Postoperative zoledronic acid for osteoporosis in primary hyperparathyroidism: a randomized placebo-controlled study.

OBJECTIVE: In primary hyperparathyroidism (PHPT) with osteoporosis, bone mineral density (BMD) improves after parathyroidectomy. It is unclear whether combining surgery with postoperative bisphosphonate treatment can further improve bone health. DESIGN: This randomized, placebo-controlled study compared the effects of surgery alone and surgery combined with zoledronic acid on bone metabolism in PHPT with osteoporosis. METHODS: Fifty-six patients (f/m 47/9, mean age 68.4 years) with PHPT and osteoporosis were randomized 1-3 months after parathyroidectomy to receive a 2-year treatment of zoledronic acid or placebo. Dual-energy X-ray absorptiometry (DXA) and bone turnover markers (N-terminal propeptide of type 1 procollagen, C-terminal telopeptide of type 1 collagen, and alkaline phosphatase) were measured annually during the 2-year follow-up. RESULTS: Two years after parathyroidectomy, BMD was significantly higher in the zoledronic acid (ZOL) group compared with the placebo (PBO) group at the femoral neck (P = 0.045 for Z-score) and lumbar spine (P = 0.039 and 0.017 for T- and Z-scores, respectively). Bone turnover markers were significantly lower in the ZOL group (P < 0.001 for all markers). Of the 18 patients who had received bisphosphonates for >1 year before surgery, BMD improved significantly in the ZOL group both in the femoral neck and lumbar spine (n = 10; all P < 0.001-0.01), but in the PBO group, only in the lumbar spine (n = 8, P = 0.03), (P = 0.08-0.95 for between-group changes). CONCLUSION: BMD increases after parathyroidectomy both with and without zoledronic acid but the increase is significantly higher with postoperative zoledronic acid.

Incidence of osteoporotic fractures in elderly women and men in Finland during 2005-2006: a population-based study.

BACKGROUND AND AIMS: Osteoporosis is a major health concern in elderly population. Low-trauma fractures offer one way of identifying these patients for treatment. Population-specific incidences of osteoporotic fractures are essential to validate tools for clinical decision making. MATERIAL AND METHODS: To evaluate population-based osteoporotic fracture incidences in Central Finland, we performed a manual search of low-trauma fractures 2005-2006 from the records of all the local health-care organizations treating trauma patients. We identified low-trauma fracture patients from radiology reports from five health centers serving the inhabitants of nine municipalities and from the patient records of two hospitals in Central Finland. The manually collected data were then compared against data from the Finnish Health Care Register. RESULTS: The crude incidence of all osteoporotic fractures in 2005-2006 in the population aged 50 years was 1254/100,000 person years: 694/100,000 person years in men and 1718/100,000 person years in women. Fracture numbers derived from register data were similar to those manually collected for hip and humerus fractures, but clearly smaller than those for wrist and ankle fractures. CONCLUSIONS: Population-based low-trauma fracture incidences, reported here for Finland, constitute a basis for calibration of fracture risk evaluation tools (e.g. the World Health Organization fracture risk evaluation tool, FRAX). This study showed that register data underestimate the incidences of, in particular, distal radius and ankle fractures.

In vivo magnetic resonance imaging and spectroscopy identifies oncolytic adenovirus responders.

At present, it is not possible to reliably identify patients who will benefit from oncolytic virus treatments. Conventional modalities such as computed tomography (CT), which measure tumor size, are unreliable owing to inflammation-induced tumor swelling. We hypothesized that magnetic resonance imaging (MRI) and spectroscopy (MRS) might be useful in this regard. However, little previous data exist and neither oncolytic adenovirus nor immunocompetent models have been assessed by MRS. Here, we provide evidence that in T2-weighted MRI a hypointense core area, consistent with coagulative necrosis, develops in immunocompetent Syrian hamster carcinomas that respond to oncolytic adenovirus treatment. The same phenomenon was observed in a neuroblastoma patient while he responded to the treatment. With relapse at a later stage, however, the tumor of this patient became moderately hyperintense. We found that MRS of taurine, choline and unsaturated fatty acids can be useful early indicators of response and provide detailed information about tumor growth and degeneration. In hamsters, calprotectin-positive inflammatory cells (heterophils and macrophages) were found in abundance; particularly surrounding necrotic areas in carcinomas and T cells were significantly increased in sarcomas, when these had been treated with a granulocyte-macrophage colony-stimulating factor-producing virus, suggesting a possible link between oncolysis, necrosis (seen as a hypointense core in MRI) and/or immune response. Our study indicates that both MRI and MRS could be useful in the estimation of oncolytic adenovirus efficacy at early time points after treatment.

