Portal Hypertensive Biliopathy Presents with Massive Bleeding during ERCP after Balloon Sphincteroplasty in a Noncirrhotic Saudi Sickler Patient.
Portal hypertensive biliopathy (PHB) is described as abnormalities of the walls of the biliary tree secondary to portal hypertension. Gastrointestinal bleeding caused by PHB is rare. PHB as a cause of serious bleeding after sphincteroplasty during ERCP is extremely rare. Here, we report a case of PHB in a young Saudi male with cell sickle anemia who developed massive hemorrhage during ERCP after balloon dilation of the ampulla of Vater. We further discussed the diagnosis and management. To the best of our knowledge, no such case has been reported.


Initial experience with a novel desensitization strategy for carboplatin-associated hypersensitivity reactions: carboplatin-hypersensitivity reactions.
Carboplatin hypersensitivity is an increasingly recognized toxicity in individuals receiving >6 cumulative courses of this important antineoplastic agent. We wished to determine if a novel multi-pronged approach to re-treating patients with a high risk for this potentially serious side effect could permit the safe delivery of this class of cytotoxic drugs. Five patients with gynecologic malignancies who had either experienced a documented carboplatin hypersensitivity reaction ( n =4) or had a "positive" carboplatin skin test ( n =1), received a multi-drug oral regimen administered over several days which was designed to block known mediators of anaphylaxis. Four of these individuals subsequently underwent treatment with either cisplatin or carboplatin employing a "dose escalation" desensitization schema. Four patients underwent successful treatment with either cisplatin or carboplatin (3, 4, 5, 6+ total additional courses) without any further evidence of hypersensitivity. In this preliminary report of a limited patient population, we have demonstrated the ability to safely deliver a platinum agent to individuals with either documented carboplatin hypersensitivity, or a high risk for this potentially serious toxicity of carboplatin. Further exploration of this novel management strategy in a larger group of patients is indicated.


[Diversity and classification system of weed community in Harbin City, China].
To analyze the causes of weed community diversity and their strategies of adaption to the high heterogeneity of urban habitats, weed communities in the central urban area of Harbin, China were studied, and a classification system was established for the weed communities. There were 175 weed species, belonging to 128 genera and 38 families. The heterogeneous urban habitats and species' temporal niche differentiation resulted in the highly diversified weed communities. The high proportions of mono-species dominance and annual species dominance communities were their response to the unstable urban habitats under human disturbances with high intensities and frequencies. A four-level classification system was established in terms of plant species and habitat conditions. Within this system, the identified 1763 weed communities could be categorized into two types of life form, 5 types of dormancy form, 22 community groups, and 119 dominance communities.


[Impact of primary and secondary prevention on morbidity and mortality of ischemic cardiopathy].
Coronary artery disease (CAD) is the major cause of death in most developed countries and in many developing countries like Mexico. Epidemiologic studies initiated in the middle of the last century found that hypercholesterolemia, hypertension, tobacco smoking, diabetes mellitus, and other conditions are important precursors of atherosclerosis. With this knowledge, prevention of CAD was started. Some countries implemented a population strategy aimed at improving health-oriented behavior, mainly nutrition, smoking, and physical exercise in the entire population. The favorable changes in risk factors and better medical treatment for CAD patients have resulted in decreased coronary mortality over the past three decades. Randomized trials of antihypertensive treatment have shown that reduction of blood pressure leads to a decreased incidence of stroke and coronary events. Similarly, large secondary and primary prevention clinical trials of statin therapy have conclusively demonstrated the benefit of cholesterol lowering in preventing coronary morbidity and mortality. Despite this large body of scientific evidence, surveys in different countries show that in the population at large and particularly, in patients with documented CAD, preventive medical therapies are underutilized and, as a consequence, many patients are not achieving the recommended goals. Measures that increase compliance by both clinicians and patients to regimens with proven benefits are urgently required.


Parathyroid Autofluorescence in Pediatric Thyroid Surgery: Experience With False Positive and False Negative Results.
Devices for near-infrared light stimulation of autofluorescence (NIRAF) allow for intraoperative identification of parathyroid glands with high sensitivity in adults. However, their performance in the pediatric population is unknown. In this case series with chart review at a tertiary academic children's hospital, we investigated pediatric patients undergoing thyroid surgery and concurrent use of a probe-based NIRAF device. Thirteen patients (ages 6-18 years) underwent thyroid and/or neck dissection procedures, and 2 patients had revision procedures for a total of 15 cases with the NIRAF device. Eight cases had NIRAF values that matched surgeon opinion of parathyroid tissue or histology when available. Six cases had false positive NIRAF readings (40.0%) and 1 case had false negative readings (6.7%). Compared with surgeon opinion or histology, the NIRAF device confirmed 26 of 34 parathyroid gland candidates (76.5%). These devices need further investigation in pediatric patients, whose tissues may have different autofluorescence characteristics.


Quickly Evaluating an Emerging Medical Technology Using Feedback From the Field: A Case Study of the BrainScope One and Infrascanner 2000 User Evaluation.
Gathering end-user feedback about candidate technologies in the operational environment prior to fielding helps to ensure that far-forward medical teams receive the most suitable technology. It is therefore a crucial step in the defense medical acquisition process. The current article reviews the methodology and provides an illustrative example of how end-user feedback was collected to evaluate the current suitability and future promise of two FDA-approved devices, the BrainScope One and Infrascanner 2000, that could potentially aid in the field evaluation of head injuries by far-forward medical teams. The BrainScope One and Infrascanner 2000 end-user evaluation is used as an example to illustrate how to collect end-user feedback from the field in order to rapidly assess the candidate technology. In this evaluation of whether and how to implement FDA-approved technology candidates for head injury assessment by far-forward medical teams, end-user feedback was collected from 158 medical personnel at 8 bases in Afghanistan, Iraq, and Kuwait using focus groups and interviews. The end users reported consistent concerns about the operational efficacy and suitability of the current versions of the devices as well as the areas where the devices showed promise for the Department of Defense (DoD). End-user feedback is shown in detail to demonstrate the depth and richness of feedback that can be gathered using this methodology. Overall, the BrainScope One and Infrascanner 2000 end-user evaluation shows the necessity and value of gathering end-user field efficacy and suitability feedback during the medical acquisition process. Limitations and best practices for this approach are discussed.


Mechanochemical ATPases and transcriptional activation.
Transcriptional activator proteins that act upon the sigma54-containing form of the bacterial RNA polymerase belong to the extensive AAA+ superfamily of ATPases, members of which are found in all three kingdoms of life and function in diverse cellular processes, often via chaperone-like activities. Formation and collapse of the transition state of ATP for hydrolysis appears to engender the interaction of the activator proteins with sigma54 and leads to the protein structural transitions needed for RNA polymerase to isomerize and engage with the DNA template strand. The common oligomeric structures of AAA+ proteins and the creation of the active site for ATP hydrolysis between protomers suggest that the critical changes in protomer structure required for productive interactions with sigma54-holoenzyme occur as a consequence of sensing the state of the gamma-phosphate of ATP. Depending upon the form of nucleotide bound, different functional states of the activator are created that have distinct substrate and chaperone-like binding activities. In particular, interprotomer ATP interactions rely upon the use of an arginine finger, a situation reminiscent of GTPase-activating proteins.


Enhancing the clinical practicum experience through journal writing.
Although journaling is commonplace, its usefulness or effectiveness has been rarely supported by empirical data or examples. The purpose of this article is to highlight integration of classroom and clinical learning, decision-making skills and level of skill acquisition in the Senior Practicum experiences through student journal entry exemplars. Critical thinking, observation and description, and empathy and release of feelings will be discussed.


Overeating among seriously overweight children seeking treatment: results of the children's eating disorder examination.
We sought to examine rates of eating disorder symptoms among seriously overweight children seeking treatment using the Eating Disorder Examination for Children (ChEDE) and to provide initial data about their association with treatment outcome. Overweight children (N = 27) 8-13 years old were interviewed using the ChEDE before participating in a family-based behavioral treatment program. Height and weight were measured pretreatment, posttreatment, and approximately 8 months posttreatment. Fifteen percent of children reported subjective bulimic episodes (SBE). Weight loss did not differ for children with and without SBEs, but concerns about body shape were related to larger weight losses during treatment. A considerable minority of treatment-seeking overweight children report an episodic sense of loss of control over eating. Loss of control is related to other disordered eating attitudes and behaviors, but does not appear to affect treatment outcome. Future studies are needed to replicate these initial findings.


Effect of abdominal drawing-in maneuver during hip extension on the muscle onset time of gluteus maximus, hamstring, and lumbar erector spinae in subjects with hyperlordotic lumbar angle.
The abdominal drawing-in maneuver (ADIM) is used to prevent abnormal movements of the lumbar spine and pelvis during therapeutic exercises. This study compared the effects of ADIM on the muscle onset time of the hamstring, gluteus maximus, and erector spinae muscles during prone hip extension exercise in subjects with or without hyperlordotic lumbar angle. Forty healthy adults (18 male, 22 female) were recruited for this study. The lumbar lordotic angles and pelvic tilt angles of the subjects were measured using the Avaliação postural analysis software. The subjects were divided into two groups: the lumbar hyperlordotic angle (LHLA) and lumbar normal lordotic angle (LNLA) groups. The muscle contraction onset time of the hamstring, gluteus maximus, and erector spinae were assessed using surface electromyography. During ADIM application, the muscle contraction onset time of the gluteus maximus was significantly increased in the LHLA group compared with the LNLA group. ADIM application during prone hip extension was more effective for gluteus maximus onset time in the LHLA group. Therefore, ADIM during prone hip extension may be useful for gluteus maximus training in individuals with lumbar hyperlordosis.


