Severe mitral valve dysfunction due to unsuspected granulomatous myocarditis: successful cardiac transplantation following attempted mitral valve repair.
Granulomatous involvement of the myocardium is a rapidly fatal disease of uncertain aetiology rarely diagnosed premorbidly. We report a patient who presented with mitral valve incompetence and congestive cardiac failure who underwent a successful mitral valve repair but could not be weaned from cardiopulmonary bypass. Urgent heart transplantation was successfully performed and histological studies of the explanted heart revealed granulomatous myocarditis involving the mitral subvalvular apparatus. Endomyocardial biopsy may be necessary in young patients presenting with mitral valve disease of unknown aetiology.


Biofouling control using microparticles carrying a biocide.
This study presents a new technological approach to minimize the use of antimicrobial (AMB) agents and their deleterious effects, based on the principle of drug-delivery systems whereby the AMB chemicals are transported on microparticles. The efficacy of microparticles carrying the quaternary ammonium compound (QAC), benzyldimethyldodecyl ammonium chloride (BDMDAC), was assessed against Pseudomonas fluorescens in both the planktonic and the biofilm state. The microparticles were prepared using a layer-by-layer (LBL) self-assembly technique. Oppositely charged molecules of polyethyleneimine (PEI), sodium polystyrene sulfonate (PSS), and BDMDAC were assembled on polystyrene (PS) cores. BDMDAC-coated particles were observed by CryoSEM and their composition analyzed by X-ray microanalysis. Zeta potential measurements indicated that changes in surface charge were compatible with a BDMDAC/particle interaction. This biocidal carrier structure had significant stability, verified by the release of only 15% of the BDMDAC when immersed in water for 18 months. Biocidal carrier activity was evaluated by determining the survival ratio of P. fluorescens planktonic and biofilm cells after different exposure periods to BDMDAC-coated particles. Tests with biofilm cells were also performed with the free QAC. An efficient AMB effect (minimum bactericidal concentration) against suspended cells was found for a concentration of 9.2 mg l(-1) of BDMDAC on coated particles after incubation for 30 min and 6.5 mg l(-1) of BDMDAC on coated particles after 60 min. Exposure of biofilms to PS-PEI/PSS/BDMDAC (0.87 mg l(-1)) resulted in a decrease in viability of 60.5% and 66.5% of the total biofilm population for 30 and 60 min exposure times, respectively. Exposure for 60 min to 6.33 mg l(-1) and 11.75 mg l(-1) of BDMDAC in PS-PEI/PSS/BDMDAC particles promoted inactivation of 80.6% and 87.2% of the total population, respectively. The AMB effects obtained with the application of free BDMDAC were statistically similar to those promoted by the application of BDMDAC coated particles. The overall results indicate that this novel AMB strategy has potential for the control of microbial growth of planktonic cells and biofouling. Moreover, the technique allows the reuse of AMB molecules and consequently reduces the environmental risks associated with excessive use of AMB agents, thereby providing real benefits to public health.


Effects of Tobacco Usage and Antiretroviral Therapy on Biomarkers of Systemic Immune Activation in HIV-Infected Participants.
Like HIV infection, smoking, which is common among HIV-infected persons, is associated with chronic, systemic inflammation. However, the possible augmentative effects of HIV infection and smoking and other types of tobacco usage on indices of systemic inflammation and the impact of combination antiretroviral therapy (cART) thereon remain largely unexplored and represent the focus of the current study. Of the total number of HIV-infected persons recruited to the study (n = 199), 100 were categorised as pre-cART and 99 as virally suppressed (HIV viral load < 40 copies/mL). According to serum cotinine levels, 144 and 55 participants were categorised as nonusers and users of tobacco, respectively. In addition to cytokines (IL-6, IL-8, and TNF-α) and chemokines (IP-10, MIG, IL-8, MCP-1, and RANTES), other biomarkers of systemic inflammation included C-reactive protein (CRP), β2-microglobulin, and those of neutrophil activation [ICAM-1, L-selectin, matrix metalloproteinase-9 (MMP-9)], microbial translocation (soluble CD14, LPS-binding protein), and oxidative stress (cyclophilin A, surfactant D). These were measured using multiplex bead array, ELISA, and immunonephelometric procedures. Viral suppression was associated with significant decreases in the levels of most of the biomarkers tested (P < 0.0037-0.0008), with the exceptions of CRP, cyclophilin A, and MMP-9. With respect to tobacco usage, irrespective of cART status, circulating levels of β2-microglobulin, cyclophilin A, and RANTES were significantly elevated (P < 0.042-0.012) in users vs nonusers. Additional analysis of the groups of tobacco users and nonusers according to cART status revealed high levels of RANTES in pre-cART/tobacco users relative to the three other subgroups (P < 0.004-0.0001), while more modest increases in cyclophilin A and MMP-9 (P < 0.019-0.027) were observed in comparison with the cART/tobacco user subgroup. Notwithstanding the efficacy of cART in attenuating HIV-associated, chronic systemic inflammation, the current study has identified RANTES as being significantly and seemingly selectively increased in those with active HIV infection who use tobacco, a mechanism which may underpin augmentative proinflammatory activity.


Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene.
Calcitonin measurement is advised in the diagnosis of thyroid nodules, as it is an accurate marker of medullary thyroid carcinoma (MTC). C-cell hyperplasia (CCH)-induced hypercalcitoninemia cannot be distinguished from that induced by MTC, unless surgery is performed. We report the clinical and biological features of a patient with a family history of cancer, including melanoma and pancreatic cancer, who had previously undergone surgery for melanoma. He presented the unusual association of papillary thyroid carcinoma (PTC), normocalcemic hyperparathyroidism, and hypercalcitoninemia with a pathological response to pentagastrin, which was histologically deemed secondary to CCH. Multiple endocrine neoplasia (MEN) 2A was diagnosed. RET gene analysis showed a p.V804M missense mutation in exon 14, a low- but variably penetrant defect found in both sporadic and MEN2A-associated MTC/CCH, and a p.G691S polymorphism in exon 11. Furthermore, the germline P48T mutation was found in the CDKN2A gene exon 1, which is known to be associated with melanoma and pancreatic cancer. The patient showed the uncommon coexistence of a germline mutation in two suppressor genes, RET and CDKN2A; this finding, deemed to be a mere coincidence, did not modify the phenotype expected by each single mutation. CCH associated with V804M RET mutation is a precancerous condition and surgery is recommended. In order to exclude MTC, surgery is advised in patients with a pathological calcitonin response to pentagastrin, in the absence of thyroid autoimmunity. CCH-induced hypercalcitoninemia can be associated with thyroid cancers other than MTC (e.g., PTC). Family history is important in scheduling specific genetic screening in high-risk patients and their relatives.


Police in an intensive care unit: what can happen?
During spring 2009 a Swedish senior paediatric intensivist and associate professor was detained and later prosecuted for mercy-killing a child with severe brain damage. The intensivist was accused of having used high doses of thiopental after having withdrawn life-sustaining treatment when the child was imminently dying. After more than 2.5 years of investigation the physician was acquitted by the Stockholm City Court. The court additionally stated that the physician had provided good end-of-life care. Since the trial it has become evident that the accusation was based on a problematic medicolegal report. Nevertheless, the event has had severe negative consequences for the physician personally and professionally, and probably also, in general, for patients in the final stage of life. This case illustrates, together with other cases, that there is a lack of correspondence between ethical soft law/healthcare law and the Penal Code. To optimise medical practice we suggest that the criminal law be carefully examined and if possible changed. Furthermore, we suggest a peer-review system for assessing medicolegal reports in cases of suspected homicide.


Complexity in the context of palliative care: a systematic review.
People receiving palliative care have complex, wide-ranging, and changing needs, not just physical distress, but also psychosocial, practical, and spiritual. Influences on complexity in palliative care are different among healthcare providers and may depend on diverse aspects of the patient's condition, time, and environment. Therefore, this study aimed to integrate and describe the perspective of complexity in palliative care. We used an integrative review, which is a method of compiling, summarizing, and analyzing existing insights from previous studies. We conducted an electronic literature search in MEDLINE (Ovid), PsycINFO (EBSCOhost), Web of Science Core Collection, and CINAHL (EBSCOhost), examining literature from May 1972 to September 2020 and updated in December 2020. Subsequently, synthesis without meta-analysis of the findings was completed. We identified 32 peer-reviewed articles published in English. The included literature mainly originated in Europe and the United States. The research methods included quantitative studies (n=13), qualitative studies (n=12), case studies (n=3), and reviews (n=4). We identified 29 that influenced complexity in palliative care, 25 perceptions of the patient, including background and physical, psychological, social, and spiritual; two perceptions in the healthcare setting; and two perceptions in the socio-cultural setting. Above all, the perceptions of complexity in palliative care included younger age, prognosis, and spirituality. In addition, we added the identified perceptions of complexity with references to the complexity model in palliative care. Although this review was limited in its search strategy and some data sources may have been overlooked, it still provided perceptions that influenced complexity in palliative care. These complex influencing perceptions are necessary for patients to receive appropriate palliative care at the right time and for health care providers to conduct a multi-disciplinary team approach. Furthermore, longitudinal prospective data are needed to examine the changes and relationships among complexity over time.


Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis.
Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.


No Benefit of Robotic-Assisted over Computer-Assisted Surgery for Achieving Neutral Coronal Alignment in Total Knee Arthroplasty.
The use of robotic-assisted surgery (RAS) in total knee arthroplasty (TKA) is becoming increasingly popular due to better precision, potentially superior outcomes and the ability to achieve alternative alignment strategies. The most commonly used alignment strategy with RAS is a modification of mechanical alignment (MA), labeled adjusted MA (aMA). This strategy allows slight joint line obliquity of the tibial component to achieve superior balancing. In the present study, we compared coronal alignment after TKA using RAS with aMA and computer-assisted surgery (CAS) with MA that has been the standard in the center for more than 10 years. We analyzed a prospectively collected database of patients undergoing TKA in a single center. Lateral distal femoral angle (LDFA) and medial proximal tibial angle (MPTA) were compared for both techniques. In 140 patients, 68 CASs and 72 RASs, we observed no difference in postoperative measurements (median 90 degrees for all, LDFA p = 0.676, MPTA p = 0.947) and no difference in outliers <2 degrees (LDFA p = 0.540, MPTA p = 0.250). The present study demonstrates no benefit in eliminating outliers or achieving neutral alignment of both the femoral and the tibial components in robotic-assisted versus computer-assisted TKA if MA is the target. To utilize the precision of RAS, it is recommended to aim for more personalized alignment strategies. The level of evidence is level III retrospective study.