Oncolytic adenovirus based on serotype 3.

Oncolytic adenoviruses have been safe in clinical trials but the efficacy has been mostly limited. All published trials have been performed with serotype 5 based viruses. The expression level of the Ad5 receptor CAR may be variable in advanced tumors. In contrast, the Ad3 receptor remains unclear, but is known to be abundantly expressed in most tumors. Therefore, we hypothesized that a fully serotype 3 oncolytic adenovirus might be useful for treating cancer. Patients exposed to adenoviruses develop high titers of serotype-specific neutralizing antibodies, which might compromise re-administration. Thus, having different serotype oncolytic viruses available might facilitate repeated dosing in humans. Ad3-hTERT-E1A is a fully serotype 3 oncolytic adenovirus controlled by the promoter of the catalytic domain of human telomerase. It was effective in vitro on cell lines representing seven major cancer types, although low toxicity was seen in non-malignant cells. In vivo, the virus had anti-tumor efficacy in three different animal models. Although in vitro oncolysis mediated by Ad3-hTERT-E1A and wild-type Ad3 occurred more slowly than with Ad5 or Ad5/3 (Ad3 fiber knob in Ad5) based viruses, in vivo the virus was at least as potent as controls. Anti-tumor efficacy was retained in presence of neutralizing anti-Ad5 antibodies whereas Ad5 based controls were blocked. In summary, we report generation of a non-Ad5 based oncolytic adenovirus, which might be useful for testing in cancer patients, especially in the context of high anti-Ad5 neutralizing antibodies.

First Report of Rapid Blight Caused by Labyrinthula terrestris on Poa annua in Colorado.

A disease characteristic of rapid blight caused by the net slime mold, Labyrinthula terrestris (1,2), was observed on three annual bluegrass (Poa annua) putting greens from a golf course in Adams County, Colorado in April 2009. Symptoms included water-soaked lesions and browning and bronzing of leaves. With microscopic observation, the fusiform cells typically associated with Labyrinthula spp. (1) were detected inside symptomatic leaf tissue. The pathogen was isolated by placing symptomatic leaves on a selective medium modified from Bigelow et al. (1) (12 g of granulated agar [Fisher Scientific, Pittsburg, PA], 10 ml of horse serum [Hema Resource and Supply, Aurora, OR], and 250 µg of ampicillin, streptomycin sulfate, and penicillin G [Sigma, St. Louis, MO] in artificial seawater at 4.0 dS/m electrical conductivity [Instant Ocean, Atlanta, GA]). Irregular-shaped digitate colonies of fusiform cells developed within 1 to 2 days. The isolated organism was then used to fulfill Koch's postulates on 2-week-old Poa trivialis 'Sabre III' seedlings and 4-week-old Poa annua seedlings planted in a 90:10 peat moss/sand mixture in 6-cm-diameter pots. Plants were inoculated with a 9 × 106 cells/ml suspension of L. terrestris cells in artificial seawater (4.0 dS/m) as described by Peterson et al. (2) and irrigated daily with artificial seawater (4.0 dS/m). Negative controls consisted of either P. trivialis or P. annua plants irrigated with artificial seawater only. There were three replications for each treatment and the experiment was repeated for each grass species. Pots were maintained at 28 to 33°C in the greenhouse with ambient light. Within 8 to 10 days of inoculation, 95% of the plants showed symptoms of severe rapid blight, while noninoculated plants showed some minor salt stress symptoms but were otherwise healthy. The organism was successfully reisolated from several plants from each replication using the method described above. Results were the same for all experiments. Rapid blight is frequently associated with high soil salinity (>2.5 dS/m total dissolved salts) (1) and sodium levels above 110 mg/kg (Mehlich-3 extraction) in diagnostic samples. Soil salinity levels from the site affected by the disease were below this guideline. However, sodium levels measured an average of 184 mg/kg. The ability of this pathogen to cause disease on plants growing in soils not measuring high in salinity, and only with elevated sodium, should be considered when attempting to ascertain rapid blight as a cause of turf damage. References: (1) D. M. Bigelow et al. Mycologia 97:185, 2005. (2) P. D. Peterson et al. Online publication. doi:10.1094/ATS-2005-0328-01-RS. Applied Turfgrass Science, 2005.

