Effects of T lymphocytes, interleukin-1, and interleukin-6 on renal fibrosis in canine end-stage renal disease.
Canine end-stage renal disease (ESRD) is defined as the almost complete failure of renal function or irreversible destruction and is characterized by extensive glomerular sclerosis, tubular atrophy, interstitial inflammation, and fibrosis. Renal fibrosis is a common pathway leading to kidney failure. Infiltrating immunocytes in the end-stage kidney and several related factors are involved in renal fibrogenesis. A total of 18 renal tissue samples were obtained from canine patients with ESRD using biopsy and necropsy procedures. The extent of renal fibrosis was histopathologically examined by Masson trichrome staining. T-cell and B-cell localization and macrophage lineages were determined by immunohistochemical staining. Additionally, interleukin-1 (IL-1), IL-2, and IL-6 levels in the canine ESRD kidney were immunohistochemically evaluated and compared with expression patterns in the normal kidney. Significant fibrosis and infiltrating immunocytes consistent with lymphocytes were observed. Although the B-cell count was increased in the end-stage kidney, immunostaining patterns disclosed a marked increase in the number of CD3(+) cells. Furthermore, the remarkable increase in IL-1 and IL-6 levels suggests that T cells in the kidneys of dogs with ESRD spontaneously express these cytokines. In this study, the correlation between the degree of renal fibrosis and cytokines in canine ESRD was examined. The present study shows that T lymphocytes and IL-6 play important roles in renal fibrosis.


The thermal effect of lasers in urology: a review article.
Lasers as a technology have a leading role in the modern urological treatment armamentarium. In this article, the application of lasers in different areas of urology is described. The major uses are in urolithiasis, benign prostatic enlargement (BPE), and management of many urological malignancies and other benign pathologies. Lasers have become an established treatment modality in urolithiasis, an acceptable alternative with the least side effect profile in BPE patients, and a novel and promising therapy in many other fields of Urology.


Challenges for professional care of advanced dementia.
Qualitative methodology based on action research identified challenges when caring for persons with advanced dementia, as perceived by key professional providers. Data collection was via five focus groups (total n = 24) and 20 follow-up individual interviews. Participants included palliative care, aged care and dementia specialist nurses, medical specialists from an area health service, residential aged care staff and general medical practitioners. Responses emphasized the need for improved knowledge and skills, and clearer policy. Concerns included accurate assessment, especially of pain, owing to the inability of people with advanced dementia to communicate their symptoms. Assessment, managing physical and behavioural symptoms, and communicating with family presented as further challenges. Conclusions are that the need for a palliative approach to care in advanced dementia should be recognized. Aged care staff can deliver palliative care to people with advanced dementia only if the staff receive relevant education and training beyond their generalist competencies.


Apogossypolone (ApoG2) induces ROS-dependent apoptosis and reduces invasiveness of PC12 cells in vitro and in vivo.
Malignant pheochromocytoma is accurately diagnosed only at occurrence of metastatic foci. However, at that time, patients are less likely to get many benefits from traditional chemotherapy. Over-expression of BCL-2 family proteins is tightly correlated with progression of pheochromocytoma. ApoG2, as the most potent gossypol derivative, has exhibited anti-tumor activities in various tumors. In the present study, we found that the staining degree of Bcl-2 being stronger than Bax was more frequently observed in pheochromocytoma than adrenocorticohyperplasia, which was possibly related to shorter overall survival. In addition, ApoG2 could induce apoptosis through up-regulation of Bax and down-regulation of Bcl-2, increasing reactive oxygen species (ROS) levels, inducing cytochrome C release and cleaving caspase proteins. Most importantly, those inhibition effects were blocked by caspase activation inhibitor Z-VAD-fmk and antioxidant N-acetyl-L-cysteine. The above results were further confirmed in vivo. Furthermore, ApoG2 could effectively inhibit tumor movement capabilities. Altogether, our results indicated that ApoG2 was a potential effective target drug for pheochromocytoma.


A novel strategy for engineering vascularized grafts in vitro.
Tissue engineering is an interdisciplinary field promising new therapeutic means for replacing lost or severely damaged tissues or organs. However, the fabrication of complex engineered tissues has been hampered due to the lack of vascularization to provide sufficient blood supply after implantation. In this article, we propose using rapid prototyping technology to prefabricate a scaffold with an inside hollowed vascular system including an arterial end, a venous end and capillary networks between them. The scaffold will be ''printed'' layer by layer. When printing every layer, a ''low-melting point'' material will be used to form a blood vessel network and a tissue-specific material will be used outside it. Hereafter the 'low-melting point' material will be evacuated by vaporization to ensure a hollowed vessel network. Then the inside hollowed capillary network can be endothelialized by using autologous endothelial cells in a cycling bioreactor while the outside material can be embedded with tissue-special cells. In the end, the new vascularized autologous grafts could be transferred to the defect site by using microsurgical techniques to connect the grafts with the host artery and vein. The strategy would facilitate construction of complex tissue engineering if the hypothesis proved to be practical.


Molecular identification and diversity of enterococci isolated from Slovak Bryndza cheese.
Three hundred and eight presumed enterococcal isolates were recovered from Bryndza, a soft sheep milk cheese. The cheese samples were obtained from five different commercial distributors in Slovakia and were taken at three different seasonal intervals. All isolates were identified to the species level using genotypic tools. Species-specific PCR using ddl genes highlighted the predominance of Enterococcus faecium (176 isolates) and assigned 50 isolates to the species Enterococcus faecalis. The remaining 82 isolates were classified using repetitive element sequence-based polymerase chain reaction (PCR) with primer (GTG)(5)-(GTG)(5)-PCR, in combination with phenylalanyl-tRNA synthase gene (pheS) sequence analysis and by whole-cell protein analysis (SDS-PAGE). These strains were identified as Enterococcus durans (59 strains), Enterococcus italicus (8 strains), Enterococcus casseliflavus (3 strains), Enterococcus gallinarum (3 strains), Enterococcus hirae (1 strain), and 8 strains were members of the species Lactococcus lactis. Of the seven enterococcal species isolated, three of them, E. durans, E. faecalis and E. faecium were present in all samples studied, with E. faecium as the predominant one. The precise identification of enterococci in Bryndza cheese is an essential step in the process of evaluation of their functional properties which will be further studied and assessed.


Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood-Brain Barrier and Suppresses Growth of Glioblastoma.
n-Butylidenephthalide (BP) has anti-tumor effects on glioblastoma. However, the limitation of BP for clinical application is its unstable structure. A polycationic liposomal polyethylenimine (PEI) and polyethylene glycol (PEG) complex (LPPC) has been developed to encapsulate BP for drug structure protection. The purpose of this study was to investigate the anti-cancer effects of the BP/LPPC complex on glioblastoma in vitro and in vivo. DBTRG-05MG tumor bearing xenograft mice were treated with BP and BP/LPPC and then their tumor sizes, survival, drug biodistribution were measured. RG2 tumor bearing F344 rats also treated with BP and BP/LPPC and then their tumor sizes by magnetic resonance imaging for evaluation blood-brain barrier (BBB) across and drug therapeutic effects. After treated with BP/LPPC in vitro, cell uptake, cell cycle and apoptotic regulators were analyzed for evaluation the therapeutic mechanism. In athymic mice, BP/LPPC could efficiently suppress tumor growth and prolong survival. In F334 rats, BP/LPPC crossed the BBB and led to tumor shrinkage. BP/LPPC promoted cell cycle arrest at the G0/G1 phase and triggered the extrinsic and intrinsic cell apoptosis pathways resulting cell death. BP/LPPC also efficiently suppressed VEGF, VEGFR1, VEGFR2, MMP2 and MMP9 expression. BP/LPPC was rapidly and efficiently transported to the tumor area across the BBB and induced cell apoptosis, anti-angiogenetic and anti-metastatic effects in vitro and in vivo.


Formulation of the rotational transformation of wave fields and their application to digital holography.
Rotational transformation based on coordinate rotation in Fourier space is a useful technique for simulating wave field propagation between nonparallel planes. This technique is characterized by fast computation because the transformation only requires executing a fast Fourier transform twice and a single interpolation. It is proved that the formula of the rotational transformation mathematically satisfies the Helmholtz equation. Moreover, to verify the formulation and its usefulness in wave optics, it is also demonstrated that the transformation makes it possible to reconstruct an image on arbitrarily tilted planes from a wave field captured experimentally by using digital holography.


[The process of drug development. The "case" of spironolactone].
In the progressive understanding of the heart failure syndrome different models have followed. Current pathophysiology model suggests that heart failure is a neurohormonal disorder: an abnormality in cardiac function and a disturbance in myocardial contractile force is the initiating event in heart failure, and the clinical expression and progression of the disease occurs as a result of subsequent extracardiac alterations. Treatment with drugs capable of antagonizing the effects of neuroendocrine activation, such as angiotensin-converting enzyme inhibitors, beta-blockers and antialdosterone agents have induced a significant reduction in morbidity and mortality in heart failure patients. The progressive understanding of the circulating homeostasis mechanisms moved from the systemic to the paracrine aspects of the neurohormonal systems and contributed to the development of new drugs. Moreover, the analysis of a drug's development can be an important step in the medical knowledge advancement. In this sense, aldosterone and spironolactone became an interesting "case", which is analyzed in this paper, going through the steps that have promoted the spironolactone from a weak diuretic to a neurohormonal drug and, finally, to a "central" drug.


Comparative Analysis of Liver Injury-Associated Cytokines in Acute Hepatitis A and B.
Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.


Risk of fracture in women with glucocorticoid requiring diseases is independent from glucocorticoid use: An analysis on a nation-wide database.
Glucocorticoid-induced osteoporosis (GIOP) is a common cause of secondary osteoporosis. However, glucocorticoid requiring diseases pose a risk themselves for fracture. The aim of the present study was to determine the risk of fracture associated with variety of glucocorticoid requiring diseases independently from glucocorticoid use and other risk factors for osteoporosis. We conducted a retrospective cross-sectional analysis of a nation-wide cohort (DeFRACalc79 database). We used multivariable regression analysis adjusting for several risk factors for fracture and glucocorticoid intake to estimate the independent role of glucocorticoid requiring illnesses on fracture risk. We found that patients with rheumatoid arthritis, connective tissue diseases, chronic obstructive pulmonary disease (COPD) and neurological diseases were at greater risk of vertebral or hip fracture (crude ORs 1.31, 1.20, 1.92 and 2.97 respectively). After adjusting for potential confounders COPD and neurological diseases remained significantly associated with an increased risk of vertebral or hip fractures (aORs 1.33, 95 % CI 1.18-1.49 and 2.43, 95 % CI 2.17-2.74). Rheumatoid arthritis, COPD, IBD and neurological diseases also significantly increased the risk of non-vertebral, non-hip fractures (aORs 1.23, 1.42, 1.52 and 1.94 respectively). Some glucocorticoid requiring diseases were independently associated with an increased risk of fractures. COPD and neurological diseases with both vertebral and non-vertebral fracture risk while RA and IBD were independently associated only with non-vertebral, non-hip fractures.


Replacing the emulsion for bake-on siliconization of containers - comparison of emulsion stability and container performance in the context of protein formulations.
Pre-filled syringes have simplified parenteral administration of protein drugs. To ensure an easy and consistent movement of the plunger, the inner glass container surface is typically siliconized. For bake-on siliconization emulsions are sprayed on and heat treated. Due to the European Union regulation REACh (Regulation concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals) the use of certain emulsion components, partially constituting the gold standard Liveo™ 365 35% Dimethicone NF Emulsion (Liveo™ 365), becomes restricted and Liveo™ 366 35% Dimethicone NF Emulsion (Liveo™ 366) has been introduced as an alternative. This change may affect the handling properties as well as the silicone layer formed. The purpose of these studies was to identify any differences that may influence the stability and safety of the final drug/device combination product to enable the use of the new emulsion. We compared silicone emulsions Liveo™ 365 and Liveo™ 366 and dilutions focusing on I) their general physical stability, II) the thermal degradation process of the emulsions and their components, and III) the resulting silicone layer concerning chemistry, morphology, and functionality. The results were linked to the assessment of the final product regarding particle formation and long-term stability. A comparison of the emulsions Liveo™ 365 and Liveo™ 366 for bake-on siliconization is presented to support the transition of the latter as it becomes mandatory with REACh. Our studies show that the two emulsions do not significantly differ with respect to handling and stability, the resultant silicone layer characteristics as well as its functionality. We conclude that the transition to the new emulsion will not significantly impact the final product or the layer performance upon storage and with respect to particle formation.