Neurological prognostication after cardiac arrest--recommendations from the Swedish Resuscitation Council.
Cardiopulmonary resuscitation is started in 5000 victims of out-of-hospital cardiac arrest in Sweden each year and the survival rate is approximately 10%. The subsequent development of a global ischaemic brain injury is the major determinant of the neurological prognosis for those patients who reach the hospital alive. Induced hypothermia is a recommended treatment after cardiac arrest and has been implemented in most Swedish hospitals. Recent studies indicate that induced hypothermia may affect neurological prognostication and previous international recommendations are therefore no longer valid when hypothermia is applied. An expert group from the Swedish Resuscitation Council has reviewed the literature and made recommendations taking into account the effects of induced hypothermia and concomitant sedation. A delayed neurological evaluation at 72 h after rewarming is recommended for hypothermia treated patients. This evaluation should be based on several independent methods and the possibility of lingering pharmacological effects should be considered.


The comparability of mother-report structured interviews and checklists for the quantification of youth externalizing symptoms.
Although structured interviews are assumed to be scientifically superior to checklists for measuring youth psychopathology, few studies have tested this hypothesis. Interviews place a much greater burden on respondents, making it critical to determine their added value when quantifying psychiatric symptoms. Confirmatory factor analysis was used to compare interviews and checklists in community (N = 251) and clinically referred (N = 406) samples of youth aged 5 to 17 years. We examined the associations between mother-reported externalizing symptoms assessed by interview versus checklist against (a) teacher-reported externalizing symptoms, and (b) child's gender, academic performance, single- versus two-parent family, and family income. Models in which associations were estimated freely were contrasted to models in which the interview and the checklist were constrained to have equal associations with the variables. Finding these models fit comparably would suggest no difference between interviews and checklists. In the community sample, both the constrained and unconstrained models provided comparable fit to the data, suggesting no marked differences between interviews and checklists. In the clinical sample, associations with the interview were generally stronger. Reducing the number of items on the interview to match those on the 6-item checklist eliminated these differences, suggesting that the increased reliability of the interview scales, afforded by additional items, enhanced their quantification of psychopathology. Consistent with previous studies, interviews were not notably superior to checklists for the measurement of externalizing symptoms. When only a few items are used, small performance differences between checklists and interviews may be due to scale length.


Impaired guanosine 3',5'-cyclic phosphate production in severe pregnancy-induced hypertension with high plasma levels of atrial and brain natriuretic peptides.
To investigate the activation of particulate guanylate cyclase in pregnant women with pregnancy-induced hypertension (PIH), plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and guanosine 3',5'-cyclic phosphate (cGMP) were measured by radioimmunoassays specific to each substance. Ten normal nonpregnant women, and 30 normal pregnant women, 17 pregnant women with mild PIH and 11 pregnant women with severe PIH in the third trimester were included in this retrospective observational study. The diagnosis and classification of hypertension were carried out according to the technical bulletin (No. 91) of the American College of Obstetricians and Gynecologists. In the pregnant women with mild PIH, plasma cGMP levels as well as ANP and BNP levels were significantly (P < 0.05) higher than those in gestational age-matched normal pregnant or nonpregnant women. But in the pregnant women with severe PIH, plasma cGMP levels were significantly lower than those in pregnant women with mild PIH (P < 0.05), although plasma ANP and BNP levels were higher than those in pregnant women with mild PIH.


Interspecies dynamics among bacteria associated with canine periodontal disease.
The etiology and pathogenic mechanisms associated with canine periodontal disease are less well understood than the disease in humans. In this study we have reconstructed defined consortia biofilms in vitro of microorganisms identified as prevalent in a same-breed cohort of dogs with or without periodontal disease. Frederiksenia canicola and Neisseria canis were selected as potential early colonizers of salivary pellicle, and Fusobacterium nucleatum and Porphyromonas gulae were included as high incidence canine oral bacteria. N. canis formed a biofilm substratum under aerobic conditions, but was unable to tolerate anaerobic conditions. Fr. canicola exhibited synergistic biofilm growth with Po. gulae under anaerobic conditions, but displayed an antagonistic relationship with Fu. nucleatum. However, strong co-adhesion between Fu. nucleatum and Po. gulae was able to overcome the inhibitory effects of Fr. canicola to facilitate three-species biofilm formation. Parvimonas micra, an anaerobic, asaccharolytic Gram-positive coccus found only under disease conditions in vivo, was able to form biofilms in conjunction with Fr. canicola and Po. gulae. Furthermore, the specific proteolytic activities of biofilms containing Fr. canicola and Po. gulae or Fu. nucleatum and Po. gulae were increased several-fold upon the addition of Pa. micra. This suggests that anaerobic cocci such as Pa. micra might provide a catalyst for progressive tissue destruction, inflammation and alveolar bone loss in canine periodontal disease, in keeping with the keystone-pathogen hypothesis.


Alterations in sialic acid content of human transferrin.
Starch gel electrophoresis of human transferrin treated with neuraminidase revealed a pattern of five bands whose intensities varied with neuraminidase concentration. Sialic acid analysis after starch block electrophoresis suggested that the bands represented the stepwise removal of sialic acid from the transferrin molecule. Evidence was also obtained for the purification of a particular genetic transferrin variant


The relative flexibility of B-DNA and A-RNA duplexes: database analysis.
An extensive analysis of structural databases is carried out to investigate the relative flexibility of B-DNA and A-RNA duplexes in crystal form. Our results show that the general anisotropic concept of flexibility is not very useful to compare the deformability of B-DNA and A-RNA duplexes, since the flexibility patterns of B-DNA and A-RNA are quite different. In other words, 'flexibility' is a dangerous word for describing macromolecules, unless it is clearly defined. A few soft essential movements explain most of the natural flexibility of A-RNA, whereas many are necessary for B-DNA. Essential movements occurring in naked B-DNAs are identical to those necessary to deform DNA in DNA-protein complexes, which suggest that evolution has designed DNA-protein complexes so that B-DNA is deformed according to its natural tendency. DNA is generally more flexible, but for some distortions A-RNA is easier to deform. Local stiffness constants obtained for naked B-DNAs and DNA complexes are very close, demonstrating that global distortions in DNA necessary for binding to proteins are the result of the addition of small concerted deformations at the base-pair level. Finally, it is worth noting that in general the picture of the relative deformability of A-RNA and DNA derived from database analysis agrees very well with that derived from state of the art molecular dynamics (MD) simulations.


[Diagnosis of pulmonary thromboembolism by transesophageal echocardiography. Report of a case].
We describe the case of a 73-year-old man, admitted after several days of moderate dyspnea, followed by sincopal episode. Transesophageal echocardiography clearly demonstrated a high resolution image indicating thromboembolus of the proximal right main pulmonary artery. The patient's clinical conditions were moderately impaired; a treatment with heparin followed by warfarin was started. At 15 and 30 days interval, TEE controls were performed, showing an incomplete but evident resolution of pulmonary thromboembolism, associated to an improvement of clinical ECG and scintigraphic parameters. Our TEE observation, in accordance with the small number of similar observations reported in literature, showed a clear direct visualization with high resolutive diagnostic possibilities for pulmonary thromboembolism; successful resolution was confirmed by repeated TEE studies.


Purpuric halos around hemangiomas in systemic amyloidosis.
A patient with systemic amyloidosis noted purpuric halos around cherry hemangiomas. This unique presentation of systemic amyloidosis has been reported once previously. A possible mechanism is the combination of amyloid deposition and excess plasminogen activator activity.


Inositol 1,4,5-trisphosphate-sensitive Ca2+ release across nonvacuolar membranes in cauliflower.
Previous studies have indicated that the vacuole represents the major inositol 1,4,5-trisphosphate (InsP3)-mobilizable Ca2+ pool in higher plants. This findings is in contrast to animal cells, in which the endoplasmic reticulum and plasma membrane constitute the dominant InsP3-sensitive membranes. We used membrane vesicles prepared from cauliflower (Brassica oleracae L.) inflorescences that were separated on continuous sucrose gradients to demonstrate that cauliflower possesses at least two distinct membrane populations that are sensitive to InsP3. One of these membrane populations in nonvacuolar in origin and relies upon a Ca(2+)-ATPase to accumulate Ca2+. In addition, we have shown that two polyclonal antibodies, raised against peptides corresponding to the animal type 1 InsP3 receptor, recognize immunologically related proteins in cauliflower, and that the distribution of immunoreactive proteins on a linear sucrose gradient reinforces the notion that cauliflower contains more than one membrane subtype that is sensitive to InsP3. To our knowledge, this is the first report describing an InsP3-sensitive Ca2+ store other than the vacuole in higher plant cells.


Mechanisms of hepatic fibrogenesis.
Substantial improvements in the treatment of chronic liver disease have accelerated interest in uncovering the mechanisms underlying hepatic fibrosis and its resolution. Activation of resident hepatic stellate cells into proliferative, contractile, and fibrogenic cells in liver injury remains a dominant theme driving the field. However, several new areas of rapid progress in the past 5-10 years also have taken root, including: (1) identification of different fibrogenic populations apart from resident stellate cells, for example, portal fibroblasts, fibrocytes, and bone-marrow-derived cells, as well as cells derived from epithelial mesenchymal transition; (2) emergence of stellate cells as finely regulated determinants of hepatic inflammation and immunity; (3) elucidation of multiple pathways controlling gene expression during stellate cell activation including transcriptional, post-transcriptional, and epigenetic mechanisms; (4) recognition of disease-specific pathways of fibrogenesis; (5) re-emergence of hepatic macrophages as determinants of matrix degradation in fibrosis resolution and the importance of matrix cross-linking and scar maturation in determining reversibility; and (6) hints that hepatic stellate cells may contribute to hepatic stem cell behavior, cancer, and regeneration. Clinical and translational implications of these advances have become clear, and have begun to impact significantly on the management and outlook of patients with chronic liver disease.