Evaluation of human cartilage endplate composition using MRI: Spatial variation, association with adjacent disc degeneration, and in vivo repeatability.
Cartilage endplate (CEP) biochemical composition may influence disc degeneration and regeneration. However, evaluating CEP composition in patients remains a challenge. We used T2* mapping from ultrashort echo-time (UTE) magnetic resonance imaging (MRI), which is sensitive to CEP hydration, to investigate spatial variations in CEP T2* values and to determine how CEP T2* values correlate with adjacent disc degeneration. Thirteen human cadavers (56.4 ± 12.7 years) and seven volunteers (36.9 ± 10.9 years) underwent 3T MRI, including UTE and T1ρ mapping sequences. Spatial mappings of T2* values in L4-S1 CEPs were generated from UTE images and compared between subregions. In the abutting discs, mean T1ρ values in the nucleus pulposus were compared between CEPs with high vs low T2* values. To assess in vivo repeatability, precision errors in mean T2* values, and intraclass correlation coefficients (ICC) were measured from repeat scans. Results showed that CEP T2* values were highest centrally and lowest posteriorly. In the youngest individuals (<50 years), who had mild-to-moderately degenerated Pfirrmann grade II-III discs, low CEP T2* values associated with severer disc degeneration: T1ρ values were 26.7% lower in subjects with low CEP T2* values (P = .025). In older individuals, CEP T2* values did not associate with disc degeneration (P = .39-.62). Precision errors in T2* ranged from 1.7 to 2.6 ms, and reliability was good-to-excellent (ICC = 0.89-0.94). These findings suggest that deficits in CEP composition, as indicated by low T2* values, associate with severer disc degeneration during the mild-to-moderate stages. Measuring CEP T2* values with UTE MRI may clarify the role of CEP composition in patients with mild-to-moderate disc degeneration.


Multiple sclerosis: relapses and timing of remissions.
Relapse is a relatively sudden worsening of neurological status in multiple sclerosis patients. The aim of this paper is to describe the frequency and timing of the subsequent clinical remission, and factors linked to a possible lack of recovery. Two hundred and twenty-three relapses in 62 multiple sclerosis patients were examined retrospectively. Kurtzke's Expanded Disability Status Scale (EDSS) scores were calculated every 3 months from 1 year before to 1 year after. Remission was defined as improvement vs. the EDSS as scored during the relapse. Recovery was defined as return to the EDSS as scored before the relapse. The frequency of improvement was 78% at 3 months, 86% at 6, and lower in males (65 vs. 81%). The frequency of recovery was 55% at 3 months, 71% at 6. Kaplan-Meier curves showed stabilization after 6 months, with improvement in 90% of patients, 100% without further relapses. Relapses without recovery were only 30%; 15% excluding short-term relapses. Incomplete remissions do not appear to be linked to the evolution of the relapse, but to further relapses in the following months; in other words, to the short-term relapse rate.


Ionic mechanism of the efferent olivo-cochlear inhibition studied by cochlear perfusion in the cat.
1. A method for perfusing the scala tympani of the cat's cochlea from basal turn to apex is described. The perfusion with modified Krebs solution did not interfere with the recording of cochlear microphonic (CM) and neural responses to sound, nor with the efferent inhibition elicited by stereotaxic stimulation of the crossed olivo-cochlear bundle (COCB) in the medulla. 2. Cochlear perfusion with solutions in which most of the chloride was replaced by large anions (sulphate or gluconate) decreased or eliminated auditory nerve or the ventral cochlear nucleus. These effects were reversible. They were only observed if the rate of perfusion (2-20 mul/min) was adequate to reduce the chloride concentration in perilymph below about 80 mM, this being estimated, in different perfusion of the same cochlea, by a chloride-selective electrode. 3. The COCB-induced negative shift of the endocochlear potential recorded with a glass micro-electrode inserted into the scala media was abolished by I.V. strychnine o.2 mg/kg. It was decreased when the perilymph chloride was reduced to 50-70 mM and could be abolished when the perilymph chloride dropped to about 5 mM. 4. The COCB-induced potentiation of the cochlear microphonic potential was also reduced by chloride substitution but the pattern of this effect differed from that of neural inhibition. 5. Similar cochlear perfusions with a solution in which the small diameter bromide anion was substituted for chloride did not affect the COCB-efferent effects. 6. The data indicate that the inhibitory transmitter released by COCB terminals elicits an increased conductance to small anions (normally to chloride) in the membrane of the auditory dendrite and of the outer hair cell. The significance of the COCB-induced negative shift of endocochlear potential and of the potentiation of CM is discussed, as well as the pre- and post-synaptic mechanisms involved in the efferent gating exerted on the auditory input. The latter would seem to involve primarily a post-synaptic mechanism at efferent axo-dendritic synapses.


Interferon-stimulated gene 15 (ISG15) and ISG15-linked proteins can associate with members of the selective autophagic process, histone deacetylase 6 (HDAC6) and SQSTM1/p62.
The ubiquitin-like interferon (IFN)-stimulated gene 15 (ISG15) and its specific E1, E2, and E3 enzymes are transcriptionally induced by type I IFNs. ISG15 conjugates newly synthesized proteins. ISG15 linkage to proteins appears to be an important downstream IFN signaling event that discriminates cellular and pathogenic proteins synthesized during IFN stimulation from existing proteins. This eliminates potentially pathogenic proteins as the cell attempts to return to normal homeostasis after IFN "stressed" conditions. However, the molecular events that occur in this process are not well known. Here, we show that the C-terminal LRLRGG of ISG15 interacts with the binder of ubiquitin zinc finger (BUZ) domain of histone deacetylase 6 (HDAC6). Because HDAC6 is involved in the autophagic clearance of ubiquitinated aggregates during which SQSTM1/p62 plays a major role as a cargo adapter, we also were able to confirm that p62 binds to ISG15 protein and its conjugated proteins upon forced expression. Both HDAC6 and p62 co-localized with ISG15 in an insoluble fraction of the cytosol, and this co-localization was magnified by the proteasome inhibitor MG132. In addition, ISG15 was degraded via the lysosome. Overexpression of ISG15, which leads to an increased conjugation level of the cellular proteome, enhanced autophagic degradation independently of IFN signaling transduction. These results thus indicate that ISG15 conjugation marks proteins for interaction with HDAC6 and p62 upon forced stressful conditions likely as a step toward autophagic clearance.


Doxorubicin-induced cardiomyopathy.
Doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) is one of the most effective chemotherapeutic agents used in the management of pediatric neoplastic disorders during the past 20 years. However, its use has been limited by well-characterized, dose-related cardiac toxicity. Recently, cardiac dysfunction has been noted in pediatric patients who had received doxorubicin years before. This article summarizes current information regarding the pathophysiology and risk factors associated with cardiotoxicity and reviews detection methods and treatments of this condition.


Retinoids control anterior and dorsal properties in the developing forebrain.
We have previously shown that retinoic acid (RA) synthesized by the retinaldehyde dehydrogenase 2 (RALDH2) is required in forebrain development. Deficiency in RA due to inactivation of the mouse Raldh2 gene or to complete absence of retinoids in vitamin-A-deficient (VAD) quails, leads to abnormal morphogenesis of various forebrain derivatives. In this study we show that double Raldh2/Raldh3 mouse mutants have a more severe phenotype in the craniofacial region than single null mutants. In particular, the nasal processes are truncated and the eye abnormalities are exacerbated. It has been previously shown that retinoids act mainly on cell proliferation and survival in the ventral forebrain by regulating SHH and FGF8 signaling. Using the VAD quail model, which survives longer than the Raldh-deficient mouse embryos, we found that retinoids act in maintaining the correct position of anterior and dorsal boundaries in the forebrain by modulating FGF8 anteriorly and WNT signaling dorsally. Furthermore, BMP4 and FGF8 signaling are affected in the nasal region and BMP4 is ventrally expanded in the optic vesicle. At the optic cup stage, Pax6, Tbx5 and Bmp4 are ectopically expressed in the presumptive retinal pigmented epithelium (RPE), while Otx2 and Mitf are not induced, leading to a dorsal transdifferentiation of RPE to neural retina. Therefore, besides being required for survival of ventral structures, retinoids are involved in restricting anterior identity in the telencephalon and dorsal identity in the diencephalon and the retina.


Changes in vocal fold gene expression and histology after injection augmentation in a recurrent laryngeal nerve injury model.
To investigate changes in neuroregenerative pathways with vocal fold denervation in response to vocal fold augmentation. Eighteen Yorkshire crossbreed swine underwent left recurrent laryngeal nerve transection, followed by observation or augmentation with carboxymethylcellulose or calcium hydroxyapatite at two weeks. Polymerase chain reaction expression of genes regulating muscle growth (MyoD1, MyoG and FoxO1) and atrophy (FBXO32) were analysed at 4 and 12 weeks post-injection. Thyroarytenoid neuromuscular junction density was quantified using immunohistochemistry. Denervated vocal folds demonstrated reduced expression of MyoD1, MyoG, FoxO1 and FBXO32, but overexpression after augmentation. Healthy vocal folds showed increased early and late MyoD1, MyoG, FoxO1 and FBXO32 expression in all animals. Neuromuscular junction density had a slower decline in augmented compared to untreated denervated vocal folds, and was significantly reduced in healthy vocal folds contralateral to augmentation. Injection augmentation may slow neuromuscular degeneration pathways in denervated vocal folds and reduce compensatory remodelling in contralateral healthy vocal folds.


Effects of nitrous oxide on the respiratory pattern of spontaneously breathing children during anaesthesia.
The effects of the withdrawal of nitrous oxide from the inspired gas mixture were studied in 10 spontaneously breathing children during nitrous oxide-halothane anaesthesia, before and during surgery, using a computerized system for the measurement, recording and analysis of data. Before surgery the decline in the alveolar nitrous oxide concentration was associated with an increase in minute ventilation (32.7%, P less than 0.05), and a decrease in alveolar carbon dioxide concentration (8.4%, P less than 0.05). These effects were produced solely by an increase in tidal volume (42.7%, P less than 0.001), as no significant change in respiratory rate was observed. The hypoventilation produced by an alveolar mixture of 60% nitrous oxide and 0.9% halothane, a reduction of VE by 50%, exceeded the hypoventilation caused by 0.9% halothane alone, which reduced VE by 36.6%; and the hypoventilation produced by nitrous oxide and halothane was rapidly reversed by the withdrawal of nitrous oxide from the inspired gas mixture. During surgery all indices of ventilation were stimulated, and there was greater variability of response, but the pattern and degree of change in response to nitrous elimination, VE increased by 33.3%, VT by 33.8%, closely resembled the changes before surgery. Five children had received papaveretum as premedication, and five thiopentone per rectum; the depression of carbon dioxide responsiveness was more severe in the group who received papaveretum, and their responses to nitrous oxide elimination were less than, and occurred later than the responses in the group given thiopentone.