Beta-adrenoceptors and responsiveness in cardiac hypertrophy associated with renal hypertension in renovascular hypertensive rats.
The possible contribution of changes in cardiac beta-adrenoceptors to alterations in cardiac responses to isoprenaline were investigated in hearts isolated from rats with renovascular hypertension (two-kidney, one-clip Goldblatt), 6, 12 and 18 weeks after renal artery clipping. Cardiac responses were determined in vitro (Langendorff preparation), and ventricular beta-adrenoceptors [( 3H]dihydroalprenolol, [3H]DHA) were then assayed in the same 44 hearts. There was no difference between renovascular hypertensive rats (RHR) and matched normotensive controls as regards chronotropic responses to isoprenaline or in atrial beta-adrenoceptor numbers or apparent affinity. Inotropic responses were significantly lower in all stages of RHR than in matched normotensive controls. There was also a significant (P less than 0.001) decrease in ventricular beta-adrenoceptor density with no significant change in apparent affinity (Kd). Inotropic responsiveness to isoprenaline (max. increment in peak dP/dt) was significantly correlated with ventricular beta-adrenoceptor density (r = 0.54, P = 0.0005). These results suggest that the reduction of ventricular beta-adrenoceptor density in that model of hypertension was responsible, at least partially, for the lowered inotropic responsiveness of the same hearts to isoprenaline.


Ketogenic Diet and Skeletal Muscle Hypertrophy: A Frenemy Relationship?
Ketogenic diet (KD) is a nutritional regimen characterized by a high-fat and an adequate protein content and a very low carbohydrate level (less than 20 g per day or 5% of total daily energy intake). The insufficient level of carbohydrates forces the body to primarily use fat instead of sugar as a fuel source. Due to its characteristic, KD has often been used to treat metabolic disorders, obesity, cardiovascular disease, and type 2 diabetes. Skeletal muscle constitutes 40% of total body mass and is one of the major sites of glucose disposal. KD is a well-defined approach to induce weight loss, with its role in muscle adaptation and muscle hypertrophy less understood. Considering this lack of knowledge, the aim of this review was to examine the scientific evidence about the effects of KD on muscle hypertrophy. We first described the mechanisms of muscle hypertrophy per se, and secondly, we discussed the characteristics and the metabolic function of KD. Ultimately, we provided the potential mechanism that could explain the influence of KD on skeletal muscle hypertrophy.


Short-term global health research projects by US medical students: ethical challenges for partnerships.
Recent interest in global health among medical students has grown drastically, and many students now spend time abroad conducting short-term research projects in low-resource settings. These short-term stints in developing countries present important ethical challenges to US-based students and their medical schools as well as the institutions that host such students abroad. This paper outlines some of these ethical issues and puts forth recommendations for ethically mindful short-term student research.


Kaempferol suppresses lipid accumulation by inhibiting early adipogenesis in 3T3-L1 cells and zebrafish.
Kaempferol is a flavonoid present in Kaempferia galanga and Opuntia ficus indica var. saboten. Recent studies have suggested that it has anti-oxidant, anti-inflammatory, anti-cancer, and anti-obesity effects. In this study, we focused on the anti-adipogenic effects of kaempferol during adipocyte differentiation. The results showed that kaempferol inhibits lipid accumulation in adipocytes and zebrafish. Oil Red O and Nile Red staining showed that the number of intracellular lipid droplets decreased in adipocytes and zebrafish treated with kaempferol. LPAATθ (lysophosphatidic acid acyltransferase), lipin1, and DGAT1 (triglyceride synthetic enzymes) and FASN and SREBP-1C (fatty acid synthetic proteins) showed decreased expression levels in the presence of kaempferol. In addition, treatment of kaempferol showed an inhibitory activity on cell cycle progression. Kaempferol delayed cell cycle progression from the S to G2/M phase through the regulation of cyclins in a dose-dependent manner. Kaempferol blocked the phosphorylation of AKT (protein kinase B) and mammalian target of rapamycin (mTOR) signaling pathway during the early stages of adipogenesis. In addition, kaempferol down-regulated pro-early adipogenic factors such as CCAAT-enhancer binding proteins β (C/EBPβ), and Krüppel-like factors (KLFs) 4 and 5, while anti-early adipogenic factors, such as KLF2 and pref-1(preadipocyte factor-1), were upregulated. These kaempferol-mediated regulations of early adipogenic factors resulted in the attenuation of late adipogenic factors such as C/EBPα and peroxisome proliferator-activated receptor γ (PPARγ). These results were supported in zebrafish based on the decrease in lipid accumulation and expression of adipogenic factors. Our results indicated that kaempferol might have an anti-obesity effect by regulating lipid metabolism.


Terminalia gum as a directly compressible excipient for controlled drug delivery.
The exudates from the incised trunk of Terminalia randii has been evaluated as controlled release excipient in comparison with xanthan gum and hydroxypropylmethylcellulose (HPMC) using carvedilol (water insoluble) and theophylline (water soluble) as model drugs. Matrix tablets were prepared by direct compression and the effects of polymer concentration and excipients-spray dried lactose, microcrystalline cellulose and dicalcium phosphate dihydrate on the mechanical (crushing strength (CS) friability (F) and crushing strength-friability ratio (CSFR)) and drug release properties of the matrix tablets were evaluated. The drug release data were fitted into different release kinetics equations to determine the drug release mechanism(s) from the matrix tablets. The results showed that the CS and CSFR increased with increase in polymer concentration while F decreased. The ranking of CS and CSFR was HPMC > terminalia > xanthan while the ranking was reverse for F. The ranking for t(25) (i.e. time for 25% drug release) at a polymer concentration of 60% was xanthan > terminalia = HPMC. The dissolution time, t(25), of theophylline matrices was significantly lower (p < 0.001) than those of carvedilol matrix tablets. Drug release from the matrices was by swelling, diffusion and erosion. The mechanical and drug release properties of the tablets were significantly (p < 0.05) dependent on the type and concentration of polymer and excipients used with the release mechanisms varying from Fickian to anomalous. Terminalia gum compared favourably with standard polymers when used in controlled release matrices and could serve as a suitable alternative to the standard polymers in drug delivery.