Conformation-dependent ˙OH/H2O2 hydrogen abstraction reaction cycles of Gly and Ala residues: a comparative theoretical study.
To determine if (•)OH can initiate the unfolding of an amino acid residue, the elementary reaction coordinates of H abstraction by (•)OH different conformations (β(L), γ(L), γ(D), α(L), and α(D)) of Gly and Ala dimethyl amides were computed using first-principles quantum computations. The MPWKCIS1K/6-311++G(3df,2p)//BHandHLYP/6-311+G(d,p) level of theory was selected after different combinations of functionals and basis sets were compared. The structures of Gly and Ala in the elementary reaction steps were compared to the conformers of the Gly, Gly(•), Ala, and Ala(•) structures in the absence of (•)OH/H(2)O, which were identified by optimizing the minima of the respective potential energy surfaces. A dramatic change in conformation is observed in the Gly and Ala conformers after conversion to Gly(•) and Ala(•), respectively, and this change can be monitored along the minimal energy pathway. The β(L) conformer of Gly (-0.3 kJ mol(-1)) and Ala (-1.6 kJ mol(-1)) form the lowest-lying transition states in the reaction with (•)OH, whereas the side chain of Ala strongly destabilizes the α conformers compared to the γ conformers, which could cause the lower reactivity shown in Ala. This effect shown in Ala could affect the abstraction of hydrogen from Ala and the other chiral amino acid residues in the helices. The energy of subsequent hydrogen abstraction reactions between Ala(•) and Gly(•) and H(2)O(2) remains approximately 90 kJ mol(-1) below the entrance level of the (•)OH reaction, indicating that the (•)OH radical can initiate an α to β transition in an amino acid residue if a molecule such as H(2)O(2) can provide the hydrogen atom necessary to re-form Gly and Ala. This work delineates the mechanism of the rapid (•)OH-initiated unfolding of peptides and proteins which has been proposed in Alzheimer's and other peptide misfolding diseases involving amyloidogenic peptides.


Approach for selecting boundary value to retrieve Mie-scattering lidar data based on segmentation and two-component fitting methods.
Fernald method is regarded as the standard method for retrieving lidar data, but the retrieval can be performed only when a boundary value is given. Generally, we can select clear atmosphere above the tropopause as a reference to determine the boundary value, but we need to use the slope method to fit the boundary value when the detecting range is lower than the tropopause. The slope method involves significant uncertainty because this algorithm is based on two hypotheses: one is that aerosol vertical distribution is homogeneous, and the other is that either molecule or aerosol components exist in the atmosphere. To reduce the uncertainty, we proposed a new approach, which segments a signal into "uniform" sub-signals to avoid the first hypothesis, and then uses nonlinear two-component fitting to avoid the second one. Compared with the approach based on the slope method, the new approach obtained more accurate boundary values and retrieving results for both of the simulated and real signals. Thus the automatic segmentation algorithm and the two-component fitting method are useful for determining the reference bin and boundary values when the effective detecting range of lidar is lower than the tropopause.


Cholinergic stimulation of phosphoinositide metabolism in isolated rat glomeruli.
Cholinergic effects on kidney function have been observed in some mammals but the intrarenal localization and the cellular mechanisms of these effects are poorly defined to date. The aim of this work was to study the effects of carbachol on phosphoinositide metabolism in freshly isolated rat glomeruli labeled with myo-[3H]inositol. Carbachol rapidly and markedly stimulates phosphoinositide metabolism with a 50% effective concentration of 3 microM. The enormous magnitude of the response is enlightened by the use of 10 mM lithium, which provokes in the presence of the agonist a large accumulation of inositol phosphates and a corresponding depletion of cellular free inositol. The response is inhibited by 85% by pirenzepine, is pertussis toxin insensitive, and shows no desensitization at maximum dose of carbachol up to 40 min of stimulation.


Pancreatic metastasis of invasive ductal breast carcinoma: A potential diagnostic pitfall.
The 42-year-old patient, diagnosed with Stage IIA breast cancer, completed the postoperative adjuvant chemotherapy and radiotherapy. At the 11th year of diagnosis, a 3 cm tumor was detected in the pancreas and pancreatectomy was performed. Although the diagnosis of primary pancreatic adenocarcinoma was made at first, then the pancreatic metastasis of breast cancer was discovered. Pancreatic metastasis of breast cancer is extremely rare, and a limited number of patients have been reported in the literature. Here, we report an additional case of this rare tumor and the problems correlating with its diagnosis.


Patterns of occurrence and concordance between subjective and objective hot flashes among Muslim and Hindu women in Sylhet, Bangladesh.
This study examined the pattern of occurrence and the rate of concordance between objective hot flashes measured by sternal skin conductance and the subjective experience of "gorom vap laga" (feeling steaming hot) among Muslim and Hindu women living in Sylhet, Bangladesh. Participants were aged 40-55, not pregnant or lactating, not using hormone therapy, and with no history of hysterectomy. Thirty women wore an ambulatory hot flash monitor for 8 h on average, from mid-morning to early evening. True positive, false negative, and false positive measures of hot flashes were examined in relation to demographic, reproductive, and lifestyle variables. On body diagrams, women were most likely to indicate hot flashes on the top of their head (64%) and upper chest (68%). The greatest number of objective hot flashes occurred during the hour of 17:00, perhaps due to the heat of the day, and the clothing and activity associated with prayer. Muslim participants demonstrated more objective hot flashes per woman than Hindu participants (1.5 vs. 0.1, P < 0.05), and Muslims had more false positive measures (86%) compared with Hindu participants (0%, P = 0.06). Among all women who reported subjective hot flashes (n = 19), the proportion of true positive scores was 19%. Overall, the frequency of objective hot flashes was low compared with reports from studies in the United States. The pattern of sweating assessed by body diagrams was not associated with variation in hot flash experience.


Expiratory volumetric MDCT evaluation of air trapping in pediatric patients with and without tracheomalacia.
The purpose of this study was to use paired inspiratory-expiratory volumetric MDCT to compare the frequency, severity, and pattern of air trapping in pediatric patients with tracheomalacia with the findings in children without tracheomalacia. The study group consisted of 15 consecutively registered pediatric patients (younger than 18 years) who had tracheomalacia, defined as 50% or greater reduction in tracheal cross-sectional luminal area between end inspiration and end expiration, diagnosed with MDCT and confirmed with bronchoscopy. The comparison group consisted of 15 consecutively registered pediatric patients without evidence of tracheomalacia at MDCT and bronchoscopy. Two blinded pediatric radiologists working in consensus interpreted the randomly viewed end-expiratory thin-section CT images of both groups of children for the presence, severity, and pattern of air trapping at three anatomic levels (upper, middle, and lower lung zones). The severity of air trapping was graded visually on a 5-point scale. The total air trapping scores, obtained by summing the values for the three anatomic levels for the study and comparison groups, were compared by Wilcoxon's rank sum test. The pattern of air trapping was categorized as lobular, segmental, lobar, diffuse, or mixed, and the patterns in the two study groups were compared by Pearson's chi-square test. The study cohort with tracheomalacia consisted of 15 patients (10 boys, five girls; mean age, 2.4 +/- 2.8 years; range, 1 month-11.8 years). The comparison group without tracheomalacia consisted of 15 patients (nine boys, six girls; mean age, 2.7 +/- 2.4 years; range, 1 month-8.1 years). Air trapping was identified in all 15 patients with tracheomalacia (median score, 5.0; range, 3-11) and in 10 of 15 children (67%) in the comparison group (median score, 3.0; range, 1-4). The median total air trapping score was significantly higher in the study cohort than in the comparison group (p = 0.002), but there were no significant differences in the air trapping patterns between the study groups (p = 0.53). Pediatric patients with tracheomalacia have a higher frequency and greater severity of air trapping than do children without tracheomalacia.


Patterns of health care interactions of individuals with alcohol use disorder: A latent class analysis.
Given the high rates at which individuals with alcohol use disorder (AUD) utilize health care for co-existing conditions, health systems are promising venues for interventions that will facilitate access to AUD treatment. However, how individuals with AUD interact with such systems and, thus, how systems should intervene is unclear. In this study, we seek to identify patterns in how individuals diagnosed with AUD within an academic health system interacted with the system prior to diagnosis. We use electronic health records from a single academic health system in a major US metropolitan area to create a deidentified retrospective cohort including all individuals age 18+ diagnosed with AUD 2010-2019 (n = 26,899). Latent class analysis (LCA) identified subgroups defined by aspects of previous system interaction and health status, including having an in-system primary care provider, previous utilization of primary and specialty care, diagnosis setting, payer, and presence of other chronic conditions. We then assessed subgroup differences in demographics and associations with in-system AUD treatment receipt in the year following diagnosis, adjusting for demographics. The population was on average 38.6 years old (standard deviation = 15.4) and predominantly male (66.1 %), White (64.5 %), and not of Hispanic/Latino ethnicity (87.8 %). Only 4.7 % received in-system treatment following diagnosis. We deemed the four-class model the optimal LCA model. This model identified subgroups that can be described as 1) average utilization (20.7 % of population), 2) low utilization (54.5 %), 3) high health burden and low utilization (14.2 %), and 4) high health burden and high utilization (10.6 %). Predicted membership in the high health burden and high utilization subgroup and low utilization subgroup were associated with higher and lower odds of treatment receipt, respectively, compared with predicted membership in the average utilization subgroup (odds ratio (OR) for high/high subgroup = 1.21, 95 % confidence interval (CI) = 1.01, 1.27; OR for low subgroup = 0.29 95 % CI = 0.24, 0.34). Individuals diagnosed with AUD within a health system interact with that system in markedly different ways and are unlikely to benefit uniformly from system-based interventions to facilitate treatment. Group-tailored interventions are more likely to have impact and provide returns on investments for systems.