Very rapid dissolution is not needed to guarantee bioequivalence for biopharmaceutics classification system (BCS) I drugs.

Currently, the EMEA, FDA, and WHO as regulatory authorities accept rapidly dissolving (>85% dissolved in 30 min) biopharmaceutics classification system (BCS) I drug products for biowaiver candidates. In the draft EMEA guideline the requirement has been set tighter, that is, the drug product should be very rapidly dissolving (>85% dissolved in 15 min) to be eligible for a biowaiver. Pharmacokinetic modeling of 32 BCS I drugs was performed to demonstrate that very rapid dissolution is not necessary to guarantee bioequivalence for them. Rapid dissolution and similar dissolution profiles are sufficient criteria for all BCS I drugs.

Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice.

Activation of the Fas/Fas ligand (FasL) system in the lungs results in a form of injury characterized by alveolar epithelial apoptosis and neutrophilic inflammation. Studies in vitro show that Fas activation induces apoptosis in alveolar epithelial cells and cytokine production in alveolar macrophages. The main goal of this study was to determine the contribution of alveolar macrophages to Fas-induced lung inflammation in mice, by depleting alveolar macrophages using clodronate-containing liposomes. Liposomes containing clodronate or PBS were instilled by intratracheal instillation. After 24 h, the mice received intratracheal instillations of the Fas-activating monoclonal antibody Jo2 or an isotype control antibody and were studied 18 h later. The Jo2 MAb induced increases in bronchoalveolar lavage fluid (BALF) total neutrophils, lung caspase-3 activity, and BALF total protein and worsened histological lung injury in the macrophage-depleted mice. Studies in vitro showed that Fas activation induced the release of the cytokine KC in a mouse lung epithelial cell line, MLE-12. These results suggest that the lung inflammatory response to Fas activation is not primarily dependent on resident alveolar macrophages and may instead depend on cytokine release by alveolar epithelial cells.

Ultrahigh resolution optical coherence tomography of Barrett's esophagus: preliminary descriptive clinical study correlating images with histology.

BACKGROUND AND STUDY AIMS: Endoscopic ultrahigh resolution optical coherence tomography (UHR OCT) achieves an axial image resolution of approximately 5 microm, which is 2 - 3 times finer than standard endoscopic OCT imaging. This study investigated the capability of endoscopic UHR OCT for imaging patients with Barrett's esophagus. PATIENTS AND METHODS: Fivty volunteers previously diagnosed with Barrett's esophagus underwent UHR OCT. Imaging was performed at 1.3 microm wavelengths with approximately 5 microm axial and approximately 15 microm transverse resolutions using a 1.8 mm/diameter linear-scanning catheter introduced through the accessory channel of a standard endoscope. OCT images were compared with endoscopic diagnosis and pinch biopsy histological appearances. RESULTS: UHR OCT images of normal esophagus, Barrett's esophagus, high grade dysplasia and esophageal adenocarcinoma were evaluated. UHR OCT images of the normal esophagus exhibited characteristic layered architecture with uniform epithelium, while images of Barrett's esophagus corresponded to crypt-like glandular structures. High grade dysplasia and esophageal adenocarcinoma images exhibited more heterogeneous structures corresponding to irregular, heterogeneous tissue morphology from distorted and cribriform or villiform glandular architecture. Fine features can be discerned more clearly with endoscopic UHR OCT. CONCLUSIONS: This study evaluated new endoscopic OCT technology and demonstrated the feasibility of carrying out UHR OCT imaging in conjunction with standard endoscopy for in vivo real-time imaging of Barrett's esophagus, dysplasia, and esophageal adenocarcinoma. A survey of normal and abnormal upper gastrointestinal tissues was performed using a research prototype OCT system with the highest axial resolution to date, and can serve as a baseline for future investigation.