Risk of breast cancer in women with history of benign disease of the breast.
A consecutive series of 791 women who had attended diagnostic breast clinics during 1967-70 and been found to be free of malignant disease were later traced to determine their subsequent incidence of breast cancer. Of the 770 (97%) successfully traced, 22 had developed breast cancer. Based on data from the Welsh Cancer Registry only eight cases of breast cancer had been expected, so that the excess risk for the group was 2.7. The increased risk occurred in all age groups and in women deemed "essentially normal" as well as in those who had had a pathological abnormality. The risk was increased when epithelial hyperplasia was present. No excess mortality from breast cancer was apparent, but follow up was short. More breast symptoms were experienced and more biopsies performed than expected in this group of women. Women with a past history of benign breast disease have a slightly increased risk of breast cancer. Selective screening of these women, however, may be uneconomic and a cause of groundless anxiety.


The pelvic girdle questionnaire: a condition-specific instrument for assessing activity limitations and symptoms in people with pelvic girdle pain.
No appropriate measures have been specifically developed for pelvic girdle pain (PGP). There is a need for suitable outcome measures that are reliable and valid for people with PGP for use in research and clinical practice. The objective of this study was to develop a condition-specific measure, the Pelvic Girdle Questionnaire (PGQ), for use during pregnancy and postpartum. This was a methodology study. Items were developed from a literature review and information from a focus group of people who consulted physical therapists for PGP. Face validity and content validity were assessed by classifying the items according to the World Health Organization's International Classification of Functioning, Disability and Health. After a pilot study, the PGQ was administered to participants with clinically verified PGP by means of a postal questionnaire in 2 surveys. The first survey included 94 participants (52 pregnant), and the second survey included 87 participants (43 pregnant). Rasch analysis was used for item reduction, and the PGQ was assessed for unidimensionality, item fit, redundancy, and differential item functioning. Test-retest reliability was assessed with a random sample of 42 participants. The analysis resulted in a questionnaire consisting of 20 activity items and 5 symptom items on a 4-point response scale. The items in both subscales showed a good fit to the Rasch model, with acceptable internal consistency, satisfactory fit residuals, and no disordered threshold. Test-retest reliability showed high intraclass correlation coefficient estimates: .93 (95% confidence interval=0.86-0.96) for the PGQ activity subscale and .91 (95% confidence interval=0.84-0.95) for the PGQ symptom subscale. Limitations The PGQ should be compared with low back pain questionnaires as part of a concurrent evaluation of measurement properties, including validity and responsiveness to change. The PGQ is the first condition-specific measure developed for people with PGP. The PGQ had acceptably high reliability and validity in people with PGP both during pregnancy and postpartum, it is simple to administer, and it is feasible for use in clinical practice.


Control of hypertension in adults with chronic kidney disease in the United States.
Although improved control of hypertension is known to attenuate progression of chronic kidney disease (CKD), little is known about the adequacy of hypertension treatment in adults with CKD in the United States. Using data from the Fourth National Health and Nutrition Survey, we assessed adherence to national hypertension guideline targets for patients with CKD (blood pressure <130/80 mm Hg), we assessed control of systolic (<130 mm Hg) and diastolic (<80 mm Hg) blood pressure, and we evaluated determinants of adequate blood pressure control. Presence of CKD was defined as glomerular filtration rate <60 mL/min per 1.73 m2 or presence of albuminuria (albumin:creatinine ratio >30 microg/mg). Multivariable logistic regression with appropriate weights was used to determine predictors of inadequate hypertension control and related outcomes. Among 3213 participants with CKD, 37% had blood pressure <130/80 mm Hg (95% confidence interval [CI], 34.5% to 41.8%). Of those with inadequate blood pressure control, 59% (95% CI, 54% to 64%) had systolic >130 mm Hg, with diastolic < or =80 mm Hg, whereas only 7% (95% CI, 3.9 to 9.8%) had a diastolic pressure >80 mm Hg, with systolic blood pressure < or =130 mm Hg. Non-Hispanic black race (odds ratio [OR], 2.4; 95% CI, 1.5 to 3.9), age >75 years (OR, 4.7; 95% CI, 2.7 to 8.2), and albuminuria (OR, 2.4; 95% CI, 1.4 to 4.1) were independently associated with inadequate blood pressure control. We conclude that control of hypertension is poor in participants with CKD and that lack of control is primarily attributable to systolic hypertension. Future guidelines and antihypertensive therapies for patients with CKD should target isolated systolic hypertension.


Postmortem computed tomography in victims of military air mishaps: radiological-pathological correlation of CT findings.
A thorough medical inquiry is included in every aviation mishap investigation. While the gold standard of this investigation is a forensic pathology examination, numerous reports stress the important role of computed tomography in the postmortem evaluation of trauma victims. To characterize the findings identified by postmortem CT and compare its performance to conventional autopsy in victims of military aviation mishaps, we analyzed seven postmortem CT examinations. Musculoskeletal injuries accounted for 57.8% of the traumatic findings identified by postmortem CT. The most frequent findings were fractures of the rib (47%), skull (9.6%) and facial bones (8.6%). Abnormally located air accounted for 24% of findings, for which CT was superior (3.5% detected by autopsy, 100% by postmortem CT, P < 0.001). The performance of autopsy in detecting injuries was superior (autopsy detected 85.8% of all injuries, postmortem CT detected 53.9%, P < 0.001), especially in the detection of superficial lesions (100% detected by autopsy, 10.5% by postmortem CT, P < 0.001) and solid organ injuries (100% by autopsy, 18.5% by postmortem CT, P < 0.001). Performance in the detection of musculoskeletal injuries was similar (91.3% for autopsy, 90.3% for postmortem CT, P = not significant). Postmortem CT and autopsy have distinct performance profiles, and although the first cannot replace the latter it is a useful complementary examination.