Characteristics and outcomes in patients with a prior myocardial infarction treated with extended dual antiplatelet therapy with ticagrelor 60 mg: findings from ALETHEIA, a multi-country observational study.
Guidelines recommend extended dual antiplatelet therapy, including ticagrelor 60 mg twice daily, in high-risk post-myocardial infarction (MI) patients who have tolerated 12 months and are not at high bleeding risk. The real-world utilization and bleeding and ischaemic outcomes associated with long-term ticagrelor 60 mg in routine clinical practice have not been well described. Register and claims data from the USA (Optum Clinformatics, IBM MarketScan, and Medicare) and Europe (Sweden, Italy, UK, and Germany) were extracted. Patients initiating ticagrelor 60 mg ≥12 months after MI, meeting eligibility criteria for the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis in Myocardial Infarction 45) 54 trial, were included. The cumulative incidence of the composite of MI, stroke, or all-cause mortality and that of bleeding requiring hospitalization were calculated. Meta-analyses were performed to combine estimates from each source. A total of 7035 patients treated with ticagrelor 60 mg met eligibility criteria. Median age was 67 years and 29% were females; 12% had a history of multiple MIs. The majority (95%) had been treated with ticagrelor 90 mg prior to initiating ticagrelor 60 mg. At 12 months from initiation of ticagrelor 60 mg, the cumulative incidence [95% confidence interval (CI)] of MI, stroke, or mortality was 3.33% (2.73-4.04) and was approximately three-fold the risk of bleeding (0.96%; 0.69-1.33). This study provides insights into the use of ticagrelor 60 mg in patients with prior MI in clinical practice. Observed event rates for ischaemic events and bleeding generally align with those in the pivotal trials, support the established safety profile of ticagrelor, and highlight the significant residual ischaemic risk in this population.Clinical Trials.gov Registration NCT04568083.


Not just money: quality of working life as employment strategy.
Scarcities of qualified personnel are becoming a common phenomenon in The Netherlands. At the same time, increasing wages to secure an adequate workforce is not always possible or sufficiently effective, and other ways of retaining and recruiting personnel have to be found. Investigates the importance of various job characteristics for retaining and recruiting employees and presents the results from a survey among employees of a Dutch hospital experiencing a tight labour market. Job characteristics other than wages, such as labour relations and work content, were found to play a major role in individuals' choices to resign or stay. Discusses consequences for employment strategies in other organizations.


Architectural control of seeded-grown magnetic-semicondutor iron oxide-TiO(2) nanorod heterostructures: the role of seeds in topology selection.
A colloidal nonaqueous approach to semiconductor-magnetic hybrid nanocrystals (HNCs) with selectable heterodimer topologies and tunable geometric parameters is demonstrated. Brookite TiO(2) nanorods, distinguished by a curved shape-tapered profile with richly faceted terminations, are exploited as substrate seeds onto which a single spherical domain of inverse spinel iron oxide can be epitaxially grown at either one apex or any location along their longitudinal sidewalls in a hot surfactant environment. The topologically controlled arrangement of the component material lattices, the crystallographic relationships holding between them, and strain distribution across individual heterostructures have been studied by combining X-ray diffraction and absorption techniques with high-resolution transmission electron microscopy investigations. Supported by such structural knowledge, the synthetic achievements are interpreted within the frame of various mechanistic models offering complementary views of HNC formation. The different HNC architectures are concluded to be almost equivalent in terms of surface-interface energy balance associated with their formation. HNC topology selection is rationalized on the basis of a diffusion-limited mechanism allowing iron oxide heterogeneous nucleation and growth on the TiO(2) nanorods to switch from a thermodynamically controlled to a kinetically overdriven deposition regime, in which the anisotropic reactivity offered by the uniquely structured seeds is accentuated under high spatially inhomogeneous monomer fluxes. Finally, the multifunctional capabilities of the heterostructures are highlighted through illustration of their magnetic and photocatalytic properties, which have been found to diverge from those otherwise exhibited by their individual material components and physical mixture counterparts.


Long-term consequences of human alpha-synuclein overexpression in the primate ventral midbrain.
Overexpression of human alpha-synuclein (alpha-syn) using recombinant adeno-associated viral (rAAV) vectors provides a novel tool to study neurodegenerative processes seen in Parkinson's disease and other synucleinopathies. We used a pseudotyped rAAV2/5 vector to express human wild-type (wt) alpha-syn, A53T mutated alpha-syn, or the green fluorescent protein (GFP) in the primate ventral midbrain. Twenty-four adult common marmosets (Callithrix jacchus) were followed with regular behavioural tests for 1 year after transduction. alpha-Syn overexpression affected motor behaviour such that all animals remained asymptomatic for at least 9 weeks, then motor bias comprising head position bias and full body rotations were seen in wt-alpha-syn expressing animals between 15 and 27 weeks; in the later phase, the animals overexpressing the A53T alpha -syn, in particular, showed a gradual worsening of motor performance, with increased motor coordination errors. Histological analysis from animals overexpressing either the wt or A53T alpha -syn showed prominent degeneration of dopaminergic fibres in the striatum. In the ventral midbrain, however, the dopaminergic neurodegeneration was more prominent in the A53T group than in the WT group suggesting differential toxicity of these two proteins in the primate brain. The surviving cell bodies and their processes in the substantia nigra were stained by antibodies to the pathological form of alpha-syn that is phosphorylated at Ser position 129. Moreover, we found, for the first time, ubiquitin containing aggregates after overexpression of alpha-syn in the primate midbrain. There was also a variable loss of oligodendroglial cells in the cerebral peduncle. These histological and behavioural data suggest that this model provides unique opportunities to study progressive neurodegeneration in the dopaminergic system and deposition of alpha-syn and ubiquitin similar to that seen in Parkinson's disease, and to test novel therapeutic targets for neuroprotective strategies.


Association Between Remote Monitoring and Interstage Morbidity and Death in Patients With Single-Ventricle Heart Disease Across Socioeconomic Groups.
Despite improvements in survival over time, the mortality rate for infants with single-ventricle heart disease remains high. Infants of low socioeconomic status (SES) are particularly vulnerable. We sought to determine whether use of a novel remote monitoring program, the Cardiac High Acuity Monitoring Program, mitigates differences in outcomes by SES. Within the Cardiac High Acuity Monitoring Program, we identified 610 infants across 11 centers from 2014 to 2021. All enrolled families had access to a mobile application allowing for near-instantaneous transfer of patient information to the care team. Patients were divided into SES tertiles on the basis of 6 variables relating to SES. Hierarchical logistic regression, adjusted for potential confounding characteristics, was used to determine the association between SES and death or transplant listing during the interstage period. Of 610 infants, 39 (6.4%) died or were listed for transplant. In unadjusted analysis, the rate of reaching the primary outcome between SES tertiles was similar (P=0.24). Even after multivariable adjustment, the odds of death or transplant listing were no different for those in the middle (odds ratio, 1.7 [95% CI, 0.73-3.94) or highest (odds ratio, 0.997 [95% CI, 0.30, 3.36]) SES tertile compared with patients in the lowest (overall P value 0.4). In a large multicenter cohort of infants with single-ventricle heart disease enrolled in a digital remote monitoring program during the interstage period, we found no difference in outcomes based on SES. Our study suggests that this novel technology could help mitigate differences in outcomes for this fragile population of patients.


[Variability of attenuated alphavirus strains in virion aggregate infection].
A natural process of infection with multiploid virions was stimulated and the genetic effects occurring in this infection were studied in experiments with homogeneous attenuated strain of Venezuelan equine encephalomyelitis virus producing the smallest plaques. The process of infection with multiploid virions was reproduced by infecting the cells with artificially obtained aggregates. Under these conditions, small- and large-plaque virus was produced which in some cases had a higher virulence than the parental strain. A possible mechanism of this phenomenon and its practical implications for the evaluation of the properties of attenuated alphavirus strains is discussed.


Health-Related Quality of Life in Patients with Ankylosing Spondylitis: Relationship with Disease-Related Variables.
Ankylosing spondylitis (AS) is a chronic progressive inflammatory disease leading to functional limitations and subsequently impaired quality of life (QoL). Despite the fact that QoL was recognized as a significant perception, it was excluded from the core domains (defined by the Assessment of Spondyloarthritis International Society), because of ambiguity of measurement choice. To assess QoL in patients with AS using a generic; Short Form-36 (SF-36) and a diseasespecific; Ankylosing Spondylitis quality of life (ASQoL) instruments and to explore its relationship to the clinical characteristics, disease activity, functional status, and radiographic severity. A total of 47 AS patients who fulfilled modified New York criteria were included. Disease activity, functional status, spinal mobility, and radiographic severity were assessed by Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Bath AS Metrology Index (BASMI) and Bath AS Radiology Index (BASRI) respectively. SF-36 and ASQoL instruments evaluated Qol. Physical health was more affected especially in patients with peripheral arthritis by SF-36 (p=0.008) and ASQoL (p=0.022) scores. Both SF-36 total and ASQoL scores correlated significantly with BASDAI (r = -0.329, p = 0.024 and r = 0.420, p = 0.003), BASFI (r = -0.399, p = 0.005 and r = 0.513, p=0.001) and BASMI (r = -0.382, p = 0.008 and r = 0.482, p= 0.001) respectively. QoL was impaired in AS patients with highest impact on physical health especially in association with peripheral arthritis. SF-36 and ASQol have a comparable achievement in the evaluation of QoL in AS patients and both physical function and spinal mobility were identified as predictors of poor QoL.