Postoperative wound complications after internal fixation of closed calcaneal fractures: a retrospective analysis of 126 consecutive patients with 148 fractures.

AIM: The aim of the study was to analyse the number of soft-tissue complications after internal fixation of calcaneal fractures and to evaluate risk factors leading to these complications. MATERIAL: A retrospective analysis of 126 consecutive patients with 148 operatively treated calcaneal fractures was performed. Only primarily closed fractures were included in the study. RESULTS: Wound healing was problematic in 35 cases (24 per cent). The wound was infected in 23 cases (16 per cent) and a wound edge necrosis was observed in 12 cases (8 per cent). The soft tissue complication needed operative treatment in 20 cases (14 per cent). The complications did not lead to amputations in any case. In the end of the follow up all wounds had healed. CONCLUSIONS: The statistical analysis identified a longer delay in surgery and longer operation time to be positive risk factors for wound complications.

Relation of postmortem blood alcohol and drug concentrations in fatal poisonings involving amitriptyline, propoxyphene and promazine.

Drugs and alcohol often occur together in fatal poisonings, complicating the process of determining the cause of death. Especially when found in concentrations generally regarded as toxic but not lethal, the question arises whether the combination of sublethal amounts was the likely cause of death. In this study, we examined poisoning deaths involving amitriptyline, propoxyphene and promazine, which are, after benzodiazepines, the most frequently occurring drugs in Finnish alcohol-related poisonings. From the forensic toxicology database, covering the years 1995-2002, we extracted 332 fatal poisonings, calculated median blood alcohol and drug concentrations, constructed concentration-concentration and concentration-response curves and evaluated the significance of the presence of therapeutic amounts of benzodiazepines. Median amitriptyline and propoxyphene concentrations were lower in alcohol-related cases than in clean drug poisonings. Correspondingly, the median blood alcohol concentrations in all drug-related poisonings were 1.5-2.2 mg/g lower than that found in clean alcohol poisonings. Alcohol concentration proved to be a more sensitive indicator of alcohol-drug interaction than drug concentration. This result suggests that when alcohol is present, relatively small overdoses of the studied drugs may result in fatal poisoning. In this context, fatal drug and alcohol concentrations and the issue of determining the most important agent in fatal drug-alcohol intoxications are discussed.

First Report of Brown Stripe of Saltgrass Caused by Bipolaris heveae in Colorado.

Inland saltgrass (Distichlis spicata var. stricta (L.) Greene) is indigenous to western North America and Australia and is a dioecious, rhizomatous, perennial, warm-season grass. It is commonly found in areas where salinity, alkalinity, and drought have eliminated many other types of vegetation (1). It has potential for revegetation of mine spoils or use along roadsides (2). During September 2004, multiple lenticular, brown lesions were observed on leaves of saltgrass accession no. 1023 at the Horticulture Field Research Center, Colorado State University, Fort Collins. Segments of symptomatic leaf tissue were surface sterilized in 0.5% sodium hypochlorite and placed on one-quarter-strength potato dextrose agar and incubated at 25°C in the dark. Dark green fungal colonies with aerial mycelium consistently grew on the medium. Slightly curved, ellipsoidal, pale-to-golden brown, smooth conidia 46 to 80 µm long and 13 to 17 µm wide (average 64.5 × 14.7 µm) with 6 to 9 septations formed after 7 days in cultures grown on V8 juice agar. The morphology and bipolar germination of conidia was consistent with the genus Bipolaris, however, conidia were often shorter than previously reported (3). The rDNA internal transcribed spacer (ITS) regions of one isolate were amplified using polymerase chain reaction (PCR) with universal fungal rDNA primers ITS1 and ITS4. PCR products were sequenced (555 bp) and exhibited 99% nucleotide identity to Bipolaris heveae isolates collected from zoysiagrass and bermudagrass in Japan (3) and rubber in Nigeria (4). To confirm pathogenicity, a suspension of 104 conidia per ml of water containing 0.1% Tween 20 was sprayed on saltgrass leaves to runoff. Plants were covered with transparent plastic bags and incubated at 25°C in the dark. After 72 h, the bags were removed and plants were placed in the greenhouse. Brown stripe symptoms were observed on all plants after 7 days, and B. heveae was consistently isolated from symptomatic tissue. To our knowledge, this is the first report of brown stripe on inland saltgrass caused by B. heveae. References: (1) D. J. Hansen et al. Am. J. Bot. 63:635, 1976. (2) K. A. Pavlicek et al. J. Range Manag. 30:377, 1977. (3) T. Tsukiboshi et al. Mycoscience 46:17, 2005. (4) G. Zhang and M. L. Berbee. Mycologia 93:1048, 2001.