Mechanisms in volume regulation in Ehrlich ascites tumor cells.
The Ehrlich ascites tumor cell has been used as a model of an unspecialized mammalian cell, in an attempt to disclose the mechanisms involved in the regulation of cellular water and salt content. In hypotonic medium Ehrlich cells initially swell as nearly perfect osmometers, but subsequently recover their volume within about 10 min with an associated net loss of KCl, amino acids, taurine and cell water. The net loss of KCl takes place mainly via separate, conductive K+ and Cl- transport pathways, and the net loss of taurine through a passive leak pathway. Ca2+ and calmodulin appear to be involved in the activation of the K+ and Cl- channels, as well as the taurine leak pathway. In hypertonic medium Ehrlich cells initially shrink as osmometers, but subsequently recover their volume with an associated net uptake of KCl and water. In this case, the net uptake of KCl is the result of the activation of an electroneutral, Na+- and Cl- -dependent cotransport system with subsequent replacement of cellular Na+ by extracellular K+ via the Na+/K+ pump. In the present review we describe the ion and taurine transporting systems which have been identified in the plasma membrane of the Ehrlich ascites tumor cell. We have emphasized the selectivity of these transport pathways and their activation mechanisms. Finally, we propose a model for the activation of the conductive K+ and Cl- transport pathways in Ehrlich cells which includes Ca2+, leukotrienes, and inositol phosphate as intracellular second messengers.


Time to immunologic recovery and determinant factors among adults who initiated ART in Felege Hiwot Referral Hospital, northwest Ethiopia.
CD4 cells are the major targets for human immunodeficiency virus (HIV) and treatment with Antiretroviral Therapy (ART) influences the CD4 cell count of HIV patients. In addition to ART, the time required to reach normal range of CD4 counts (500 cells/mm3) can be affected by clinical, socio-demographic, and behavioral factors. This retrospective cohort study was conducted to determine the incidence of having the normal range of CD4 cell counts and factors that affect the time required to reach this normal range among adult HIV patients who initiated into ART. Data of 4 years were retrospectively retrieved from routinely registered characteristics of 937 ART users enrolled in 2010. Survival time until immunologic recovery and its determinant factors were examined using the frailty model with different parametric distributions alternatively. Most (80.8%) of the ART attendants had CD4 cell count of 200 cells/mm3 or less at initiation. The overall incidence rate of immunologic recovery was 12.67 persons per 1000 person-months (95% CI 11.30, 14.20). The dependency of frailties of immunologic recovery by residence was statistically significant (Theta = 0.05, p value = 0.006). Baseline age (Adjusted Hazard Ratio (AHR) = 0.98, 95% CI 0.97, 0.99), baseline CD4 count (AHR = 1.006, 95% CI 1.005, 1.008), and female sex (AHR = 1.34, 95% CI 1.03, 1.73) were significantly associated with shorter survival time for immunologic recovery. Higher baseline CD4 count, lower baseline age, and female sex were positively associated with the time to immunologic recovery, which also dependent on proximity/residence of ART users. Therefore, further scale up of ART services with due emphasis to patients with low CD4 count at baseline particularly for male and older ART users are recommended to reach the normal range of CD4 count in a shorter time of treatment.


Background strain and the differential susceptibility of podocyte-specific deletion of Myh9 on murine models of experimental glomerulosclerosis and HIV nephropathy.
We previously reported that podocyte-specific deletion of Myh9 (conventional myosin heavy chain 2A) in C57BL/6 mice does not cause spontaneous kidney disease but instead results in a predisposition to glomerulosclerosis in response to a second model of glomerular injury. In contrast, other investigators reported that podocyte-specific deletion of Myh9 (PodΔMyh9) resulted in spontaneous glomerulosclerosis in mice on a mixed background, suggesting that the glomerulosclerosis is dependent on background strain. In order to elucidate the cause of this strain dependent effect Podocin::Cre and Myh9(flox) alleles were backcrossed to mouse strain FVB/N, which is highly susceptible to glomerulosclerosis, with the aim of intercrossing susceptible FVB/N and resistant C57BL/6 mice in subsequent congenic analyses. However, after backcrossing mice to FVB/N and aging mice to 28 weeks, we found no evidence of glomerular disease in PodΔMyh9 mice vs control littermates (urine MAC ratio all p>0.05). We also tested C57BL/6 PodΔMyh9 mice for a predisposition to injury from models other than Adriamycin including HIV nephropathy (HIVAN), puromycin nephropathy, and sheep nephrotoxic serum. In the Tg26 model of HIVAN, we found that podocyte-specific deletion of Myh9 resulted in a modest hypersensitivity in adults compared to Tg26+ control littermates (urine MAC ratio, p<0.05 or less). In contrast, we found that PodΔMyh9 mice were not predisposed to injury in response to other injury models including puromycin nephropathy and sheep nephrotoxic serum. While the mechanism of injury in these models is not fully understood, we conclude that PodΔMyh9 results in a variable susceptibility to glomerulosclerosis in response to different models of glomerular injury. In addition, based on the lack of a spontaneous phenotype of glomerulosclerosis in both C57BL/6 and FVB/N mice, we propose that Myh9 is not absolutely required in adult podocytes.


Obesity and the risk of systemic lupus erythematosus among women in the Nurses' Health Studies.
Obesity is increasingly prevalent and related to increased risk of several autoimmune diseases, likely via generation of inflammatory adipokines. Prior studies have not evaluated obesity in relation to systemic lupus erythematosus (SLE) risk. We prospectively evaluated whether obesity was associated with increased SLE risk among women in the U.S. Nurses' Health Study cohorts. We conducted a prospective cohort study among 238,130 women in the Nurses' Health Studies (NHS, 1976-2012; NHSII, 1989-2013). Incident SLE was confirmed by American College of Rheumatology 1997 criteria and validated through medical record review. Body mass index (BMI, kg/m2) was calculated at baseline and on biennial questionnaires. Cox proportional hazards models estimated HRs (95% CIs) for SLE by cumulative average BMI category {18.5 to <25 [normal (reference)], 25 to <30 (overweight), ≥30 (obese)}, adjusting for potential time-varying confounders. Models were performed separately in each cohort; results were meta-analyzed. Sensitivity analyses used simple time-varying BMI, a 4-year lag between exposure and SLE risk window to address potential reverse causation, and evaluated BMI at age 18 and weight change since age 18. A secondary analysis started follow-up in both cohorts at similar calendar years when the prevalence of obesity in the U.S. increased most dramatically [1988 (NHS)/1989 (NHSII)]. We identified 153 NHS incident SLE cases and 115 incident NHSII cases during 5,602,653 person-years of follow-up. At baseline, 8.4% of women in NHS and 11.8% in NHSII were obese. Mean age at enrollment was 42.5 (SD 7.2) years in NHS and 34.4 (SD 4.7) years in NHSII. Cumulative average obesity was significantly associated with SLE risk in NHSII [HR = 1.85 (1.17-2.91)], but not in NHS [HR = 1.11 (0.65-1.87)] compared to normal BMI. In the meta-analysis of both cohorts, obesity was not significantly associated with increased risk of SLE [HR = 1.46 (0.88-2.40)]. Simple time-varying BMI and lagging the exposure window by 4 years produced similar findings to the primary analysis. In NHSII, a 4.54 kg gain between age 18 and enrollment slightly increased SLE risk [HR = 1.09 (1.02-1.18)]. In the secondary analysis starting follow-up of both cohorts at similar calendar years, the point estimate for obesity in NHS was higher than the primary analysis [HR = 1.67 (0.81-3.45)]. We observed an 85% significantly increased risk of SLE among obese compared to normal BMI women in the more recent NHSII cohort, but no association was observed in the earlier NHS cohort. Secular trends in obesity may account for the differences between the two birth cohorts.


A success for science or technology? The Rockfeller Foundation's role in malaria eradication in Italy, 1924-1935.
The Rockefeller Foundation's malaria control work in Italy provides an important and instructive episode in the history of malariology. The pattern of the Rockefeller Foundation's early malaria control work, using its role in Italy in the 1920s and 1930s is an example of its strategy and methods. Although the history of malaria control usually is written with a focus on the scientific and laboratory achievements of scientists and physicians, the technology of malaria control also has been very important as in the case of Italy in the 1920s and 1930s.


The bone remodelling cycle.
The bone remodelling cycle replaces old and damaged bone and is a highly regulated, lifelong process essential for preserving bone integrity and maintaining mineral homeostasis. During the bone remodelling cycle, osteoclastic resorption is tightly coupled to osteoblastic bone formation. The remodelling cycle occurs within the basic multicellular unit and comprises five co-ordinated steps; activation, resorption, reversal, formation and termination. These steps occur simultaneously but asynchronously at multiple different locations within the skeleton. Study of rare human bone disease and animal models have helped to elucidate the cellular and molecular mechanisms that regulate the bone remodelling cycle. The key signalling pathways controlling osteoclastic bone resorption and osteoblastic bone formation are receptor activator of nuclear factor-κB (RANK)/RANK ligand/osteoprotegerin and canonical Wnt signalling. Cytokines, growth factors and prostaglandins act as paracrine regulators of the cycle, whereas endocrine regulators include parathyroid hormone, vitamin D, calcitonin, growth hormone, glucocorticoids, sex hormones, and thyroid hormone. Disruption of the bone remodelling cycle and any resulting imbalance between bone resorption and formation leads to metabolic bone disease, most commonly osteoporosis. The advances in understanding the cellular and molecular mechanisms underlying bone remodelling have also provided targets for pharmacological interventions which include antiresorptive and anabolic therapies. This review will describe the remodelling process and its regulation, discuss osteoporosis and summarize the commonest pharmacological interventions used in its management.


Framework for analyzing an ethical problem and conducting an ethical consultation.
Clinical ethics are an intrinsic aspect of practice in health care settings. However, health care professionals may have minimal training in ethics and communication. Clinical ethics committees, with a multidisciplinary composition, are in a position to offer clinical consultative services from a collaborative framework. Using this framework, as well as standard guidelines for conducting an ethics consultation, most often elicits essential beliefs, values, concerns, and opinions pertinent to the case at hand. Through enhancement of the communication process, group consensus is usually achieved. The framework guiding the consultation and communication process is delineated and illustrated through case analysis.


Prevention of myocardial infarction.
There is a significant relationship between high blood pressure and a variety of other risk factors for coronary heart disease. Antihypertensive treatment reduces the incidence of coronary heart disease, but at a lower level than expected from epidemiological data. It is proposed that there is an alternative route to coronary heart disease from a 'factor X' via various metabolic disturbances, in addition to the route via hypertension. There have been a number of trials comparing the effects of diuretics with beta-blockers in the treatment of hypertension. However, the number of endpoints is very small in these trials, making it difficult to conclude that there is any difference between the effects of the two types of drug on patients. In contrast, in post-myocardial infarction trials, where the number of endpoints was much larger, beta-blockers had a positive effect. Thus larger antihypertensive drug trials are needed to study the effect of beta-blockers in primary prevention.