Vasoprotective effect of PDGF-CC mediated by HMOX1 rescues retinal degeneration.
Blood vessel degeneration is critically involved in nearly all types of degenerative diseases. Therefore strategies to enhance blood vessel protection and survival are highly needed. In this study, using different animal models and cultured cells, we show that PDGF-CC is a potent vascular protective and survival factor. PDGF-CC deficiency by genetic deletion exacerbated blood vessel regression/degeneration in various animal models. Importantly, treatment with PDGF-CC protein not only increased the survival of retinal blood vessels in a model of oxygen-induced blood vessel regression but also markedly rescued retinal and blood vessel degeneration in a disease model of retinitis pigmentosa. Mechanistically, we revealed that heme oxygenase-1 (HMOX1) activity is critically required for the vascular protective/survival effect of PDGF-CC, because blockade of HMOX1 completely abolished the protective effect of PDGF-CC in vitro and in vivo. We further found that both PDGF receptors, PDGFR-β and PDGFR-α, are required for the vasoprotective effect of PDGF-CC. Thus our data show that PDGF-CC plays a pivotal role in maintaining blood vessel survival and may be of therapeutic value in treating various types of degenerative diseases.


[Angiographically unexplained myocardial ischemia in high grade coronary stenosis with main stem involvement in intravascular ultrasound].
For seven weeks a 57-year-old man had been complaining of recurrent non-radiating retrosternal pain and pressure on slightest exertion. Admission physical examination was unremarkable except for evidence of peripheral vascular disease. Cardiovascular risk factors were hypertension, hyperlipoproteinaemia and obesity. The resting ECG was unremarkable. Objective signs of myocardial ischaemia were produced in the exercise ECG (angina at 100 Watt, negative T waves in V2 to V6 and borderline S-T depression in V4). Myocardial scintigraphy showed reversible reduced perfusion of the anterior wall near the apex and also of the apex and septum. Left ventricular (LV) angiography demonstrated a normally contracting LV, while selective coronary angiogram revealed a 20% reduction in caliber of the proximal branch of the anterior interventricular branch (AIVB), with otherwise normal coronary arteries. Subsequent intravascular ultrasound (IVUS) showed a circular echo-poor 80% stenosis at the origin of the AIVB with extension to the main stem. A bypass from the internal mammary artery to the AIVB and an aortocoronary venous bypass to the intermediate branch were performed. The patient was free of symptoms postoperatively. If cases where there is a discrepancy between clinical and coronary angiographic findings--the latter being unclear or inconsistent, especially in the area of the left main stem, bifurcations or vessel origin--IVUS may contribute decisively to demonstrating coronary anatomy or pathology, and to indicating the type of revascularizing measures.


Analysis of the serum components in acute period after subarachnoid hemorrhage.
Multi-profile monitoring of various blood serum factors during acute subarachnoid haemorrhage (SAH) is crucial for successful treatment. The aim of the study is to evaluate the serum concentration of different blood factors in the acute period of SAH. 31 patients with confirmed aneurysmal SAH were enrolled in a prospective study. The concentrations of the following serum compounds were assessed on the day of admission and reassessed after 5 days: lipids profile, cardiac functionality enzymes and markers, electrolytes, osmolality, CRP (C-reactive protein), glucose, creatinine, urine. The mean level of high-density lipoprotein (HDL) changed significantly from 43.9±23.9 mg/dL to 27.5±19,8 mg/dL, p=0,013 (mean dif. 16.5±14,1 mg/dL; 37,3%). Concentration of low-density lipoprotein (LDL) decreased by 28.6% (mean dif. 26.78±61.32; p=0.047). Values of triglicerydes and total cholesterol did not differ significantly between the initial evaluations and these repeated after 5 days. The overall serum ions (Na < sup > + < /sup > , K < sup > + < /sup > , Mg < sup > 2+ < /sup > , Ca < sup > 2+ < /sup > ) concentrations and osmolality did not differ significantly between the initial measurements and after 5 days from SAH. The only mean value that appeared to be substantially increased at initial measurement was NT-proBNP and reached 1928.8±4952 pg/ ml, this value dropped down to 392.87±1147.9 mg/ml after 5 days (mean dif. 1535.96±4808.76 pg/ml; 79,6%; p = 0.247). CRP increased over 2 fold after 5 days up to 29.267±28.614 mg/L (mean dif. 16.06±34.05 pg/L; 121.6%; p=0.028). At 5-day follow up hematocrit dropped to 33.38 ± 3.81% from the initial value of 39.63 ± 2,56% (p=0.02). This study showed a significant decrease in the serum level of LDL and HDL, while triglycerides were moderately heightened. Routine monitoring of lipid profile and statin administration at the early stage of SAH is recommended.


Conformational analysis of PKI(5-22)amide, the active inhibitory fragment of the inhibitor protein of the cyclic AMP-dependent protein kinase.
Fourier-transform i.r. spectroscopy, 1H-n.m.r. spectroscopy and X-ray scattering were used to study the conformation and shape of the peptide PKI(5-22)amide, which contains the active site of the inhibitor protein of the cyclic AMP-dependent protein kinase [Cheng, Van Pattern, Smith & Walsh (1985) Biochem. J. 231, 655-661]. The X-ray-scattering solution studies show that the peptide has a compact structure with Rg 0.9 nm (9.0 A) and a linear maximum dimension of 2.5 nm (25A). Compatible with this, Fourier-transform i.r. and n.m.r. determinations indicate that the peptide contains approx. 26% alpha-helix located in the N-terminal one-third of the molecule. This region contains the phenylalanine residue that is one essential recognition determinant for high-affinity binding to the protein kinase catalytic site.