NG-nitro-L-arginine methyl ester inhibits bone metastasis after modified intracardiac injection of human breast cancer cells in a nude mouse model.
We investigated the effects of NG-nitro-L-arginine-methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, on bone metastasis of human breast cancer, MDA-231 cells. Tumor cells (2 x 10(5) cells in 0.2 ml of phosphate-buffered saline; PBS) were injected through the diaphragm into the left ventricle of the heart of laparotomized nude mice (male 5-week-old ICR-nu/nu). L-NAME (2 mg/mouse/injection in 0.1 ml of PBS) was given intraperitoneally to mice 6 h and 3 h before and immediately, 3 h, 6 h, 18 h and 21 h after the intracardiac injection of tumor cells. As a control, 0.1 ml of PBS was injected instead of L-NAME. The effect of NG-nitro-D-arginine-methyl ester (D-NAME; 2 mg/mouse/injection), an inactive analogue of L-NAME, was also investigated to evaluate the specificity of L-NAME action. Radiographical examination 31 days after the tumor-cell injection showed that the incidence and number of osteolytic bone metastases and the number of bones with metastasis in L-NAME-treated mice were significantly reduced compared with those in PBS-treated mice (P < 0.05). The differences between PBS-treated and D-NAME-treated mice were not significant. Our findings suggest that specific and appropriate NOS inhibitors may represent a new pharmacological approach to therapy for cancer patients at risk of developing osteolytic bone metastases.


Childhood-onset anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) necrotizing myopathy needs to be distinguished from muscular dystrophy: A case study.
A 24-year-old woman visited our hospital with a complaint of walking disability. She had no family history of consanguineous marriage, and her developmental history was unremarkable, with good physical performance just before the onset. At the age of 13, she developed difficulty in walking and visited a pediatrician. Her serum CK level was 10,000 IU/l and she was diagnosed with muscular dystrophy by muscle biopsy. At the age of 16, she became wheelchair dependent and was admitted to our hospital. Physical examination revealed diffuse muscle atrophy and proximal weakness, with no calf hypertrophy or selectivity of muscle involvement. Needle EMG and MR images indicated inflammatory myopathy. Muscle biopsy revealed necrotic and regenerating fibers and lymphocyte infiltration. She was re-diagnosed with inflammatory myopathy and recovered walking capacity after immunotherapy. Subsequently, she was tested positive for anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. To distinguish treatable inflammatory myopathy from muscular dystrophy, a comprehensive assessment of patient history, family history, selectivity of muscle involvement, findings suggestive of inflammation in EMG and CT/MR imaging, and muscle pathology is necessary.


Thyroid Stimulating Hormone Reference Range and Prevalence of Thyroid Dysfunction in the Korean Population: Korea National Health and Nutrition Examination Survey 2013 to 2015.
No nationwide epidemiological study evaluating the prevalence of subclinical and overt forms of hypothyroidism and hyperthyroidism has yet been conducted in Korea. This study aimed to evaluate the reference range of serum thyroid stimulating hormone (TSH) and the national prevalence of thyroid dysfunctions in Korea. Nation-wide cross-sectional data were analyzed from a representative sample of the civilian, non-institutionalized Korean population (n=6,564) who underwent blood testing for thyroid function and anti-thyroid peroxidase antibody (TPOAb) as part of the Korea National Health and Nutrition Examination Survey VI (2013 to 2015). The reference interval of serum TSH in the Korean reference population was 0.62 to 6.68 mIU/L. Based on this reference interval, the prevalence of overt and subclinical hypothyroidism was 0.73% (males 0.40%, females 1.10%) and 3.10% (males 2.26%, females 4.04%), respectively. The prevalence of hypothyroidism increased with age until the age group between 50 to 59 years. Positive TPOAb were found in 7.30% of subjects (males 4.33%, females 10.62%). The prevalence of overt and subclinical hypothyroidism TPOAb-positive subjects was 5.16% and 10.88%, respectively. The prevalence of overt and subclinical hyperthyroidism was 0.54% (males 0.30%, females 0.81%) and 2.98% (males 2.43%, females, 3.59%), respectively. The Serum TSH reference levels in the Korean population were higher than the corresponding levels in Western countries. Differences were found in the prevalence of hypothyroidism and hyperthyroidism according to age, sex, and TPOAb positivity. This study provides important baseline information for understanding patterns of thyroid dysfunction and diseases in Korea.


Effect of heparin binding on Helicobacter pylori resistance to serum.
The objective of this study was to evaluate the effect of heparin binding to Helicobacter pylori cells on their survival in the presence of fresh rabbit serum with or without active complement components. Three H. pylori strains were compared and the amounts of heparin added reflected the physiological concentrations that can be found in animal tissues. No growth of H. pylori was noted in the presence of serum. Serum with or without active complement produced a reduction in c.f.u. for strains SPM 326, CCUG 17874(T) and SS1. However, addition of heparin resulted in increased survival of bacterial cells in serum with or without active complement. It appears that heparin binding to H. pylori can prevent bacterial cell death due to the alternative complement system. Heparin binding could also protect from heated serum (complement-inactivated), indicating protection from other serum components besides complement. In vivo, the process of heparin binding could possibly result in facilitated colonization due to a higher survival rate.


Altered exocrine function can drive adipose wasting in early pancreatic cancer.
Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.


Psychotic features in chronic posttraumatic stress disorder and schizophrenia: comparative severity.
Psychotic features are frequent in combat veterans with chronic posttraumatic stress disorder (PTSD), may correlate with severity of PTSD symptoms, and may reflect a distinct subtype of the disorder. These psychotic features include auditory and visual hallucinations and delusional thinking that is usually paranoid in nature. Psychotic features may be under-recognized in chronic PTSD because patients are reluctant to report these symptoms and because they may not have overt changes in affect or bizarre delusions characteristic of other psychoses, e.g., schizophrenia. To further assess these phenomena, we compared clinical ratings on the Positive and Negative Syndrome Scale (PANSS) and other assessments, including the Clinical Global Impression Scale and the Structured Clinical Interview with Psychotic Screen, in veterans meeting DSM-IV criteria for chronic PTSD with well-defined comorbid psychotic features (N = 40) or chronic schizophrenia (N = 40). The patients with schizophrenia had modestly higher composite PANSS scores and positive symptom scores although average scores in both groups were moderate to severe in intensity. Negative symptom and general psychopathology subscale scores were comparable in both groups. Regarding specific positive symptoms, hallucinations were comparable between groups in severity; however, schizophrenia patients had slightly more intense delusions and conceptual disorganization. These data further validate the occurrence of positive as well as negative symptoms of psychosis in chronic PTSD in a range of severity that may approach that of patients with schizophrenia. Although meeting DSM-IV criteria for two different major psychiatric disorders, these two patient populations were remarkably similar with respect to not only positive but also negative symptoms.


Biosecurity in multifunctional landscapes: challenges for approaches based on the concept of 'shared responsibility'.
Biosecurity policy in NSW is based on the concept of 'shared responsibility' that emphasises small government and devolution of responsibility to stakeholders. This paper draws on a case study of the cattle tick program to illustrate the challenges for governments implementing a 'shared responsibility' biosecurity strategy in the multifunctional rural landscapes that are now typical of the more closely settled regions of south-eastern Australia. Agriculture may remain the dominant land use in these regions but other values underpin landownership and management for an increasing proportion of landholders who are not farmers by occupation, are disconnected from traditional producer networks, and often lack the knowledge and skills to effectively manage biosecurity threats. We describe the challenges posed by multifunctionality including a high property turnover rate, rapidly increasing rural land values, in-migration of new landholders and multiple landholder types holding different values and beliefs that influence their cattle tick management practices. We suggest ways biosecurity programs within a 'shared responsibility' framework can more effectively engage producers. These include negotiating with industry or a representative body the level of responsibility and management decisions being delegated, and to building the social and human capital of landholders taking into account the specific information and training needs of new and non-farmer landholders in addition to cattle tick management.


Thin-film characterization using a scanning laser acoustic microscope with surface acoustic waves.
The use of surface acoustic waves in a scanning laser acoustic microscope for the characterization of the mechanical or acoustic properties of thin films deposited on piezoelectric substrates is demonstrated. Quantitative measurements of mass loading effects of 5000-A-thick tungsten films deposited on lithium niobate substrates were obtained using 100-MHz surface acoustic waves. No information about the tungsten film could be obtained using 100-MHz compressional waves. Methods of generating surface waves on nonpiezoelectric materials so that this technique could be used on arbitrary substrates are discussed.


Human mesenchymal stem cells and renal tubular epithelial cells differentially influence monocyte-derived dendritic cell differentiation and maturation.
Mesenchymal stem cells (MSCs) possess immunosuppressive properties. But also fully differentiated human renal tubular epithelial cells (RTECs) are able to modulate T-cell proliferation in vitro. In this study we compared two MSC populations, human adipose derived stem cells (ASCs) and human amniotic mesenchymal stromal cells (hAMSCs), and RTECs regarding their potential to inhibit monocyte-derived dendritic cell (DC) differentiation and maturation in indirect co-culture. In the presence of hAMSCs and RTECs, monocytes stimulated to undergo DC differentiation were inhibited to acquire surface phenotype of immature and mature DCs. In contrast, ASCs showed only limited suppressive capacity. Secretion of IL-12p70 was suppressed in hAMSC co-cultures and high IL-10 levels were detected in all co-cultures. Prostaglandin E(2) was found in ASC and hAMSC co-cultures, whereas soluble human leukocyte antigen-G was highly elevated only in RTEC co-cultures. Thus, inhibition of DC generation by MSCs and RTECs might be mediated by different soluble factors.