Prognostic value of 5-microRNA based signature in T2-T3N0 colon cancer.
The role of adjuvant chemotherapy in stage T2-T3N0 colon cancer (CC) is controversial and there are currently no reliable factors allowing for individual selection of patients with high risk of relapse for such therapy. We searched for microRNA-based signature with prognostic significance in this group. We assessed by qRT-PCR expression of 754 microRNAs (miRNAs) in tumour samples from 85 stage pT2-3N0 CC patients treated with surgery alone. MiRNA expression was compared between two groups of patients: 40 and 45 patients who did and did not develop distant metastases after resection, respectively. Additionally, miRNA expression was compared between CC and normal colon mucosa samples and between the mismatch repair (MMR) competent and deficient tumours. Low expression of miR-1300 and miR-939 was significantly correlated with shorter distant metastasis-free survival (DMFS) in Cox univariate analysis (p.adjusted = 0.049). The expression signature of five miRNAs (miR-1296, miR-135b, miR-539, miR-572 and miR-185) was found to be prognostic [p = 1.28E-07, HR 8.4 (95 % CI: 3.81-18.52)] for DMFS and cross-validated in a leave-one-out analysis, with the sensitivity and specificity of 74 and 78 %, respectively. The expression of miR-592 was significantly associated with the MMR status (p.adjusted <0.01). The expression of several novel miRNAs were found to be tumour specific, e.g. miR-888, miR-523, miR-18b, miR-302a, miR-423-5p, miR-582-3p (p < 0.05). We developed a miRNA expression signature that may be predictive for the risk of distant relapse in early stage CC and confirmed previously reported association between miR-592 expression and MMR status.


Rivaroxaban Rebound Acute Coronary Event: A Post Marketing Experience.
We present a 65-year-old male who received rivaroxaban therapy prior to and after left knee replacement surgery. The patient developed generalized weakness soon after stopping rivaroxaban. An electrocardiogram showed acute infero-lateral ischemia and an echocardiogram reported an akinetic antero-apical wall segment, an apical clot and a reduced systolic function. A subsequent coronary angiogram revealed two-vessel coronary artery thrombosis. The case illustrates a temporal relationship of coronary thrombosis following rivaroxaban cessation.


Warm Weather and Surgical Site Infections: A Meta-analysis.
Seasonal variability, in terms of warm weather, has been demonstrated to be a significant risk factor for surgical site infections (SSIs). However, this remains an underexposed risk factor for SSIs, and many clinicians are not aware of this. Therefore, a systematic review and meta-analysis has been conducted to investigate and quantify this matter. Articles were searched in Embase, Medline Ovid, Web of Science, Cochrane Central, and Google Scholar, and data were extracted from relevant studies. Meta-analysis used random effects models to estimate and compare the pooled odds ratios (OR) and corresponding confidence intervals (CIs) of surgery performed during the warmest period of the year and the colder period of the year. The systematic review included 20 studies (58,599,475 patients), of which 14 studies (58,441,420 patients) were included for meta-analysis. Various types of surgical procedures across different geographic regions were included. The warmest period of the year was associated with a statistically significant increase in the risk of SSIs (OR 1.39, 95%CI: [1.34-1.45], P < 0.0001). Selection of specific types of surgical procedures (eg, orthopedic or spinal surgery) significantly altered this increased risk. The current meta-analysis showed that warm weather seasons are associated with a statistically significant risk increasement of 39% in developing SSIs. This significant risk factor might aid clinicians in preoperative patient information, possible surgical planning adjustment for high risk patients, and potentially specific antibiotic treatments during the warmer weather seasons that could result in decrease of SSIs.


Atom interferometry with trapped fermi gases.
We realize an interferometer with an atomic Fermi gas trapped in an optical lattice under the influence of gravity. The single-particle interference between the eigenstates of the lattice results in macroscopic Bloch oscillations of the sample. The absence of interactions between fermions allows a time-resolved study of many periods of the oscillations, leading to a sensitive determination of the acceleration of gravity. The experiment proves the superiority of noninteracting fermions with respect to bosons for precision interferometry and offers a way for the measurement of forces with microscopic spatial resolution.


Involvement of mono-oxygenases as a major mechanism of deltamethrin-resistance in larvae of three species of mosquitoes.
Role of mono-oxygenases as a mechanism of resistance to the synthetic pyrethroid, deltamethrin in the larvae of Culex quinquefasciatus Say, Aedes aegypti L. and Anopheles stephensi Liston developed by laboratory selections with deltamethrin, DDT or deltamethrin and the synergist, piperonyl butoxide (PBO) in the ratio of 1:5, was investigated. There was a significant correlation with mono-oxygenase activity and larval LC50 to deltamethrin in various strains of all the three species. In addition, the activity of glucose-6-phosphate dehydrogenase (G6PD), the main NADPH generating enzyme for mono-oxygenases, also showed enhanced activity in deltamethrin and DDT-selected strains. The present data, therefore, clearly suggest that deltamethrin resistance in the larvae of Cx. quinquefasciatus, Ae. aegypti and An. stephensi is mainly due to the detoxification of deltamethrin by microsomal mono-oxygenases. High activity of G6PD observed in DDT-selected strains seems to be related to its role as a rate-limiting enzyme in GSH-dependent dehydrochlorination of DDT.


MEASUREMENT OF CONTROLLED ATTENUATION PARAMETER: A SURROGATE MARKER OF HEPATIC STEATOSIS IN PATIENTS OF NONALCOHOLIC FATTY LIVER DISEASE ON LIFESTYLE MODIFICATION - A PROSPECTIVE FOLLOW-UP STUDY.
Liver biopsy is a gold standard method for hepatic steatosis assessment. However, liver biopsy is an invasive and painful procedure and can cause severe complications therefore it cannot be frequently used in case of follow-up of patients. Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). To evaluate hepatic steatosis, transient elastography with controlled attenuation parameter (CAP) measurement is an option now days. Aim of this study is to evaluate role of measurement of controlled attenuation parameter, a surrogate marker of hepatic steatosis in patients of nonalcoholic fatty liver disease on lifestyle modification. In this study, initially 37 participants were included who were followed up after 6 months with transient elastography, blood biochemical tests and anthropometric measurements. The results were analyzed by Multivariate linear regression analysis and paired samples t-test (Dependent t-test) with 95% confidence interval. Correlation is calculated by Pearson correlation coefficients. Mean CAP value for assessing hepatic steatosis during 1st consultation (278.57±49.13 dB/m) was significantly improved (P=0.03) after 6 months of lifestyle modification (252.91±62.02 dB/m). Only fasting blood sugar (P=0.008), weight (P=0.000), body mass index (BMI) (P=0.000) showed significant positive correlation with CAP. Only BMI (P=0.034) and weight (P=0.035) were the independent predictor of CAP value in NAFLD patients. Lifestyle modification improves the hepatic steatosis, and CAP can be used to detect the improvement of hepatic steatosis during follow-up in patients with NAFLD on lifestyle modification. There is no relation between CAP and Fibroscan score in NAFLD patients. Only BMI and weight can predict CAP value independently.


Childhood granuloma annulare: a review.
Granuloma annulare (GA) is a self-limited benign inflammatory dermatosis of unknown origin characterized by the development of papules arranged in an annular, circinate pattern, mainly involving the extensor surfaces of lower and upper extremities. The diagnosis depends on clinical and histological features. There are four main variants of GA: localized GA (LGA), subcutaneous GA (SGA), generalized GA (GGA) and perforating GA (PGA) and 2 uncommon subtypes: papular umbilicated GA and linear or segmental GA. Children most commonly present with the localized and subcutaneous forms. The aim of this review was to provide an update on the etiology, diagnosis and management of GA focusing on the pediatric age.


Biotin-decorated hollow gold nanoshells for dual-modal imaging-guided NIR-II photothermal and radiosensitizing therapy toward breast cancer.
Radiotherapy (RT) is dominantly used in breast cancer therapy but is facing fierce side effects because of the limited difference between tumor and normal tissues in response to ionizing radiation. Herein, we construct a core-shell nanoparticle of UiO-66-NH2@AuNS. Then the solid gold shell was etched into hollow AuNS (HAuNS) and further modified with biotin-PEG-SH (PEG-bio) to obtain HAuNS@PEG-bio. HAuNS@PEG-bio demonstrates effective near infrared II (NIR-II) region photothermal therapy (PTT) performance, and the increase of temperature at the tumor site promotes the blood circulation to alleviate the hypoxia in the tumor microenvironment (TME). Meanwhile, HAuNS exhibits strong X-ray absorption and deposition ability due to the high atomic coefficient of elemental Au (Z = 79) and hollowed-out structure. Through the dual radiosensitization of the high atomic coefficient of Au and the hypoxia alleviation from PTT of HAuNS, the breast cancer cells could undergo immunogenic cell death (ICD) to activate the immune response. At the in vivo level, HAuNS@PEG-bio performs NIR-II photothermal, radiosensitization, and ICD therapies through cellular targeting, guided by infrared heat and CT imaging. This work highlights that the constructed biotin-decorated hollow gold nanoshell has a promising potential as a diagnostic and treatment integration reagents for the breast cancer.


A systems biology-led insight into the role of the proteome in neurodegenerative diseases.
Multifactorial disorders are the result of nonlinear interactions of several factors; therefore, a reductionist approach does not appear to be appropriate. Proteomics is a global approach that can be efficiently used to investigate pathogenetic mechanisms of neurodegenerative diseases. Here, we report a general introduction about the systems biology approach and mechanistic insights recently obtained by over-representation analysis of proteomics data of cellular and animal models of Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders, as well as of affected human tissues. Expert commentary: As an inductive method, proteomics is based on unbiased observations that further require validation of generated hypotheses. Pathway databases and over-representation analysis tools allow researchers to assign an expectation value to pathogenetic mechanisms linked to neurodegenerative diseases. The systems biology approach based on omics data may be the key to unravel the complex mechanisms underlying neurodegeneration.