The HIV epidemic in Jamaica: a need to strengthen the National HIV Program.
To assess the status of the HIV epidemic and programmatic implementation in Jamaica while identifying strategies for achieving effective HIV control. The assessment included a review of the core indicators of the UNAIDS Global Monitoring Framework, a desk review of program reports, and unstructured interviews of stakeholders. HIV prevalence among adults in Jamaica was 1.5% in 2018 with an estimated 32 617 persons living with HIV (PLHIV) and 27 324 persons (83.8%) diagnosed with HIV; 12 711 (39.0% of all PLHIV or 46.5% aware of their status) were on anti-retroviral therapy (ART) in the public health sector and 61.8% PLHIV on ART were virally suppressed. HIV prevalence among men who have sex with men remains high (31.4% in 2011, 29.6% in 2017) but has declined among female sex workers (12% in 1990, 2% in 2017). HIV prevalence among public sexually transmitted infection clinic attendees, prison inmates and the homeless has increased in recent years. During 2018 approximately 200 000 persons (14% of the population 15-49 years) were tested with 1 165 newly diagnosed PLHIV, indicating that many of the estimated 1 600 newly infected persons in 2018 were unaware of their status. Critical policy initiatives are needed to reduce barriers to HIV services, ensure young persons have access to condoms and contraceptives, affirm the rights of the marginalized, reduce stigma and discrimination, and introduce pre-exposure prophylaxis. While HIV spread in Jamaica has slowed, the UNAIDS Fast Track goals are lagging. The HIV program must be strengthened to effectively control the epidemic.


[Double aortic arch with dominant left arch: case report].
A vascular ring is defined as an anomaly of the great arteries (aortic arch and its branches) that compresses the trachea or esophagus. Double aortic arch is the most common vascular ring. Double aortic arch is very rare and typically becomes symptomatic in infancy or early childhood. We present a 7-year-old girl admitted to our clinic for evaluation of recurrent respiratory infection with dysphagia. Double aortic arch was suspected from echocardiography and diagnosed with cardiac computed tomography. Left aortic arcus was larger than the right at computed tomography and cardiac catheterisation. After surgery the symptoms improved strikingly. We conclude that vascular ring should be considered in the patients presenting with recurrent pulmonary infections and dysphagia. Early diagnosis and treatment may prevent chronic, irreversible complications.


Comparison of the 2000 and 2005 outbreaks of tularemia in the Duzce region of Turkey.
Tularemia caused by Francisella tularensis, which is considered a biological warfare agent, is a widely distributed zoonosis. In this study, we aimed to compare a 2005 outbreak of tularemia that was confirmed as waterborne by PCR to outbreak of tularemia that was reported as waterborne in 2000 and to investigate the changes of epidemiological characteristics between these two outbreaks occurring in the same region. In the present study, a total of 11 patients were diagnosed with tularemia. In the 2000 outbreak, oropharyngeal type was observed 19 patients, and ulceroglandular type in 3 patients. In the 2005 outbreak, oropharyngeal type was observed in 8 patients, and oculoglandular type in 3 patients. However, our cases are not sufficient to make a conclusion that the characteristics of tularemia seem to be changing.


Peripubertal aromatase inhibition in male rats has adverse long-term effects on bone strength and growth and induces prostatic hyperplasia.
Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved.


Self-Assembling RNA Nanoparticle for Gene Expression Regulation in a Model System.
In the search for enzymatically processed RNA fragments, we found the novel three-way junction motif. The structure prediction suggested the arrangement of helices at acute angle approx. 60°. This allows the design of a trimeric RNA nanoparticle that can be functionalized with multiple regulatory fragments. Such RNA nano-object of equilateral triangular shape was applied for gene expression regulation studies in two independent cellular systems. Biochemical and functional studies confirmed the predicted shape and structure of the nanoparticle. The regulatory siRNA fragments incorporated into the nanoparticle were effectively released and triggered gene silencing. The regulatory effect was prolonged when induced with structuralized RNA compared to unstructured siRNAs. In these studies, the enzymatic processing of the motif was utilized for function release from the nanoparticle, enabling simultaneous delivery of different regulatory functions. This methodology of sequence search, RNA structural prediction, and application for rational design opens a new way for creating enzymatically processed RNA nanoparticles.


Building medical image classifiers with very limited data using segmentation networks.
Deep learning has shown promising results in medical image analysis, however, the lack of very large annotated datasets confines its full potential. Although transfer learning with ImageNet pre-trained classification models can alleviate the problem, constrained image sizes and model complexities can lead to unnecessary increase in computational cost and decrease in performance. As many common morphological features are usually shared by different classification tasks of an organ, it is greatly beneficial if we can extract such features to improve classification with limited samples. Therefore, inspired by the idea of curriculum learning, we propose a strategy for building medical image classifiers using features from segmentation networks. By using a segmentation network pre-trained on similar data as the classification task, the machine can first learn the simpler shape and structural concepts before tackling the actual classification problem which usually involves more complicated concepts. Using our proposed framework on a 3D three-class brain tumor type classification problem, we achieved 82% accuracy on 191 testing samples with 91 training samples. When applying to a 2D nine-class cardiac semantic level classification problem, we achieved 86% accuracy on 263 testing samples with 108 training samples. Comparisons with ImageNet pre-trained classifiers and classifiers trained from scratch are presented.


Polymer-anchored DNA gene monolayers.
Monolayers of DNA chains of polymeric dimensions, considered here to be longer than approximately 100 nucleotides, are widely encountered in biomolecular diagnostics as well as present for a model system for investigating behavior of polyelectrolytes at interfaces. A major challenge in advancing such applications is assembling the DNA on the surface in a controlled way. Although covalent immobilization is expected to produce optimal stability, the multitude of potential reactive sites along the contour of long DNA molecules requires that any chemical transformations be strictly site-specific to preserve control over attachment geometry and function. A synthetic approach to fabricating monolayers of DNA genes on gold using polymeric anchor (adhesion) films is presented that (i) possesses stringent site-specificity of surface-attachment, (ii) exhibits excellent stability to elevated temperatures, allowing denaturation of duplex chains at 90 degrees C without loss of surface-linked strands, and (iii) achieves surface coverages suitable for investigating multichain polyelectrolyte behavior in regimes of strong interchain interactions.