The Kautsky curve is a built-in barcode.

We identify objects from their visually observable morphological features. Automatic methods for identifying living objects are often needed in new technology, and these methods try to utilize shapes. When it comes to identifying plant species automatically, machine vision is difficult to implement because the shapes of different plants overlap and vary greatly because of different viewing angles in field conditions. In the present study we show that chlorophyll a fluorescence, emitted by plant leaves, carries information that can be used for the identification of plant species. Transient changes in fluorescence intensity when a light is turned on were parameterized and then subjected to a variety of pattern recognition procedures. A Self-Organizing Map constructed from the fluorescence signals was found to group the signals according to the phylogenetic origins of the plants. We then used three different methods of pattern recognition, of which the Bayesian Minimum Distance classifier is a parametric technique, whereas the Multilayer Perceptron neural network and k-Nearest Neighbor techniques are nonparametric. Of these techniques, the neural network turned out to be the most powerful one for identifying individual species or groups of species from their fluorescence transients. The excellent recognition accuracy, generally over 95%, allows us to speculate that the method can be further developed into an application in precision agriculture as a means of automatically identifying plant species in the field.

Lossless compression of eye movement signals.

Compression of digital signals is widely employed in several areas such as speech signals. Concerning biomedical signals almost merely ECG signals have so far been compressed, in fact, in very many applications. To our knowledge, this compression study is the first one presented in the case of eye movement signal which are investigated in several medical specialties. In this study eye movements are electro-oculographically recorded. Tests performed to signals of patients of an equilibrium laboratory gave compression ratios generated with essential lossless compression methods.

Lossless ECG encoding.

We have studied the lossless encoding of ECG signals. With suitable code we aim to reduce the storage space needed by ECG signals. Several methods designed for ECG compression use lossy, i.e. irreversible techniques, in which the original signal is lost, but the restored approximation is almost equal to the original. We aimed, however, to use reversible methods which are able to restore the original signal exactly. We have examined various methods and developed a new approach based on structural recognition and extraction of ECG complexes. Comparative conclusions are drawn from the compression efficiency of lossless and lossy methods. In this study, the effect of sampling frequency, resolution and filtering is also examined.

Modelling ECG signals with hidden Markov models.

In this paper, we have studied the use of continuous probability density function hidden Markov models for the ECG signal analysis problem. Our previous work has focused on syntactic pattern recognition methods in signal processing. Hidden Markov model is basically a non-deterministic probabilistic finite state machine, which can be constructed inductively. It has been widely used in speech recognition and DNA modelling. We have found that hidden Markov models are very suitable for ECG recognition and analysis problems and that they are able to model accurately segmented ECG signals.

Segmentation of digital signals based on estimated compression ratio.

We have studied the problem of approximating a digital signal with a suitable continuous broken line. We use the approximative broken line for further analysis of the signal as detection of peaks, waves, and other structural features. We can also save considerable amount of storage space with an approximation that does not lose too much significant information about the original signal. Our work is based on examining different distance metrics and different segmentation methods with respect to the remaining residual error in the resulting approximation. The aim of the work has been to develop a method that can perform segmentation with an acceptable amount of residual error without a need to define a large set of parameters that control the segmentation process. Our contribution is to examine the effect of the estimated compression ratio of the resulting approximation and finding an estimate of this compression ratio. We first define a target in the form of a compression ratio of the resulting approximation and then by applying our method, try to find a suitable threshold parameter to achieve this target. We have tested our method with electrocardiogram (ECG) signals and the compression ratio of the approximation has been found to be a suitable target to control the segmentation process.