The factor VIII C1 domain contributes to platelet binding.
Activated factor VIII (FVIIIa) forms a procoagulant complex with factor IXa on negatively charged membranes, including activated platelet surfaces. Membrane attachment involves the FVIII C2 domain; involvement of the adjacent C1 domain has not been established. Binding of recombinant FVIII C1C2 and C2 proteins to platelets was detected by flow cytometry using (1) anti-C2 monoclonal antibody ESH8 followed by a phycoerythrin-labeled secondary antibody; (2) biotinylated C1C2 detected by phycoerythrin-labeled streptavidin, and (3) C1C2 and C2 site-specifically labeled with fluorescein. Highest binding and lowest background were obtained using fluorescein-conjugated proteins. More than 90% of activated platelets bound C1C2, compared with approximately 50% for equimolar C2. Estimates using fluorescent microbeads indicated approximately 7,000 C1C2-binding sites per platelet, approximately 1,400 for C2, and approximately 3,000 for fluorescein-labeled FVIIIa. Unlike C2 or FVIII(a), C1C2 bound to approximately 700 sites/platelet before activation. C1C2 binding to activated platelets appeared independent of von Willebrand factor and was competed effectively by FVIII(a), but only partially by excess C2. Fluorescein-labeled FVIIIa was competed much more effectively by C1C2 than C2 for binding to activated platelets. Two monoclonal antibodies that inhibit C2 binding to membranes competed platelet binding of C2 more effectively than C1C2. Thus, the C1 domain of FVIII contributes to platelet-binding affinity.


[Changes in ultrastructure of lung aerohematic barrier and blood gas indices in long term exercise].
The aim of the study was to find out the key manifestations of reorganization of lung aerohematic barrier (AB) components (cellular and tissue) in the process of a prolonged physical exercise, taking into account changes in the indices of blood acid-basic balance (ABB). The physical exercise (running in treadbane, 2 hours daily, rotation frequency -- 19 r/min) was reproduced in white laboratory rats, body weight 180.0-200.0 gr. Pulmonary tissue specimens were collected after 3, 7, 10-60 days. ABB was determinate in capillary blood samples with the apparatus "Microastrup". The materials were used for general histological, electronmicroscopic and morphometric examination. The digital findings were treated with MS Excel. The earliest informative sign of appearance of surfactant dependent atelectasis and alveolar epithelium is trombocytes stasis in interaalveolar capillary lumens with plasma insudation into the depth of aerohematic barrier that is negatively reflected on the processes of ventilation and gas exchange with the tendency of development of hypercapnia and metabolic acidosis to the end (50-60 days) of the experiment. The structural basis of this state is collagen formation in aerohematic barrier tissue component.


[Incidence and prevalence of occupational diseases in Spain].
To estimate the impact of occupational diseases in Spain in terms of incidence and prevalence and to compare them with the notifications actually made. Data of incidence and prevalence were obtained from studies carried out in Spain and in other countries. These studies were mostly based on epidemiological investigations, occupational diseases monitoring systems and surveys with representative samples of workers. Data of incidence and prevalence were applied to the whole of working population in Spain in 2006. Spain, 2006. Incidence and prevalence of occupational diseases and illness (including musculoskeletal, skin, respiratory and mental diseases and malignant cancers). It is estimated that a mean of 87 856 incident cases of occupational diseases occurred in Spain in 2006, most of them musculoskeletal diseases (30 757 estimated incident cases) and skin diseases (12 481 cases). Moreover, according to our estimations, 9153 respiratory diseases, 8205 cases of mental illness and 6082 malignant cancers related to different occupational exposures were diagnosed in Spain in 2006. A total of 999 591 male workers and 1 007 862 female workers suffered some disease or illness related to their working conditions, the most common being musculoskeletal and mental diseases. Occupational diseases impact could be quite over what it is showed in the official occupational diseases registry in Spain. It is necessary to give visibility to this problem to provide adequate care and prevention of occupational diseases in the population.


[Changes in psychophysical load of high school students as a result of educational reform].
The material comprised 2679 secondary school pupils (1959 girls and 1020 boys) from several Polish big cities, among whom 1281 pupils took up the old school program and 1968--the new program. The present studies were initiated in school year 1985/86 and were completed in 1989/1990. The psychophysical load of pupils was evaluated by means of a standard questionnaire comprising 77 questions grouped into problems, allowing us to determine the pupil's psychophysical load associated with school education, extra school occupations, daily time-table, situation in the class and family as well as psychic general feeling. The overall score obtained for all answers informed about the total psychophysical load. Answers to selected questions objectively specified the prevailing load-causing situations, as well as estimated the subjective feeling of the burden of these loads. The results led to the following conclusions: both prior to and after the introduction of changes in school programs (educational reform), the overall psychophysical situation of girls and boys deteriorated with years of school education. Introduction of changes in school programs has led to an increase overall psychophysical load of pupils in all classes compared, with the exception of the final class (before the examination for the secondary-school certificate). After the educational reform, the load was heaviest in the second class of secondary school. The psychophysical load of girls exceeded that of boys. Likewise, the loads associated with the objectively prevailing load-causing situations as well as those associated with subjective feeling of the burden of these loads were heavier in girls than in boys, both before and after the introduction of changes in school programs.


Label-Free White Blood Cell Classification Using Refractive Index Tomography and Deep Learning.
Objective and Impact Statement. We propose a rapid and accurate blood cell identification method exploiting deep learning and label-free refractive index (RI) tomography. Our computational approach that fully utilizes tomographic information of bone marrow (BM) white blood cell (WBC) enables us to not only classify the blood cells with deep learning but also quantitatively study their morphological and biochemical properties for hematology research. Introduction. Conventional methods for examining blood cells, such as blood smear analysis by medical professionals and fluorescence-activated cell sorting, require significant time, costs, and domain knowledge that could affect test results. While label-free imaging techniques that use a specimen's intrinsic contrast (e.g., multiphoton and Raman microscopy) have been used to characterize blood cells, their imaging procedures and instrumentations are relatively time-consuming and complex. Methods. The RI tomograms of the BM WBCs are acquired via Mach-Zehnder interferometer-based tomographic microscope and classified by a 3D convolutional neural network. We test our deep learning classifier for the four types of bone marrow WBC collected from healthy donors (n=10): monocyte, myelocyte, B lymphocyte, and T lymphocyte. The quantitative parameters of WBC are directly obtained from the tomograms. Results. Our results show >99% accuracy for the binary classification of myeloids and lymphoids and >96% accuracy for the four-type classification of B and T lymphocytes, monocyte, and myelocytes. The feature learning capability of our approach is visualized via an unsupervised dimension reduction technique. Conclusion. We envision that the proposed cell classification framework can be easily integrated into existing blood cell investigation workflows, providing cost-effective and rapid diagnosis for hematologic malignancy.


Childhood anxious/withdrawn behaviour and later anxiety disorder: a network outcome analysis of a population cohort.
Several previous studies have identified a continuity between childhood anxiety/withdrawal and anxiety disorder (AD) in later life. However, not all children with anxiety/withdrawal problems will experience an AD in later life. Previous studies have shown that the severity of childhood anxiety/withdrawal accounts for some of the variability in AD outcomes. However, no studies to date have investigated how variation in features of anxiety/withdrawal may relate to continuity prognoses. The present research addresses this gap. Data were gathered as part of the Christchurch Health and Development Study, a 40-year population birth cohort of 1265 children born in Christchurch, New Zealand. Fifteen childhood anxiety/withdrawal items were measured at 7-9 years and AD outcomes were measured at various interviews from 15 to 40 years. Six network models were estimated. Two models estimated the network structure of childhood anxiety/withdrawal items independently for males and females. Four models estimated childhood anxiety/withdrawal items predicting adolescent AD (14-21 years) and adult AD (21-40 years) in both males and females. Approximately 40% of participants met the diagnostic criteria for an AD during both the adolescent (14-21 years) and adult (21-40 years) outcome periods. Outcome networks showed that items measuring social and emotional anxious/withdrawn behaviours most frequently predicted AD outcomes. Items measuring situation-based fears and authority figure-specific anxious/withdrawn behaviour did not consistently predict AD outcomes. This applied across both the male and female subsamples. Social and emotional anxious/withdrawn behaviours in middle childhood appear to carry increased risk for AD outcomes in both adolescence and adulthood.


Use of ofloxacin in open fractures and in the treatment of post-traumatic osteomyelitis.
In two open prospective studies, the efficacy and tolerance of ofloxacin in the prevention of infection in patients with open fractures (n = 58) and in the treatment of chronic post-traumatic osteomyelitis (n = 115) were examined. In the study with open fractures, bone and/or soft tissue infection occurred in only four cases (6.5%). During an observation period of at least 12 months, post-traumatic osteomyelitis was seen in two patients with III degree open fractures (9%), while in the groups with I degree and II degree open fractures no bone infection could be found. Therefore, the rate of post-traumatic osteomyelitis related to all patients was 3.3%. In the second study with 115 patients suffering from chronic post-traumatic osteomyelitis 141 different Gram-positive and Gram-negative pathogens were isolated. 73% were Gram-positive cocci with Staphylococcus aureus in more than 50% of the cases. An elimination rate of more than 90% was found in the Gram-positive and Gram-negative bacteria, leading to a clinical cure in 85% and a recurrence of infection in 5% of the cases. The tolerability of ofloxacin was excellent. No drug-related allergic reactions were observed. Diarrhoea and headache occurred in less than 2% of patients. With adequate surgical treatment, ofloxacin proved to be a useful antimicrobial agent in the prevention and therapy of bone infection.


Fatty acid based antimicrobials from Streptomyces sp. SORS-24, an endophyte isolated from Sonchus oleraceus.
Due to the rise in bacterial resistance towards various therapeutic agents, interest is now developing towards fatty acid based antimicrobials because of their non-specific mode of action. A strain SORS 24 isolated from Sonchus oleraceus (Sow thistle) showed significant activity against Escherichia coli ATCC 25922 (25 mm), Chlorella vulgaris (20 mm), Bacillus subtilis DSM 10 (ATCC 6051) and Pseudomonas sp. (15 mm). It displayed an LC50 value of 10 µg/ml against Artemia salina (Brine shrimp) nauplii and an EC50 value of 0.8 µg/ml in the (DPPH) diphenylpicrylhydrazyl antioxidant assay. The strain also displayed genotoxicity against a PolA deficient strain, E. coli K-12 AB 3027 (15 mm). Mass spectrometry (HPLC-MS) showed that the strain produced oleamide (9-Octadecenamide) and erucamide (13-Docosenamide). Both of the purified fatty acid amides showed prominent activity against B. subtilis DSM 10 (ATCC 6051) (20 mm) and E. coli ATCC 25922 (15 mm). Significant genotoxicity was observed against E. coli K-12 AB 3027 (15 mm). The 16S gene sequencing revealed that the strain belonged to species, Streptomyces tanashiensis. As far as our understanding, this is the first report of this species producing these fatty acid based antimicrobials.