Bayesian semiparametric copula estimation with application to psychiatric genetics.
This paper proposes a semiparametric methodology for modeling multivariate and conditional distributions. We first build a multivariate distribution whose dependence structure is induced by a Gaussian copula and whose marginal distributions are estimated nonparametrically via mixtures of B-spline densities. The conditional distribution of a given variable is obtained in closed form from this multivariate distribution. We take a Bayesian approach, using Markov chain Monte Carlo methods for inference. We study the frequentist properties of the proposed methodology via simulation and apply the method to estimation of conditional densities of summary statistics, used for computing conditional local false discovery rates, from genetic association studies of schizophrenia and cardiovascular disease risk factors.


Visual feedback and anticipatory hand orientation during infants' reaching.
Infants 5, 7, and 9 mo. of age were videorecorded while reaching for a dowel that either was stationary or changed orientation after initiation of a reach. Visual fixation and hand orientation were monitored throughout each reach, as was the efficiency with which infants contacted the stimulus. In reaching for the stationary stimulus, the 5-mo.-olds showed significantly poorer hand orientation adjustment throughout their reach than 9-mo.-olds. The 7-mo.-olds began a reach with the hand poorly oriented as did 5-mo.-olds, but just before object contact their performance matched that of the 9-mo.-olds. On change-orientation trials, the 5-mo.-olds' reaching was disrupted. They missed, stopped, or withdrew their reach on over half of these trials, and hand orientation on contact was significantly worse than on no-change trials. By contrast, older infants were more skilled in using visual feedback to make corrective adjustments in hand orientation during execution of the reach to secure a smooth contact with the stimulus. These infants showed no difference in hand orientation on contact for change in comparison to no-change trials. The 9-mo.-olds' performance surpassed that of the 7-mo.-olds only in the efficiency with which they contacted the stimulus and the incidence of grasps on first contact.


A Microsoft-Excel-based tool for running and critically appraising network meta-analyses--an overview and application of NetMetaXL.
The use of network meta-analysis has increased dramatically in recent years. WinBUGS, a freely available Bayesian software package, has been the most widely used software package to conduct network meta-analyses. However, the learning curve for WinBUGS can be daunting, especially for new users. Furthermore, critical appraisal of network meta-analyses conducted in WinBUGS can be challenging given its limited data manipulation capabilities and the fact that generation of graphical output from network meta-analyses often relies on different software packages than the analyses themselves. We developed a freely available Microsoft-Excel-based tool called NetMetaXL, programmed in Visual Basic for Applications, which provides an interface for conducting a Bayesian network meta-analysis using WinBUGS from within Microsoft Excel. . This tool allows the user to easily prepare and enter data, set model assumptions, and run the network meta-analysis, with results being automatically displayed in an Excel spreadsheet. It also contains macros that use NetMetaXL's interface to generate evidence network diagrams, forest plots, league tables of pairwise comparisons, probability plots (rankograms), and inconsistency plots within Microsoft Excel. All figures generated are publication quality, thereby increasing the efficiency of knowledge transfer and manuscript preparation. We demonstrate the application of NetMetaXL using data from a network meta-analysis published previously which compares combined resynchronization and implantable defibrillator therapy in left ventricular dysfunction. We replicate results from the previous publication while demonstrating result summaries generated by the software. Use of the freely available NetMetaXL successfully demonstrated its ability to make running network meta-analyses more accessible to novice WinBUGS users by allowing analyses to be conducted entirely within Microsoft Excel. NetMetaXL also allows for more efficient and transparent critical appraisal of network meta-analyses, enhanced standardization of reporting, and integration with health economic evaluations which are frequently Excel-based.


[Continuous dopaminergic stimulation, pulsatile dopaminergic stimulation].
Levodopa is the gold standard treatment for Parkinson's disease. The therapeutic effect may however be compromised by the inevitable risk of motor complications, with fluctuating motor control and dyskinesia, particularly in the younger patient. The Multiple pathophysiological mechanisms are undoubtedly involved but pulsed dopaminergic stimulation appears to play a determining role. This underlines the importance of a treatment which achieves a most stable and physiological dopaminergic stimulation as possible. Dopaminergic agonists provide a promising alternative. Another possibility is to modulate the peripheral kinetics of levodopa as soon as it is introduced using catechol-O-methyl transferase inhibitors.


Synthesis of membrane-bound colony-stimulating factor 1 (CSF-1) and downmodulation of CSF-1 receptors in NIH 3T3 cells transformed by cotransfection of the human CSF-1 and c-fms (CSF-1 receptor) genes.
NIH 3T3 cells cotransfected with the human c-fms proto-oncogene together with a 1.6-kilobase cDNA clone encoding a 256-amino-acid precursor of the human mononuclear phagocyte colony-stimulating factor CSF-1 (M-CSF) undergo transformation by an autocrine mechanism. The number of CSF-1 receptors on the surface of transformed cells was regulated by ligand-induced receptor degradation and was inversely proportional to the quantity of CSF-1 produced. A tyrosine-to-phenylalanine mutation at position 969 near the receptor carboxyl terminus potentiated its transforming efficiency in cells cotransfected by the CSF-1 gene but did not affect receptor downmodulation. CSF-1 was synthesized as an integral transmembrane glycoprotein that was rapidly dimerized through disulfide bonds. The homodimer was externalized at the cell surface, where it underwent proteolysis to yield the soluble growth factor. Trypsin treatment of viable cells cleaved the plasma membrane form of CSF-1 to molecules of a size indistinguishable from that of the extracellular growth factor, suggesting that trypsinlike proteases regulate the rate of CSF-1 release from transformed cells. The data raise the possibility that this form of membrane-bound CSF-1 might stimulate receptors on adjacent cells through direct cell-cell interactions.