Dynamic shoulder flexion strength: for use in occupational risk analysis and clinical assessment.

Given the likelihood of increased risk of musculoskeletal injury when joint torque strength demands approach the maximum isometric torque, this study determined the flexion torque strength capabilities of the shoulder in young men and women. To our knowledge this is the first study to report dynamic shoulder flexion torques. Peak static flexion torque values were collected at shoulder angles of 0° (anatomical position) and 45° of flexion in 25 female and 26 male subjects seated in an upright position. Dynamic concentric and eccentric shoulder flexion torques were collected at 50° s(-1) angular velocity from 0° to each subject's comfortable flexion limit on a KIN-COM dynamometer. Results indicated that for both static and dynamic strength measures, female subjects produced, on average, half of the torque output of males. Mean male flexion torques were: static at 0° = 89.9 N m; static at 45° = 68.6 N m; dynamic at 45° = 46.9 N m (concentric); dynamic at 45° = 75.3 N m (eccentric).

Prediction of normal spirometric values for adults incapable of standing.

A significant problem exists in predicting normal values for pulmonary function in subjects unable to stand for measurement of height. We studied 196 normal men and women to determine the relationship between sitting and standing height. Two predictors of standing height are recommended: (1) standing-to-sitting height ratio; and (2) multiple regression equations using sitting height and age. Either of these relationships can be selected as a predictor of height for substitution into any standard spirometric prediction equations. Spirometric prediction equations using age and sitting height are also presented.

Fifteen-year interval spirometric evaluation of the Oregon predictive equations.

The 1969 Oregon spirometric predictive equations were evaluated by retesting 199 of the 988 original sample population after 15 years. The 1969 data were used to test for sample bias between the retested and not-retested groups. There was no significant difference in mean values for age, height, or test results except for a five-year age difference in men. Regression analysis of residuals and the differences between calculated and predicted values of annual decrements of FVC, FEV1, and FEF25-75% on age revealed no statistically significant age trend. Although residual means were statistically significant for FVC and FEV1 for men and FVC and FEF25-75% for women, the differences between calculated and predicted annual decrements were significant only for women in FEF25-75%. Although group performance was accurately predicted for most tests, test SDs and SEMs demonstrated considerable individual variation. Lower limits of normality are suggested to assist in evaluating previously-tested patients.

Normal values and evaluation of forced end-expiratory flow.

A new spirometric measurement was performed with 803 healthy, nonsmoking men and women. Using the forced vital capacity curves, the forced end-expiratory flow (FEF75-85%) had a negative correlation with age and a positive correlation with height. Prediction formulas and nomograms were constructed. Comparison with the forced mid-expiratory flow (FEF25-75%) showed generally larger correlation coefficients for physical characteristics and coefficients of variation for the FEF75-85%. Expressing both the FEF75-85% and FEF25-75% as ratios of forced vital capacity did not improve the coefficients. The mean flow rates of 75 male smokers were compared with 213 non-smokers 30 to 49 years of age. The FEF75-85% significantly distinguished between a group of smokers and a group of nonsmokers, but the FEF25-75% showed no significant difference. In 9 patients with presumed peripheral airways disease, FEF25-75% ranged from 70 to 110 per cent of predicted normal but FEF75-85% was 30 to 72 per cent of predicted. An extensively studied control group of 22 healthy, asymptomatic, nonsmoking subjects had FEF75-85% values of 80 to 163 per cent of predicted. Both small groups of 9 patients and 22 control subjects had FEF75-85% values within 1.65 standard error of estimate. In subgroups of 319 persons, use of 75 per cent of predicted mean for FEF75-85% was of greater value in attempting to screen normal from abnormal population than using 1.65 standard error of estimate. The FEF75-85% is suggested as a useful simple ventilatory test to detect early obstructive pulmonary disease.