Repeat sprint fatigue and altered neuromuscular performance in recreationally trained basketball players.
The primary aim of the present study was to investigate how the fatigue induced through a repeat sprint protocol acutely affected different measures of neuromuscular performance. Recreationally trained basketball players (n = 25) volunteered to participate in the study, and performed three countermovement jumps (CMJ), as well as three drop jumps (DJ) prior to a fatiguing repeat sprint protocol. These procedures were repeated two minutes, and 15 minutes, following the protocol. Various force-time metrics were extracted from the jump tasks, and linear mixed models with subject ID as the random factor, and time as the fixed factor were used to investigate changes across the three time points. To account for the performance during the repeat sprint protocol, a second, two factor model was performed with time and repeat sprint ability (RSA) as the fixed factors. Study results indicated that the sample as a whole merely experienced fatigue-induced decreases in jump height from pre-repeat sprint ability protocol (pre-RSA) within the CMJ compared to two minutes post-repeat sprint ability protocol (post-RSA1) and 15 minutes post-repeat sprint ability protocol (post-RSA2), while jump height within the DJ was only significantly different from pre-RSA at post-RSA1. Further, despite the implementation of the fatiguing RSA protocol, over the course of the three time-points, participants seemed to perform the two jump tasks more efficiently, seen through significantly lower contraction times, greater eccentric (ECC) peak power, and greater ECC mean deceleration force within the CMJ following the RSA task. The two-factor model revealed that several significant time*RSA interactions were found for metrics such as ECC peak velocity and peak power in the CMJ, as well as reactive strength index in the DJ. This suggests that the level of RSA influenced changes across CMJ and DJ characteristics and should be accounted for when interpreting fatigue-induced changes in neuromuscular performance.


Rotundic acid induces Cas3-MCF-7 cell apoptosis through the p53 pathway.
In the present study, the functions and mechanisms of rotundic acid (RA) underlying its induction of apoptosis in caspase-3-transfected MCF-7 human breast cancer cells (Cas3-MCF-7 cells) were investigated. RA induced apoptosis in Cas3-MCF-7 cells more efficiently compared with that in MCF-7 cells transfected with control plasmid. The results from an MTT assay demonstrated that RA effectively inhibited Cas3-MCF-7 cell viability in a dose-dependent manner and induced cell apoptosis via caspase-3 activity within 12 to 48 h. Western blotting and fluorescence-activated cell sorting demonstrated that RA initiated Cas3-MCF-7 cell apoptosis via p53 activation. The silencing of the p53 gene in the Cas3-MCF-7 cell line led to decreased RA-induced Cas3-MCF-7 cell caspase-3 activity and cell apoptosis. Collectively, the results of the present study indicate that caspase-3 serves a critical function in rotundic acid-induced apoptosis, and suggest that caspase-3 deficiency may contribute to the chemotherapy-resistance of breast cancer. Reconstitution of caspase-3 sensitizes MCF-7 breast cancer cells to chemotherapy. RA has the potential for development as a novel drug combined with reconstitution of caspase-3 gene therapy for the treatment of human breast cancer with caspase-3 deficiency.


Mining HIV protease cleavage data using genetic programming with a sum-product function.
In order to design effective HIV inhibitors, studying and understanding the mechanism of HIV protease cleavage specification is critical. Various methods have been developed to explore the specificity of HIV protease cleavage activity. However, success in both extracting discriminant rules and maintaining high prediction accuracy is still challenging. The earlier study had employed genetic programming with a min-max scoring function to extract discriminant rules with success. However, the decision will finally be degenerated to one residue making further improvement of the prediction accuracy difficult. The challenge of revising the min-max scoring function so as to improve the prediction accuracy motivated this study. This paper has designed a new scoring function called a sum-product function for extracting HIV protease cleavage discriminant rules using genetic programming methods. The experiments show that the new scoring function is superior to the min-max scoring function. The software package can be obtained by request to Dr Zheng Rong Yang.


Information technology tools to improve treatment of patients with depression: focus on guidelines implementation.
Information technology has the potential to improve and support the treatment of depression. Use of clinical guidelines can improve outcome of treatment, but implementation of guidelines is a demanding process and the resulting user compliance is often poor. Electronic health records, clinical decision support systems and other information technology tools seem at first glance to be a preferable way to implement clinical guidelines since they require user's active and problem oriented participation. This article reviews attempts made so far at use of information tools for implementation of clinical guidelines for depression treatment and discusses their effects. It turns out that there are few existing solutions, ambiguous effects and that usage is often limited. In future the factors determining development of successful electronic tools for clinical guidelines implementation will need to be further specified. Further research projects are underway in Slovenia to investigate these issues.


Cardiorespiratory response to lower body negative pressure.
The cardiovascular effects of supine lower body negative pressure (LBNP, 0 mm Hg, -8 mm Hg, -15 mm Hg, -25 mm Hg, -35 mm Hg, and -45 mm Hg) were studied in humans (n = 10). The LBNP's were applied in a random order (three per session) for 20 min, with 15 min between each LBNP. Leg blood flow, cardiac output (Q), stroke volume (SV) and estimated lung blood volume were significantly reduced at -15 mm Hg. Increasing LBNP to -35 mm Hg did not result in further changes. When the LBNP was increased to -45 mm Hg, Q and SV were lower than comparable values at -15 mm Hg. Heart rate was unchanged up to -25 mm Hg, after which it increased proportionally to the LBNP. Systolic blood pressure was maintained throughout. Diastolic blood pressure was unchanged below -45 mm Hg, but was significantly elevated at -45 mm Hg. Mean arterial pressure was maintained up to LBNP's of -35 mm Hg by increased vascular resistance, in spite of reduced thoracic blood volume, as indicated by reduced central venous pressure and Q. Greater levels of LBNP were outside the physiological adjustment range and blood pressure dropped progressively.


Challenges in constructing statistically based structure-activity relationship models for developmental toxicity.
Regulatory agencies are increasingly called upon to review large numbers of environmental contaminants that have not been characterized for their potential to pose a health risk. Additionally, there is special interest in protecting potentially sensitive subpopulations and identifying developmental toxicants that may be present in the environment. Thus, there is an urgent need for efficient methods to screen large numbers of chemicals for their potential to pose a developmental hazard. One potential screening method involves the use of statistically based structure-activity relationship (SAR) tools to predict activity of untested chemicals. Such systems rely on statistical analyses to discern relationships between structure and activity for a training set of substances. Predictions can then be made for an untested substance as long as its structural features are encompassed by chemicals of the training set. In theory, such systems could assist regulatory agencies in their screening efforts; however, to date, there has been little independent evaluation of these tools for this use. To contribute to such an evaluation, the International Life Sciences Institute Risk Science Institute (ILSI RSI) convened a Working Group to examine methodology used to construct statistically based SAR systems for developmental toxicity. This document reports on the deliberations of the Working Group, which concluded that an improved process is needed for utilizing developmental toxicity data in the construction of statistically based SAR models. The process must be objective, reproducible, rational and transparent. Moreover, it must be informed by the expertise of developmental toxicologists and biologists and must be subject to peer review.


Bleomycin-induced lung injury in the rat: effects of the platelet-activating factor (PAF) receptor antagonist BN 52021 and platelet depletion.
Bleomycin is a highly effective antitumor agent, but pulmonary toxicity, characterized by an acute inflammatory reaction and associated pulmonary edema, limits clinical use of the drug. Platelets and platelet-activating factor (PAF), a membrane-derived phospholipid, have been implicated in the mechanisms that can mediate pulmonary microvascular injury. We sought to investigate the role of PAF in bleomycin-induced lung injury in the rat, using the PAF receptor antagonist BN 52021; and the role of platelets though the use of an anti-platelet antibody. Lung injury was induced by intratracheal bleomycin (1.5 mg) and assessed by measurements of lung wet weight and total pulmonary extravascular albumin space (TPEAS). Bleomycin caused a significant increase in both indices after 48 hr, compared with control animals (p less than 0.05). A single dose of BN 52021 (20 mg/kg orally) significantly reduced the bleomycin-induced increase in lung weight, but not the rise in TPEAS (p greater than 0.05). Increasing the dose of BN 52021 (20 mg/kg/12 hr, orally) had no additional effect. Reducing circulating platelet numbers by approximately 75% had no effect on either the increase in lung weight or TPEAS, observed 48 hr after bleomycin (p greater than 0.05). PAF may partially contribute to the acute inflammatory reaction seen after intratracheal bleomycin in rats.


Young Basketball Players' Multiple Object Tracking Skills Were Unaffected by Stroop-Induced Mental Fatigue.
We aimed to examine the acute effect of mental fatigue on young basketball players' three-dimensional multiple object tracking (3D-MOT) skills. Our participants were 12 adolescent basketball players (M age = 16.66, SD = 1.87 years; M years of practice = 2.66, SD = 1.07 years). In nine lab visits, we used visits 1 to 7 to familiarize participants with 3D-MOT, a subjective scale of mental fatigue, and a Stroop task involving mental set shifting. In the last two visits, participants performed in both experimental (EXP) and control (CON) conditions that were presented in randomized order. In the EXP condition, participants performed 3D-MOT pre- and post-60 minutes of induced mental fatigue; in the CON condition, they watched a documentary. After each condition, B participants performed the National Aeronautics and Space Administration Task Load Index (NASA-TLX). 3D-MOT performance measures were the "score" and "fastest trial score success." The response time on the Stroop tasks increased throughout the mental fatigue inducement in the experimental condition (p = .0037). The NASA-TLX responses were higher following the EXP condition than following the CON condition for mental demand, temporal demand, and performance (all ps < .05). Still, there were no significant EXP versus CON differences on the 3D-MOT performance indicators.


Pain scoring--a method for assessing acute antianginal therapy comparison of the response to acute sublingual administration of an isosorbide dinitrate tablet, isosorbide dinitrate spray and nitroglycerin spray in unstable angina.
It is difficult to assess acute therapeutic intervention therapy, particularly in patients with unstable angina. Our aim was to evaluate the feasibility of a pain-scoring method and to compare the response to sublingual administration of an isosorbide dinitrate (ISDN) tablet, ISDN spray or nitroglycerin (NTG) spray. Pain scoring was assessed by the subjective grading of the patients' pain severity from 1 to 10. We studied 205 patients (mean age 66 +/- 13 years). Pain attenuation, defined as at least 50% reduction in pain intensity, occurred in the ISDN tablet, ISDN spray and NTG spray groups after 360 +/- 290, 318 +/- 289 and 233 +/- 271 s, respectively (p = 0.0005). In conclusion, pain scoring is a feasible and useful clinical method to assess antianginal therapy in unstable angina patients. Sublingual nitrate sprays, particularly NTG, seem to alleviate anginal pain faster than ISDN tablets in this patient population.


