein cows and to 20 cows receiving yeast continuously in a split-plot design. Milk yield of cows fed cottonseed hulls with corn silage was 2.4 kg/d higher than with corn silage plus bermudagrass hay and .7 kg/d higher than with corn silage only or corn silage plus alfalfa hay. Whole cottonseed depressed milk yield by 1 kg/d. Cows fed yeast had increased DMI, and yeast interacted with forage so that more milk was produced by cows fed alfalfa diets. Yeast depressed milk protein percentage. Holstein cows in a commercial Florida dairy were fed no yeast or 10 g/d continuously for 60 d; milk fat percentage was greater (3.51 vs. 3.37%) with yeast. In summary, effects on milk and SCM were positive when cottonseed hulls were utilized with corn silage, negative with whole cottonseed, and neutral with supplemental tallow. Yeast effects on SCM, although not significant for either experiment, tended to be positive for both (mean +1.2 kg/d per cow).

Pleural amyloidosis mimicking mesothelioma: a clinicopathologic study of two cases.

Two cases of pleural amyloidosis are presented. The patients are two men, 70 and 72 years of age respectively. Neither patient had evidence of systemic amyloidosis. Each presented clinically with symptoms of chest pain and dyspnea. Radiologically, both patients showed diffuse pleural thickening similar to that observed in malignant mesothelioma. In both patients, surgical decortication of the pleura was performed. Histologically, the lesions were characterized by the presence of an amorphous eosinophilic material with focal collections of a lymphoplasmacytic infiltrate. Focal clusters of giant cells were admixed with the lymphoplasmacytic infiltrate. Histochemical stains for Congo red showed strong positive apple-green birefringency. Immunohistochemical studies using kappa and lambda light chains showed polyclonality. The cases discussed herein represent an unusual presentation of amyloid and one that needs to be considered in the differential diagnosis of malignant mesothelioma.

Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces.

Using ellipsometry, anodized tantalum interference color, and Coomassie blue staining in conjunction with immunologic identification of proteins adsorbed at interfaces, we have previously found that fibrinogen is the main constituent deposited by plasma onto many man-made surfaces. However, the fibrinogen deposited from normal plasma onto glass and similar wettable materials is rapidly modified during contact activation until it can no longer be identified antigenically. In earlier publications, we have called this modification of the fibrinogen layer "conversion," to indicate a process of unknown nature. Conversion of adsorbed fibrinogen by the plasma was not accompanied by marked change in film thickness, so that we presumed that this fibrinogen was not covered but replaced by other protein. Conversion is now showen to be markedly delayed in plasma lacking high molecular weight kininogen, slightly delayed in plasma lacking factor XII, and normal in plasma that lack factor XI or prekallikrein. We conclude that intact plasma will quickly replace the fibrinogen it has deposited on glass-like surfaces by high molecular weight kininogen and, to a smaller extent, by factor XII. Platelets adhere preferentially to fibrinogen-coated surfaces; human platelets adhere to hydrophobic nonactivating surfaces, since on these, adsorbed firbinogen is not exchanged by the plasma. The adsorbed fibrinogen will be replaced on glass-like surfaces during surface activation of clotting, and platelets failing to find fibrinogen will not adhere.