A re-evaluation of the role of inhaled corticosteroids in the management of patients with chronic obstructive pulmonary disease.
Inhaled corticosteroids (ICS) (in fixed combinations with long-acting β2-agonists [LABAs]) are frequently prescribed for patients with chronic obstructive pulmonary disease (COPD), outside their labeled indications and recommended treatment strategies and guidelines, despite having the potential to cause significant side effects. Although the existence of asthma in patients with asthma-COPD overlap syndrome (ACOS) clearly supports the use of anti-inflammatory treatment (typically an ICS/LABA combination, as ICS monotherapy is usually not indicated for COPD), the current level of ICS/LABA use is not consistent with the prevalence of ACOS in the COPD population. Data have recently become available showing the comparative efficacy of fixed bronchodilator combinations (long-acting muscarinic antagonist [LAMA]/LABA with ICS/LABA combinations). Additionally, new information has emerged on ICS withdrawal without increased risk of exacerbations, under cover of effective bronchodilation. For patients with COPD who do not have ACOS, a LAMA/LABA combination may be an appropriate starting therapy, apart from those with mild disease who can be managed with a single long-acting bronchodilator. Patients who remain symptomatic or present with exacerbations despite effectively delivered LAMA/LABA treatment may require additional drug therapy, such as ICS or phosphodiesterase-4 inhibitors. When prescribing an ICS/LABA, the risk:benefit ratio should be considered in individual patients.


Vascular-endothelial-growth-factor (VEGF) targeting therapies for endocrine refractory or resistant metastatic breast cancer.
Vascular-endothelial-growth-factor (VEGF) is a key mediator of angiogenesis. VEGF-targeting therapies have shown significant benefits and been successfully integrated in routine clinical practice for other types of cancer, such as metastatic colorectal cancer. By contrast, individual trial results in metastatic breast cancer (MBC) are highly variable and their value is controversial. To evaluate the benefits (in progression-free survival (PFS) and overall survival (OS)) and harms (toxicity) of VEGF-targeting therapies in patients with hormone-refractory or hormone-receptor negative metastatic breast cancer. Searches of CENTRAL, MEDLINE, EMBASE, the Cochrane Breast Cancer Group's Specialised Register, registers of ongoing trials and proceedings of conferences were conducted in January and September 2011, starting in 2000. Reference lists were scanned and members of the Cochrane Breast Cancer Group, experts and manufacturers of relevant drug were contacted to obtain further information. No language restrictions were applied. Randomised controlled trials (RCTs) to evaluate treatment benefit and non-randomised studies in the routine oncology practice setting to evaluate treatment harms. We performed data collection and analysis according to the published protocol. Individual patient data was sought but not provided. Therefore, the meta-analysis had to be based on published data. Summary statistics for the primary endpoint (PFS) were hazard ratios (HRs). We identified seven RCTs, one register, and five ongoing trials from a total of 347 references. The published trials for VEGF-targeting drugs in MBC were limited to bevacizumab. Four trials, including a total of 2886 patients, were available for the comparison of first-line chemotherapy, with versus without bevacizumab. PFS (HR 0.67; 95% confidence interval (CI) 0.61 to 0.73) and response rate were significantly better for patients treated with bevacizumab, with moderate heterogeneity regarding the magnitude of the effect on PFS. For second-line chemotherapy, a smaller, but still significant benefit in terms of PFS could be demonstrated for patients treated with bevacizumab (HR 0.85; 95% CI 0.73 to 0.98), as well as a benefit in tumour response. However, OS did not differ significantly, neither in first- (HR 0.93; 95% CI 0.84 to 1.04), nor second-line therapy (HR 0.98; 95% CI 0.83 to 1.16). Quality of life (QoL) was evaluated in four trials but results were published for only two of these with no relevant impact. Subgroup analysis stated a significant greater benefit for patients with previous (taxane) chemotherapy and patients with hormone-receptor negative status. Regarding toxicity, data from RCTs and registry data were consistent and in line with the known toxicity profile of bevacizumab. While significantly higher rates of adverse events (AEs) grade III/IV (odds ratio (OR) 1.77; 95% CI 1.44 to 2.18) and serious adverse events (SAEs) (OR 1.41; 95% CI 1.13 to 1.75) were observed in patients treated with bevacizumab, rates of treatment-related deaths were lower in patients treated with bevacizumab (OR 0.60; 95% CI 0.36 to 0.99). The overall patient benefit from adding bevacizumab to first- and second-line chemotherapy in metastatic breast cancer can at best be considered as modest. It is dependent on the type of chemotherapy used and limited to a prolongation of PFS and response rates in both first- and second-line therapy, both surrogate parameters. In contrast, bevacizumab has no significant impact on the patient-related secondary outcomes of OS or QoL, which indicate a direct patient benefit. For this reason, the clinical value of bevacizumab for metastatic breast cancer remains controversial.


1.85-A resolution crystal structure of human ornithine transcarbamoylase complexed with N-phosphonacetyl-L-ornithine. Catalytic mechanism and correlation with inherited deficiency.
The crystal structure of human ornithine transcarbamoylase complexed with the bisubstrate analog N-phosphonacetyl-L-ornithine has been solved at 1.85-A resolution by molecular replacement. Deleterious mutations produce clinical hyperammonia that, if untreated, results in neurological symptoms or death (ornithine transcarbamylase deficiency). The holoenzyme is trimeric, and as in other transcarbamoylases, each subunit contains an N-terminal domain that binds carbamoyl phosphate and a C-terminal domain that binds L-ornithine. The active site is located in the cleft between domains and contains additional residues from an adjacent subunit. Binding of N-phosphonacetyl-L-ornithine promotes domain closure. The resolution of the structure enables the role of active site residues in the catalytic mechanism to be critically examined. The side chain of Cys-303 is positioned so as to be able to interact with the delta-amino group of L-ornithine which attacks the carbonyl carbon of carbamoyl phosphate in the enzyme-catalyzed reaction. This sulfhydryl group forms a charge relay system with Asp-263 and the alpha-amino group of L-ornithine, instead of with His-302 and Glu-310, as previously proposed. In common with other ureotelic ornithine transcarbamoylases, the human enzyme lacks a loop of approximately 20 residues between helix H10 and beta-strand B10 which is present in prokaryotic ornithine transcarbamoylases but has a C-terminal extension of 10 residues that interacts with the body of the protein but is exposed. The sequence of this C-terminal extension is homologous to an interhelical loop found in several membrane proteins, including mitochondrial transport proteins, suggesting a possible mode of interaction with the inner mitochondrial membrane.


Tests for equivalence or non-inferiority--why?
Drugs are sometimes assessed in clinical trials designed to test their equivalence or non-inferiority to a standard therapy. Non-inferiority trials, in particular, appear to be increasingly used to test new drugs, such as the oral hypoglycaemics reviewed in this issue of DTB. Here we summarise the main features of equivalence and non-inferiority trials and suggest what to look out for when reading study reports.


Pharm. D. pathways to biomedical research: the National Institutes of Health special conference on pharmacy research.
To address the shortage of research-trained pharmaceutical scientists (or doctor of pharmacy [Pharm.D.] scientists), a 2-day pharmacy research conference titled "Pharm.D. Pathways to Biomedical Research" was convened on December 13-14, 2006, at the National Institutes of Health (NIH) campus (Bethesda, MD). The workshop included invited speakers and participants from academia, industry, and government. Forty-two pharmacy schools were represented, including deans and clinical pharmaceutical scientists with current NIH funding. In addition, several pharmacy professional organizations were represented--American Association of Colleges of Pharmacy, American College of Clinical Pharmacy, American Society of Health-System Pharmacists, and the Accreditation Council on Pharmaceutical Education. The workshop was divided into three sessions followed by breakout discussion groups: the first session focused on presentations by leading pharmaceutical scientists who described their path to success; the second session examined the NIH grant system, particularly as it relates to training opportunities in biomedical research and funding mechanisms; and the third session addressed biomedical research education and training from the perspective of scientific societies and academia. We summarize the discussions and findings from the workshop and highlight some important considerations for the future of research in the pharmacy community. This report also puts forth recommendations for educating future pharmaceutical scientists.


Differences in the Experience of Caregiving Between Spouse and Adult Child Caregivers in Dementia With Lewy Bodies.
Dementia caregiving has been associated with increased burden, depression, grief, a decreased sense of well-being and quality of life, and a weakening of social support. Little is known about the experience of caregiving in Dementia with Lewy Bodies (DLB). The present study examines differences in the caregiving experience of spouse versus adult child caregivers of individuals with DLB. In this cross-sectional analytic study of spouses (n = 255) and adult children (n = 160) caregivers of individuals with DLB, participants completed an online survey of burden, grief, depression, well-being, quality of life, and social support. Adult child caregivers were more likely to care for women (p < .001) and see the care recipient less often (p < .001) than spouses. Adult child caregivers reported lower quality of life (p < .001) and more caregiver burden (p < .009), but also greater social support (p < .001) than spouses. Between group analyses of caregiver type by disease severity demonstrated that spousal caregivers experience greater grief with advancing disease (p = .005), while adult child caregivers increase social support with advancing disease (p < .001). Spouses and adult children experience DLB caregiving differently. This was explained by the younger age of the adult child caregiver, frequency of contact with the care recipient, and differences in the care recipient's characteristics, frequency of neuropsychiatric symptoms, and disease severity. DLB caregiver support for this population should target psychoeducation for complicated neuropsychiatric symptoms in the care recipient. Screening all DLB caregivers for burden, grief, and depression is suggested to identify those that may benefit most from intervention. Spouses specifically may benefit from interventions that target increasing social support, while adult child caregivers may benefit from interventions aimed at mitigating burden and improving quality of life.


Cultural similarity, cultural competence, and nurse workforce diversity.
Proponents of health workforce diversity argue that increasing the number of minority health care providers will enhance cultural similarity between patients and providers as well as the health system's capacity to provide culturally competent care. Measuring cultural similarity has been difficult, however, given that current benchmarks of workforce diversity categorize health workers by major racial/ethnic classifications rather than by cultural measures. This study examined the use of national racial/ethnic categories in both patient and registered nurse (RN) populations and found them to be a poor indicator of cultural similarity. Rather, we found that cultural similarity between RN and patient populations needs to be established at the level of local labor markets and broadened to include other cultural parameters such as country of origin, primary language, and self-identified ancestry. Only then can the relationship between cultural similarity and cultural competence be accurately determined and its outcomes measured.