Distinctive morphometric measurement of frontal sinuses among the female ethnic populations living in Karachi.
To determine uniqueness of frontal air sinuses in female ethnic populations living in Karachi. The cross-sectional descriptive study was conducted at the Radiology Department of Jinnah Postgraduate Medical Centre, Karachi, from November 2018 to April 2019, and comprised adult females who were divided into four equal ethnic groups. Frontal sinus X-ray radiography was done using the Water's view. Width, height and area of the right and left frontal sinuses were measured. The radiographs were saved in photograph format and measurements were done using RadiAnt DICOM software. Measurements of height, width and area were noted. Data was analysed using SPSS 23. There were 108 females; 27(25%) in each of the four groups. The overall mean age was 35.14±8.68 years. Variability in terms of width, height and area were noted in both right and left frontal air sinuses (p<0.001). The width, height and area of right and left frontal sinuses showed variability among female ethnic groups living in Karachi.


Epidermal langerhans cells of AIDS patients express HIV-1 regulatory and structural genes.
In this study we searched for the presence of human immunodeficiency virus (HIV-1)-spliced mRNA in epidermal cells from AIDS patients. Using reverse polymerase chain reaction and Southern hybridization we detected mRNA for HIV-1 regulatory (tat, rev, nef) and structural genes (env) in epidermal cells highly enriched for Langerhans cells, but not in Langerhans cell-depleted epidermal cells in two of three HIV-1-infected patients tested. In contrast to the expression of HIV-1 mRNA, T-cell-specific mRNA was readily detectable in all preparations of Langerhans cell-depleted but in only one preparation of Langerhans cell-enriched epidermal cells. This indicates that contaminating T cells are a very unlikely source of virus-specific mRNA in our epidermal cell preparations. Our data suggest that Langerhans cells are the main, if not the only, cell type infected with HIV-1 within the epidermis of AIDS patients and demonstrate that HIV-1 regulatory as well as structural genes are transcribed in these cells.


[A new German Scale for Assessing Parental Stress after Preterm Birth (PSS:NICU_German/2-scales)].
Background Preterm birth is known to be a stressful and anxious situation for parents, which might have long-term impact on the psychological health of mothers and even on the development of their preterm infants. Objective The Parental Stressor Scale: Neonatal Intensive Care Unit (PSS:NICU) was developed to assess parental stress after preterm birth through three subscales [1]. The aim of the present study was to examine the psychometric properties and the dimensionality of the German version of the PSS:NICU to develop a reliable German version of the PSS:NICU. Methods For the development (exploratory factor analysis) 100 parents of preterm infants answered the questionnaire. Results The Sights and Sounds subscale was removed from the German version of the PSS:NICU due to low number of items. NICU_German/2-scales was developed consisting of 2 subscales: Infant Behavior and Appearance (7 Items, Cronbach's α=0,82) and Parental Role Alteration (6 Items, Cronbach's α=0,87). Conclusions The PSS:NICU_German/2-scales is a reliable and economic scale for the assessment of parental stress after preterm birth.


Apoptosis is involved in paraoxon-induced histological changes in rat cerebellum.
Acute toxicity of organophosphorus compounds is primarily caused by inhibition of acetylcholinesterase (AChE) at cholinergic synapses. The current study was designed to investigate the effects of paraoxon on histological changes as well as the role of mitochondrion-dependent apoptosis in causing this damage in the rat cerebellum. Adult male Wistar rats were intraperitoneally injected with paraoxon at 0.3, 0.7, or 1 mg/kg. Control animals were injected with corn oil as a vehicle. At 14 or 28 days after intoxication, histological changes and alterations in the expression of apoptosis-related proteins, including Bax, Bcl-2, and caspase-3, were investigated in the cerebellum using cresyl violet staining and western blotting, respectively. Findings showed the decreased thickness of both molecular and granular layers and reduction in the number of Purkinje cells in animals treated with a higher convulsive dose of paraoxon (1 mg/kg). In addition, exposure of rats to 1 mg/kg of paraoxon activated apoptosis pathway confirmed by an increase in Bax and caspase-3 and a decrease in Bcl-2 protein levels. According to our results, cerebellar histological changes and alterations in the expression of apoptosis-related proteins occur following exposure to a high convulsive dose of paraoxon and persist for a long time.


A paradigm of uphill running.
The biomechanical management of bioenergetics of runners when running uphill was investigated. Several metabolic and mechanical variables have been studied simultaneously to spread light on the locomotory strategy operated by humans for effective locomotion. The studied variables were: heart rate, heart rate variability, oxygen intake and blood lactate, metabolic cost, kinematics, ground reaction force and muscular activity. 18 high-level competitive male runners ran at 70% VO2max on different uphill slope conditions: 0%, 2% and 7%. Modifications were significant in almost all variables studied, and were more pronounced with increasing incline. Step frequency/length and ground reaction force are adjusted to cope with both the task of uphill progression and the available (limited) metabolic power. From 0% to 7% slope, step frequency and ground reaction force and metabolic cost increased concurrently by 4%, 12% and 53%, respectively (with a 4% step length decrease as well). It is hypothesised that this biomechanical management is allowed by an environment-body communication performed by means of specific muscular activity.


Longitudinal and bidirectional associations between family conflict and adolescents' e-cigarette use.
This study examined potential longitudinal and bidirectional relationships between family conflict and adolescent e-cigarette use, and whether gender moderated these associations. Adolescents (NT1 = 1334; Mage = 13.11, SD = 0.82; 52% female; 50% White) from the United States completed surveys in the spring of 2016 and again in the fall of 2017. Logistic regression analyses indicated that after controlling for previous e-cigarette use, family conflict was positively associated with a greater likelihood of e-cigarette use 6 months later. Results from multiple regression analyses indicated that after controlling for previous family conflict, e-cigarette use was associated with increases in later family conflict, particularly for girls. Study findings highlight reducing family conflict and supporting family functioning as a possible intervention target for adolescent e-cigarette use, a major public health problem.


Long-term results of trapeziometacarpal silicone arthroplasty.
Long-term results of trapeziometacarpal (TMC) joint silicone arthroplasty were evaluated. From 1975 to 1990, 90 TMC joint silicone implants were placed in 85 patients with TMC joint arthritis caused by osteoarthritis and inflammatory arthritis. Sixty-two implants in 58 patients were available for follow-up evaluation averaging 16.4 years (range, 10-25 years) with a 10-year minimum. Patient satisfaction; range of motion; grip, key pinch, and tip pinch strengths; and radiographs were recorded. Eighty-four percent of the thumbs had satisfactory results with good-to-excellent pain relief and function. Grip, key pinch, and tip pinch strengths increased. The number of thumb tips able to touch the palmar base of the small finger increased. Subluxation was apparent in 19% of implants but was not clinically important; however, implant fracture occurred in 6% and required revision. None of the 62 implants had frank silicone synovitis. Silicone arthroplasty seems to be a reliable option for disabling TMC joint arthritis and is associated with a high degree of patient satisfaction.


Homocysteine, renin and aldosterone in patients with Cushing's syndrome.
In the present study, we assessed the levels of fasting homocysteine in patients with active Cushing's syndrome using two different assay methods. To determine a possible link between homocysteine and renin-angiotensin-aldosterone system (RAAS), nine patients with Cushing's syndrome and nine patients with metabolic syndrome were given a 1-month treatment with angiotensin II (AII) receptor blocker valsartan. Plasma homocysteine, active renin and aldosterone did not differ significantly among patients with Cushing's syndrome, patients with metabolic syndrome and controls. As expected, active renin increased significantly during valsartan treatment in patients with Cushing's syndrome as well as in patients with metabolic syndrome. Plasma homocysteine did not change after valsartan treatment, suggesting a lack of direct relationship between homocysteine and RAAS. Our data suggest that homocysteine might not serve as a reliable marker of endogenous hypercortisolism or of cardiovascular risk associated with Cushing's syndrome and metabolic syndrome.


Engaging Nursing Voice and Presence During the Federal Election Campaign 2015.
During the Canadian federal election in 2015, we conducted a systematic inquiry into the methods and messages developed by national nursing organizations to communicate their policy platforms and their strategies for member and public engagement. Throughout the campaign and in the post-election period, the nursing organizations presented an outward-looking view to improve health and healthcare for Canadians. We observed ways in which they adopted a nursing lens on the issues by showcasing background research, by drawing on relevant nursing knowledge and by communicating clear policy messages based on nursing expertise. The organizations and their members were effective in using social media as a primary tool for reaching out to the candidates, the public and the opinion leaders. The increasing engagement of nursing students in political action is noted as a promising sign for the future impact of the profession. Although the nursing presence was visible in this election, healthcare did not become a strong issue for the public and the political parties. We include a section on post-election uptake of issues raised during the campaign. We conclude with a call for a policy research agenda that deepens our knowledge of political advocacy with a view to identifying how patterns of engagement are defining nursing's collective influence and contributions to health equity.


The use of algeness in the face and neck: a safe, alternative filler for cosmetics and reconstruction.
The search for effectiveness and safety in the use of dermal fillers, is an ongoing challenge for aesthetic physicians, plastic surgeons and the science of bioengineering. Understanding the variety of characteristics, capabilities, advantages and disadvantages of available injectables is essential to reduce complication rates and achieve satisfying aesthetic and functional results. Algeness is a 100% natural, biodegradable tissue implant, consisting of a gel derived from agarose. This paper analyzes the use of this newly introduced agarose gel as an alternative filler in the face and neck for aesthetic and functional indications. All participants gave informed consent before taking part and there was no ethics approval required. As this work describes opinions based on clinical experienced physicians and not the results of a monocentric study. Algeness is competitive with other available hydrophilic biomaterials, such as hyaluronic acid, and has the advantage of its unique hydrocolloid nature. Compared to other injectables, it exhibits good tolerability, excellent persistence, negligible immunological reaction, biocompatibility and maximal safety-all properties combined with immediate volume restoration and predictable outcomes. "What you see (on injection), is what you get (as a result)". Level of evidence: Level V, opinions based on clinical experience.


Hereditary persistence of fetal hemoglobin presenting as fetal-maternal hemorrhage.
This report describes a case of hereditary persistence of fetal hemoglobin (HPFH) presenting initially as a marginal placental abruption in a primiparous woman at 27 weeks gestation. Persistent but erratic elevation of percent hemoglobin F positive cells, as determined by a modified Kleihauer-Betke method, complicated the remainder of her pregnancy. The clinical impression of placental abruption with possible extension could not be documented by ultrasound or examination of the placenta at delivery. Hemoglobin electrophoresis followed by quantitative fetal hemoglobin first suggested the diagnosis of HPFH, which was confirmed seven months postpartum. Furthermore, the magnitude of percent positive F-cells could be profoundly altered by subtle changes in pH of the acid elution reagent. This case demonstrates that positive acid elution tests for maternal-fetal transfusion may be caused by elevated maternal hemoglobin F. Erratic results, elevated quantitative hemoglobin-F and sensitivity to reagent pH should alert the pathologist to this diagnosis and alter clinical management.


Identifying and Understanding the Health Information Experiences and Preferences of Individuals With TBI, SCI, and Burn Injuries.
Traumatic brain injury, spinal cord injury, and burn injury can cause lifelong disability and changes in quality of life. In order to meet the challenges of postinjury life, various types of health information are needed. We sought to identify preferred sources of health information and services for persons with these injuries and discover how accessibility could be improved. Thirty-three persons with injury participated in semistructured interviews. Responses to interview questions were coded using NVivo. Participants' difficulties accessing health information varied by injury type and individually. The majority of respondents found information via the Internet and advocated its use when asked to describe their ideal health information system. Nearly all participants supported the development of a comprehensive care website. When searching for health information, participants sought doctor and support group networks, long-term health outcomes, and treatments specific to their injury. To optimize the quality of health information resources, Internet-based health-care platforms should add or highlight access points to connect patients to medical professionals and support networks while aggregating specialized, injury-specific research and treatment information.


Review of microarray experimental design strategies for genetical genomics studies.
Genetical genomics approaches provide a powerful tool for studying the genetic mechanisms governing variation in complex traits. By combining information on phenotypic traits, pedigree structure, molecular markers, and gene expression, such studies can be used for estimating heritability of mRNA transcript abundances, for mapping expression quantitative trait loci (eQTL), and for inferring regulatory gene networks. Microarray experiments, however, can be extremely costly and time consuming, which may limit sample sizes and statistical power. Thus it is crucial to optimize experimental designs by carefully choosing the subjects to be assayed, within a selective profiling approach, and by cautiously controlling systematic factors affecting the system. Also, a rigorous strategy should be used for allocating mRNA samples across assay batches, slides, and dye labeling, so that effects of interest are not confounded with nuisance factors. In this presentation, we review some selective profiling strategies for genetical genomics studies, including the selection of individuals for increased genetic dissimilarity and for a higher number of recombination events. Efficient designs for studying epistasis are also discussed, as well as experiments for inferring heritability of transcriptional levels. It is shown that solving an optimal design problem generally requires a numerical implementation and that the optimality criteria should be intimately related to the goals of the experiment, such as the estimation of additive, dominance, and interacting effects, localizing putative eQTL, or inferring genetic and environmental variance components associated with transcriptional abundances.


Preparation and biological evaluation of (64)Cu labeled Tyr(3)-octreotate using a phosphonic acid-based cross-bridged macrocyclic chelator.
Somatostatin receptors (SSTr) are overexpressed in a wide range of neuroendocrine tumors, making them excellent targets for nuclear imaging and therapy, and radiolabeled somatostatin analogues have been investigated for positron emission tomography imaging and radionuclide therapy of SSTr-positive tumors, especially of the subtype-2 (SSTr2). The aim of this study was to develop a somatostatin analogue, Tyr(3)-octreotate (Y3-TATE), conjugated to a novel cross-bridged macrocyclic chelator, 11-carboxymethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4-methanephosphonic acid (CB-TE1A1P). Unlike traditional cross-bridged macrocycles, such as 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A), CB-TE1A1P-Y3-TATE was radiolabeled with (64)Cu in high purity and high specific activity using mild conditions. Saturation binding assays revealed that (64)Cu-CB-TE1A1P-Y3-TATE had comparable binding affinity but bound to more binding sites in AR42J rat pancreatic tumor cell membranes than (64)Cu-CB-TE2A-Y3-TATE. Both radiopharmaceuticals showed comparable uptake in SSTr2 positive tissues in AR42J tumor-bearing rats. (64)Cu-CB-TE1A1P-Y3-TATE demonstrated improved blood clearance compared to (64)Cu-CB-TE2A-Y3-TATE, as the tumor/blood ratios of (64)Cu-CB-TE1A1P-Y3-TATE were shown to be significantly higher than those of (64)Cu-CB-TE2A-Y3-TATE at 4 and 24 h postinjection. (64)Cu-CB-TE1A1P-Y3-TATE, in spite of a relatively high kidney uptake, accumulated less in nontarget organs such as liver, lung, and bone. Small animal PET/CT imaging of (64)Cu-CB-TE1A1P-Y3-TATE in AR42J tumor bearing rats validated significant uptake and good contrast in the tumor. This study suggests that CB-TE1A1P is a promising bifunctional chelator for (64)Cu-labeled for Y3-TATE, owing to high binding affinity and target tissue uptake, the ability to radiolabel the agent at lower temperatures, and improved tumor/nontarget organ ratios over (64)Cu-CB-TE2A-Y3-TATE.


Development and Piloting of a Patient-Centered Report Design for Stress Myocardial Perfusion Imaging Results.
The management of coronary disease epitomizes the call to better engage patients in shared medical decision-making. Myocardial perfusion imaging (MPI) is the foundation of diagnosis, risk stratification, and subsequent therapy; however, MPI reports are currently interpretable by specialists but not patients. To design and test a patient-centered report for stress MPI test results. This qualitative study of outpatients who underwent an MPI stress test and clinicians used a mixed methods approach. Phase 1 (December 2018 to July 2019) used qualitative methods to design a patient-centered reporting tool, with 5 focus groups with 36 patients and 2 focus groups with 27 clinicians. Phase 2 (June to September 2019) consisted of pilot testing the reporting tool with feedback from a structured survey given to patients who received MPI reports before and after implementing the tool. Key themes around patient experiences with the current MPI reporting and their desire for a more useful report were identified, which led to a sample reporting tool after serial iterations with feedback. Differences in patient knowledge and engagement were assessed between patients before and after implementation of the new reporting tool using χ2 tests. From patient focus groups (26 patients; mean [SD] age, 66.3 [9.6] years, 9 [35%] women), 3 themes on the inadequacies of current MPI reporting were identified: (1) inconsistent delivery of results, (2) use of medical jargon, and (3) unclear posttest course. We identified 5 themes for a more patient-centered MPI report: desire for written information, discussion of the report with medical personnel, presentation of results in simple language with use of visual graphics, comparisons with normal results, and personalized risk estimates. In a pilot survey with 123 patients split into a pre-implementation group (69 patients; mean [SD] age, 68.2 [8.5] years; 27 [51%] women) and a postimplementation group (54 patients; mean [SD] age, 66.4 [8.7] years; 30 [56%] women), the patient-centered report led to more patients reading the entire report (45 [83%] vs 46 [67%]; P = .04) and improved knowledge of future risk of cardiac events (41 [76%] vs 20 [29%]; P < .001). There was also a numerically higher percentage of patients who found the report easy to read (45 [83%] vs 44 [68%]; P = .05) and understand (42 [78%] vs 43 [66%]; P = .16), although these results were not statistically significant. This study identified key elements of a patient-centered report design for stress MPI test results, which improved patient engagement and knowledge. These preliminary data support further implementation and study of a more patient-centered MPI report.


Ventricular fibrillation during carotid endarterectomy and bailout stenting: a case report.
Carotid artery manipulation is not a special technique but reports of intraoperative ventricular fibrillation are rare. The risk of fatal arrhythmias may be hidden behind routine surgical techniques and anesthetic management. We focused on QT prolongation and QT dispersion. A 77-year-old man underwent carotid endarterectomy and bailout stenting. Although there were no obvious preoperative risk factors for intraoperative ventricular tachyarrhythmia, ventricular fibrillation (VF) had occurred during a maneuver of the carotid artery under hypercapnia. QTc was prolonged from 317 ms before surgery to 458 ms before the onset of VF. QTc dispersion between leads II and III was also increased to 50 ms. Hypomagnesemia was noted after resuscitation by electrical defibrillation, adrenaline, and noradrenaline. We considered that the combination of multiple risk factors led to the development of ventricular fibrillation. It should be noted that carotid artery manipulation has the potential to cause arrhythmias.


[Review and comparison of culture-techniques for articular chondrocytes].
In-vitro techniques for articular chondrocytes allow the analysis of their metabolism in the presence and absence of mediators or drugs against osteoarthritis or rheumatoid arthritis, as well as the synthesis of de-novo cartilage tissue for implantation into articular defects in vivo. This review aims to give an overview about the basics of different methods of cultivation of articular chondrocytes and about several specific demands (e.g., phenotypical stability with synthesis of aggrecan and type-II collagen, no cell-to-cell contact, low proliferation rates, low matrix molecule turn-over) to such methods. Current techniques for the cultivation of articular chondrocytes and their development were identified via "medline". Their evaluation was based on our own experience and on data from the literature. Two- and three-dimensional culture systems are employed to maintain articular chondrocytes in vitro. Two-dimensional cultures (monolayer) support the proliferation of articular chondrocytes, but lead to a de-differentiation to fibroblast-like cells. Three-dimensional set-ups (e.g., organ, alginate, agarose cultures) not only maintain the articular cartilage phenotype, but they also support the re-differentiation of de-differentiated chondrocytes. The choice of a culture system for in-vitro studies with articular chondrocytes should be adapted to the question asked.


Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3.
Osteoblast-specific expression of the bone protein osteocalcin is controlled at the transcriptional level by the steroid hormone 1 alpha,25-dihydroxyvitamin D3. As this protein may represent a marker for bone activity in human disease, we examined the regulation of its expression at the molecular level by evaluating human osteocalcin gene promoter function. We describe regions within the promoter that contribute to basal expression of the gene in osteoblast-like cells in culture. Further, we define a 21-base-pair DNA element with the sequence 5'-GTGACTCACCGGGTGAACGGG-3', which acts in cis to mediate 1 alpha,25-dihydroxyvitamin D3 inducibility of the osteocalcin gene. This response element bears sequence similarity with other short DNA segments, particularly those for estrogen and thyroid hormone, which act together with their respective trans-acting receptors to modulate gene transcription.