Association between underweight and tooth loss among Korean adults.
There is growing interest in the relationship between body mass index and oral health. Previous study showed that being underweight was significantly associated with having lower masticatory performance. This study was performed to assess the relationship between an underweight body mass index lower than 18.5 and the number of natural teeth using nationally representative data. Initially, a total of 25,534 individuals were candidates in the Korean National Health and Nutrition Examination Survey. The analysis in this study was confined to 17,870 subjects who were 19 years or older and without missing values for outcome variables. Body mass index and number of natural teeth were evaluated. Multiple regression analysis was used to evaluate the risk of tooth loss in relation to body mass index. Adjusted odds ratios and their 95% confidence intervals for chewing discomfort in individuals who were underweight, normal, overweight, obese, and extremely obese were 1.712(1.156-2.535), 1.111(0.939-1.315), 1(reference), 0.949(0.798-1.128), and 1.172(0.807-1.700), respectively, after adjustment. The association between underweight and tooth loss was proven by multiple logistic regression analyses after adjusting for confounding factors. Underweight may be considered a potential risk indicator for tooth loss in Korean adults.


Supercontinuum generation in quadratic nonlinear waveguides without quasi-phase matching.
Supercontinuum generation (SCG) is most efficient when the solitons can be excited directly at the pump laser wavelength. Quadratic nonlinear waveguides may induce an effective negative Kerr nonlinearity, so temporal solitons can be directly generated in the normal (positive) dispersion regime overlapping with common ultrafast laser wavelengths. There is no need for waveguide dispersion engineering. Here, we experimentally demonstrate SCG in standard lithium niobate (LN) waveguides without quasi-phase matching (QPM), pumped with femtosecond pulses in the normal dispersion regime. The observed large bandwidths (even octave spanning), together with other experimental data, indicate that negative nonlinearity solitons are indeed excited, which is backed up by numerical simulations. The QPM-free design reduces production complexity, extends the maximum waveguide length, and limits undesired spectral resonances. Finally, nonlinear crystals can be used where QPM is inefficient or impossible, which is important for mid-IR SCG. QPM-free waveguides in mid-IR nonlinear crystals can support negative nonlinearity solitons, as these waveguides have a normal dispersion at the emission wavelengths of mid-IR ultrafast lasers.


Functional balance and dual-task reaction times in older adults are improved by virtual reality and biofeedback training.
Virtual reality (VR) training has been used successfully to rehabilitate functional balance and mobility in both traumatic brain injury (TBI) survivors and elderly subjects. Similarly, computer-based biofeedback (BF) training has resulted in decreased sway during quiet stance and decreased reaction times during a dual-task reaction time paradigm in elderly subjects. The objective of this study was to determine the effect of VR and BF training on balance and reaction time in older adults. Two groups of twelve healthy older adults completed 10-week training programs consisting of two 30-min sessions per week. VR training required that participants lean sideways to juggle a virtual ball. Participants in the BF group viewed a red dot representing their center of gravity on a screen and were required to move the dot to the four corners of the monitor. Measures of functional balance and mobility (Community Balance and Mobility Scale [CB&M]), sway during quiet stance, and reaction time during a dual task paradigm were recorded before training, as well as 1 week and 1 month after the end of the program. Both groups showed significant improvements on the CB&M, as well as decreased reaction times with training. Postural sway during quiet stance did not change significantly.


Photocurrent generation with two-dimensional van der Waals semiconductors.
Two-dimensional (2D) materials have attracted a great deal of interest in recent years. This family of materials allows for the realization of versatile electronic devices and holds promise for next-generation (opto)electronics. Their electronic properties strongly depend on the number of layers, making them interesting from a fundamental standpoint. For electronic applications, semiconducting 2D materials benefit from sizable mobilities and large on/off ratios, due to the large modulation achievable via the gate field-effect. Moreover, being mechanically strong and flexible, these materials can withstand large strain (>10%) before rupture, making them interesting for strain engineering and flexible devices. Even in their single layer form, semiconducting 2D materials have demonstrated efficient light absorption, enabling large responsivity in photodetectors. Therefore, semiconducting layered 2D materials are strong candidates for optoelectronic applications, especially for photodetection. Here, we review the state-of-the-art in photodetectors based on semiconducting 2D materials, focusing on the transition metal dichalcogenides, novel van der Waals materials, black phosphorus, and heterostructures.


[Periodic structure of physiologic and pathologic tremor].
By the method of a spectral analysis and intervalography the authors studied the changes of finger tremor in intellectual and nitroglycerine tests in 45 normals and 15 patients with funkctional disorders of the CNS. The studies demonstrated some similarities between the frequency characteristics of the physiological tremor and the EEG. On the basis of electromyographical examination of 115 patients with cerebral atherosclerosis the authors systematized different forms of pathological tremor according to the topical principle. The conclusion is made that the state of the brain has a certain influence on the dynamics of the periodical structure of tremor.


Chinese hamster cell variants resistant to the A chain of ricin carry altered ribosome function.
Ricin, a toxic lectin from Ricinus communis, is composed of two different polypeptide chains, A and B, and the ricin A chain (RA) blocks protein synthesis. We studied cell lines resistant to cytotoxic action of RA. One low-RA-resistant cell line, AR10, isolated from Chinese hamster ovary (CHO) cells, was resistant to a low dose of RA (1 microgram/ml) and showed a 10-fold-higher resistance to RA and ricin than that of CHO. We further mutagenized AR10 to isolate high-RA-resistant cell lines AR100-6, AR100-9, and AR100-13, which were resistant to higher doses of RA and ricin (100- to 1,000-fold) than CHO was. The binding of [125I]ricin to AR10, AR100-6, AR100-9, and AR100-13 cells was decreased to about 30% of that of CHO. The internalization of [125I]ricin in AR10 cells and in the high-RA-resistant clones was the same. Polyuridylate-dependent polyphenylalanine synthesis, using S-30 extracts from either AR100-9 or AR100-13, was about 100-fold more resistant to the inhibitory action of RA than when CHO, AR10, and AR100-6 cells extracts were used. The protein synthesis with ribosomes (80S) from AR100-9 or AR100-13 was 10- to 100-fold more resistant to RA than it was with parental ribosomes when combined with the S-100 fraction of CHO cells. The polyphenylalanine synthesis assay using the ribosomes constituted from the 60S subunit of AR100-9 and the 40S subunit of CHO indicated that the resistant phenotype of AR100-9 cells is due to an alteration of the 60S ribosomal subunit.


Subcellular localization of diffusible ions in the yeast Saccharomyces cerevisiae: quantitative microprobe analysis of thin freeze-dried sections.
In yeast cells, of which the intracellular potassium had been partly replaced by rubidium or caesium, the intracellular ion distribution was studied by means of energy-dispersive X-ray microanalysis. The cells were rapidly frozen and thin sections were cut at low temperature on a cryo-ultramicrotome without the use of a trough liquid. By this dry cryosectioning procedure, complete retention of the diffusbile ions in the cells was obtained. Unless the sections had been exposed to moisture, no signs of redistribution were apparent. For quantitative determinations a gelatin standard, containing known amounts of the elements of interest, was prepared in the same way as the cells. The concentrations of potassium, rubidium, caesium and chloride in the nucleus, the cytoplasm and the vacuole could be measured. The intracellular distributions of potassium, rubidium and caesium were very similar. The concentrations of these ions in the cytoplasm were about equal to those in the nucleus and twice those in the vacuole. The total concentration in the cytoplasm was 180-190 mmol/kg fresh weight, in the nucleus 190-200 mmol/kg fresh weight and in the vacuole 75-90 mmol/kg fresh weight. The permeability of the yeast cell for chloride is markedly lower than for the cations.


Limiting dilution analysis of virus-specific memory B cells by an ELISPOT assay.
Many acute viral infections induce long-term, sometimes even life-long humoral immunity. To characterize this immune response, accurate quantitation of memory B cells and plasma cells is essential. Plasma cells can be quantitated directly ex vivo by virtue of their ability to spontaneously secrete antibody. Memory B cells on the other hand, do not spontaneously secrete antibody but require antigenic stimulation in order to proliferate and differentiate into antibody secreting cells (ASC). In this study, an ELISPOT-based limiting dilution assay (LDA) was developed for quantitating virus-specific B cell memory following acute lymphocytic choriomeningitis virus (LCMV) infection of adult mice. Antiviral memory B cell precursor (MBCp) frequencies were calculated from in vitro stimulated cultures using either a conventional ELISA-based LDA to measure accumulated virus-specific antibody in the culture medium or a new ELISPOT-based LDA that identifies the antibody-secreting daughter cells directly. In terms of sensitivity, the ELISPOT-based LDA and the ELISA-based LDA both calculated LCMV-specific MBCp frequencies to be approximately 1/2 x 10(4) spleen cells. However, compared to the 12 days of in vitro stimulation required to estimate MBCp frequencies by the ELISA-based LDA, the ELISPOT-based LDA required only 3-6 days of stimulation to quantitate MBCp frequencies. If cell division was blocked by gamma-irradiation or treatment with mitomycin C, the MBCp frequency dropped below detection (< 1 MBCp/10(6) cells), indicating that virus-specific B cells quantitated by this assay must both proliferate and differentiate into antibody secreting cells in order to be detected. Naive, uninfected mice did not have LCMV-specific memory B cells, demonstrating that only in vivo-generated antiviral B cells from LCMV-immune mice were detected by this assay. chi 2 analysis of the ELISPOT-based LDA showed that the MBCp frequency data fit a linear regression model (p = 0.0137), indicating single-hit kinetics in which only one cell type was limiting. These results indicate that the ELISPOT-based LDA provides a rapid and statistically accurate method to quantitate virus-specific B cells.


The exoskeleton expansion: improving walking and running economy.
Since the early 2000s, researchers have been trying to develop lower-limb exoskeletons that augment human mobility by reducing the metabolic cost of walking and running versus without a device. In 2013, researchers finally broke this 'metabolic cost barrier'. We analyzed the literature through December 2019, and identified 23 studies that demonstrate exoskeleton designs that improved human walking and running economy beyond capable without a device. Here, we reviewed these studies and highlighted key innovations and techniques that enabled these devices to surpass the metabolic cost barrier and steadily improve user walking and running economy from 2013 to nearly 2020. These studies include, physiologically-informed targeting of lower-limb joints; use of off-board actuators to rapidly prototype exoskeleton controllers; mechatronic designs of both active and passive systems; and a renewed focus on human-exoskeleton interface design. Lastly, we highlight emerging trends that we anticipate will further augment wearable-device performance and pose the next grand challenges facing exoskeleton technology for augmenting human mobility.


An RNAi-based approach to down-regulate a gene family in vivo.
Genetic redundancy poses a major problem to the analysis of gene function. RNA interference allows the down-regulation of several genes simultaneously, offering the possibility to overcome genetic redundancy, something not easily achieved with traditional genetic approaches. Previously we have used a polycistronic miR155-based framework to knockdown expression of three genes of the early B cell factor family in cultured cells. Here we develop the system further by generating transgenic mice expressing the RNAi construct in vivo in an inducible manner. Expression of the transgene from the strong CAG promoter is compatible with a normal function of the basal miRNA/RNAi machinery, and the miR155 framework readily allows inducible expression from the Rosa26 locus as shown by Gfp. However, expression of the transgene in hematopoietic cells does not lead to changes in B cell development and neuronal expression does not affect cerebellar architecture as predicted from genetic deletion studies. Protein as well as mRNA levels generated from Ebf genes in hetero- and homozygous animals are comparable to wild-type levels. A likely explanation for the discrepancy in the effectiveness of the RNAi construct between cultured cells and transgenic animals lies in the efficiency of the sequences used, possibly together with the complexity of the transgene. Since new approaches allow to overcome efficiency problems of RNAi sequences, the data lay the foundation for future work on the simultaneous knockdown of several genes in vivo.


Multi-Gaussian phase function model for off-axis laser beam scattering.
Within the small-angle approximation, a multi-Gaussian phase function model provides a new description of the multiple-scattering process and leads to improved agreement with experimental data. A general formula for the off-axis laser beam irradiance is given explicitly for a two-component Gaussian phase function. The predictions of the theory are compared with both the calculations based on the Mie scattering phase function and the results of measurements. It appears that the best fit of the model to experimental results requires an adjustment of the weight factors of the component phase functions. The solution, written in the form of a multiple-scattering series, allows one to interpret individual terms of the scattering series as scattering events of different orders.


SOX11 contributes to the regulation of GDF5 in joint maintenance.
Individual skeletal elements of the vertebrate limbs arise through a segmentation process introducing joints in specific locations. However, the molecular pathways controlling joint formation and subsequent joint maintenance are largely unknown. In this study, we focused on SOX11, and its contribution to the regulation of GDF5, a secreted signal necessary for proper joint formation and postnatal joint homeostasis. Sox11 is initially expressed broadly in the murine cartilage condensations at early stages of skeletal development, but its expression is specifically increased in the forming joint interzone as is forms. SOX11 overexpression can directly activate GDF5 expression both in vitro and in micromass cell cultures prepared from chick limb buds. Conserved SOX family binding sites are present in the 5' UTR region of the GDF5 gene and we show SOX11 can specifically bind to one of them. While misexpression of Sox11 in developing chick limbs through RCAS virus infection does not induce Gdf5 expression in ectopic locations, it does enhance its expression. To explore the roles of Sox11 in joint homeostasis, we analyzed adult knee joints in an osteoarthritis mouse model where the medial meniscus and the medial collateral ligament were removed. We also analyzed knee joints from human subjects who underwent total knee replacement surgery. We find that SOX11 is mainly expressed in the weight-bearing areas of knee joints, and its expression is decreased in degraded cartilage during progression of knee osteoarthritis in both mice and humans. This work implicates SOX11 as a potential regulator of GDF5 expression in joint maintenance and suggests a possible role in the pathogenesis of osteoarthritis.


The noradrenaline receptor coupled adenylate cyclase system in brain. Lack of modification by changes in the availability of serotonin.
The present studies were undertaken to ascertain whether or not an alteration in the availability of serotonin (5HT) can modify central noradrenergic function at the level of the noradrenaline (NA) receptor coupled adenylate cyclase system in brain. The chronic but not acute administration of the 5HT uptake inhibitors amitriptyline and chlorimipramine reduced the sensitivity of the cyclic AMP generating system to NA in the limbic forebrain. This subsensitivity was linked to a decrease in the Bmax value of beta-adrenergic binding sites without appreciable changes in the Kd values, as assessed by specific 3H-dihydroalprenolol binding. The specific 5HT uptake inhibitor fluoxetine did not change either the responsiveness of the cyclic AMP generating system to NA or the density of beta-adrenergic receptor sites. Raphé lesions which selectively reduced the level of 5HT also did not cause any changes in the neurohormonal responsiveness or the density of beta-adrenergic receptor sites. In contrast, medial forebrain bundle lesions which reduced the levels of both 5HT and catecholamines (NA and dopamine) in the forebrain, increased the responsiveness of the cyclic AMP generating system to NA. It can thus be concluded that a selective change in the availability of 5HT per se does not modify noradrenergic receptor function at the level of the NA receptor coupled adenylate cyclase system. The subsensitivity of the noradrenergic receptor system developed following amitriptyline and chlorimipramine may in all likelihood be due to the in vivo conversion to the secondary amines, nortriptyline and desmethylchlorimipramine respectively. These secondary amine metabolites are potent inhibitors of the NA reuptake and consequently could be responsible for the demonstrated in vivo down-regulation of central adrenergic receptor function (homospecific down-regulation).


Geriatrics, interprofessional practice, and interorganizational collaboration: a knowledge-to-practice intervention for primary care teams.
Caring for frail seniors requires health professionals with skills and knowledge in 3 core competencies: geriatrics, interprofessional practice, and interorganizational collaboration. Despite a growing population of frail seniors in all developed countries, significant gaps exist in preparation of health professionals in these skills. To help close these gaps, a knowledge-to-practice (KTP) process was undertaken to increase the capacity of newly created family health teams and longer standing Community Health Centers in the Province of Ontario, Canada. Each team identified a staff member to become its facilitator in the 3 core skill sets. Guided by a KTP framework, a set of training modules were created, compiled into a digital toolkit for transfer into practice, translated in a multimethods workshop, and implemented using a variety of strategies to optimize practice change. Staff from 82% of the targeted primary care teams learned to use the toolkit in a train-the-facilitator process that was highly valued, and prompted a range of changes in personal and team practice. A digital toolkit for primary care teams remains an enduring and often used resource. Closing the knowledge gap in the core competencies for frailty focused care is complex. A KTP framework helped guide a staged multimethod process that produced both individual and team practice change and on online toolkit that has a continuing influence.


Wheeze in preschool children: who is followed-up, who is treated and who is hospitalized?
This study determined the proportions of children < or = 5 yrs of age with reported wheeze who were undergoing medical follow-up, receiving anti-asthma medication, or admitted to hospital; and investigated factors important in determining which children would receive these treatments. The symptomatic children represented a wheeze prevalence of 16% of the study sample of 1,422 children. The cumulative incidence of treatment and hospitalization and point prevalence of current medical follow-up were determined using a parent-answered postal questionnaire study of a population-based random sample of 222 children. Odds ratios (OR) were calculated for wheeze severity, environmental, social, familial and demographic factors found to affect the likelihood of these treatment end-points. Among 222 children with wheeze, 99 (35%) were under current medical review, 165 (75%) had received medication, and 48 (22%) reported being hospitalized. Current follow-up was more likely in girls (OR 2.22; 95% confidence interval (95% CI) 1.12-4.38), with more than three attacks of wheeze in the last year (OR 17.44; 95% CI 5.22-58.3), or with a household pet (cat or dog) where inhalants were wheeze precipitants (OR 13.65; 95% CI 3.16-58.94). Treatment became more likely in older children (OR 3.91; 95% CI 1.10-12.71), with inhalants as wheeze precipitants (OR 4.66; 95% CI 1.08-20.14) or with a household pet (OR 2.28; 95% CI 1.04-5.03). Hospitalization was less likely with frequent wheeze (OR 0.30; 95% CI 0.12-0.77), but more likely if shortness of breath occurred with wheeze. Medical follow-up and treatment are related to wheeze severity and exposure to inhaled precipitants, whereas hospital admission occurred in children with attacks causing shortness of breath, and with decreasing frequency of attacks per year.


Predictors of optimal virological response to potent antiretroviral therapy.
Current potent antiretroviral therapy (using a protease inhibitor and two nucleoside reverse transcriptase inhibitors) produces a durable suppression of HIV replication in less than 75% of treated patients. Identification of predictors of successful therapy might allow the development of improved strategies to increase response rates. We analyzed retrospectively the results from a multicenter, randomized, double-blind Phase III study of combination anti-HIV therapy with nelfinavir, zidovudine, and lamivudine to evaluate the relationship between virological response over 48 weeks of treatment to variables which could potentially serve as early predictors of long-term response. The goal was to produce long-term suppression of viral load to sensitive (<400 copies HIV RNA/ml) and ultrasensitive (<50 copies HIV RNA/ml) limits of quantification with the Amplicor PCR assay. Baseline viral load, the change in viral load over the first 4 weeks of treatment, the 2 h post-dose nelfinavir levels and the time to respond to HIV RNA levels of <400 copies/ml and <50 copies/ml have the best predictive value in determining response and response duration. Patients who achieved very low viral nadirs (<50 copies HIV RNA/ml) had significantly longer responses than those who achieved nadirs of 50-400 copies HIV RNA/ml. Parameters that can be measured easily at baseline or early after therapy is started can identify patients at high risk of failure with standard treatment. Such patients may be candidates for more aggressive therapy or for alternative strategies designed to improve outcome. In addition, these results support the use of ultra-sensitive HIV RNA assays to predict long-term outcome of anti-HIV therapy.