SUBTLEX-UK: a new and improved word frequency database for British English.
We present word frequencies based on subtitles of British television programmes. We show that the SUBTLEX-UK word frequencies explain more of the variance in the lexical decision times of the British Lexicon Project than the word frequencies based on the British National Corpus and the SUBTLEX-US frequencies. In addition to the word form frequencies, we also present measures of contextual diversity part-of-speech specific word frequencies, word frequencies in children programmes, and word bigram frequencies, giving researchers of British English access to the full range of norms recently made available for other languages. Finally, we introduce a new measure of word frequency, the Zipf scale, which we hope will stop the current misunderstandings of the word frequency effect.


Diagnosing the ability of reservoir operations to meet hydropower production and fisheries needs under climate change in a western cordillera drainage basin.
Water regulation has contributed to the decline in Pacific salmon in British Columbia (Canada) despite attempts to manage reservoir operations to achieve operational requirements while meeting environmental needs to limit fish thermal stress. The ability of reservoir managers to meet these trade-offs in a changing climate is unknown. Here, we examine the reliability and vulnerability of the Nechako Reservoir to meet hydropower production commitments and fisheries needs under two projected Shared Socioeconomic Pathway scenarios (SSP2-4.5 and SSP5-8.5). While our findings are specific to the operation of the Nechako Reservoir, the issues that emerge are likely common to many reservoirs in areas where reservoir inflow regimes are currently snow-storage dominated. We found that projected changes in the timing of water availability have little to no influence on hydropower generation commitments. However, larger water releases will be required to avoid compromising reservoir safety, possibly endangering downstream fish habitat through scouring. Furthermore, the temperature of water released from the reservoir is projected to more frequently exceed a level, 20°C, that is detrimental to migrating sockeye salmon. Water released is subject to further warming as it travels towards the lower reaches of the Nechako River used by migrating salmon. Hence, there is a need to adapt reservoir operations to ensure reservoir safety and mitigate adverse effects on salmon habitat. The online version contains supplementary material available at 10.1007/s10584-023-03632-y.


Update on Nitazoxanide: A Multifunctional Chemotherapeutic Agent.
The thiazolide nitazoxanide (NTZ) is a broad-spectrum antiinfective drug that adversely affects viability, growth, and proliferation of a range of extracellular and intracellular protozoan, helminths, anaerobic and microaerophilic bacteria, and viruses. Current review compiled the potential chemotherapeutic efficacy of NTZ against a variety of such disease-causing macro and/or micro-organisms as well as neoplastic cells, using various search engines viz. Web of Science, Scopus and Pub- Med up to February 2017. The most accepted anti-infective mechanism of NTZ involves impairment of the energy metabolism in anaerobic pathogens by inhibition of the pyruvate: ferredoxin/ flavodoxin oxidoreductase (PFOR). In parasitic-protozoan NTZ also induces lesions/voids in the cell membrane and depolarises the mitochondrial membrane along with the inhibition of quinone oxidoreductase NQO1, nitroreductase-1 and protein disulphide isomerase. NTZ also inhibits the glutathione-S-transferase (a major detoxifying enzyme) and modulates a gene (avr-14 gene) encoding for the alphatype subunit of glutamate-gated chloride ion channel present in the nematodes. Apart from well recognized non-competitive inhibition of the PFOR in anaerobic bacteria, NTZ also showed a variety of other antibacterial mechanisms viz. inhibits pyruvate dehydrogenase in the Escherichia coli, disrupts the membrane potential and pH homeostasis in the Mycobacterium tuberculosis, suppresses the chaperone/usher (CU) pathway of the gram-negative bacteria and stimulates host macrophage autophagy in the tubercular patients. NTZ also suppresses the viral replication by inhibiting maturation of the viral hemagglutinin and the viral transcription factor immediate early 2 (IE2) as well as by activating the eukaryotic translation initiation factor 2α (an antiviral intracellular protein). Additionally, NTZ expresses inhibitory effect on the tumour cell progression by modulating drug detoxification (glutathione-S-transferase P1), unfolded protein response, autophagy, anti-cytokines activities and c-Myc inhibition. These potentially versatile molecular interactions of NTZ within invading pathogen(s) and immunomodulatory efficacy over the hosts, justify the multifunctional chemotherapeutic significance of this chemical agent.


Metformin and SGLT2i as First-line Combination Therapy in Type 2 Diabetes: A Real-world Study With a Focus on Ethnicity.
Suboptimal glucose control early in the diagnosis of type 2 diabetes (T2D) is strongly associated with subsequent morbidity and mortality, termed the 'glycaemic legacy'. Additionally, it is known that Asian and Black individuals are at increased risk of T2D, and its associated complications compared to their White counterparts. However, ethnicity does not currently feature in the treatment algorithm of T2D, unlike in other cardiovascular disease states such as hypertension. We therefore sought to evaluate the real-world impact of early intensive treatment with combination therapy on cardiorenal outcomes compared to standard treatment in T2D, with a focus on ethnicity. We performed a retrospective cohort study of all patients aged 18 or over with T2D using the TriNetX platform. TriNetX is a global collaborative network providing access to real time, anonymised medical records. We included patients who were initiated with Metformin and an SGLT2i within one month of diagnosis of T2D and compared this cohort with individuals who received Metformin only for a period of at least 1 year. We evaluated cardiovascular and renal outcomes at three years and stratified by ethnicity. We excluded individuals with a personal history of an outcome of interest. We identified 49,651 individuals with T2D who were treated with Metformin and an SGLT2i and 1,028,806 patients with T2D who were treated with Metformin alone. A total of 98,094 individuals were included in the core analysis. The Metformin only group had a greater risk of mortality (RR 1.44, [95% CI 1.34-1.55], P<0.0001), CKD (RR 1.10, [95% CI 1.04-1.16], P = 0.0004), diabetic nephropathy (RR 1.06, [95% CI 1.01-1.12], P = 0.0239), heart failure (RR 1.13, [95% CI 1.07-1.21], P < 0.0001) and hospitalisation (RR 1.24, [95% CI 1.21-1.27], P < 0.0001) compared to individuals treated with Metformin and SGLT2i. Black individuals had a reduced risk of mortality (RR 0.71, [95% CI 0.55-0.92], P = 0.0099) and IHD (RR 0.73, [95% CI 0.64-0.84], P < 0.0001) compared to White individuals. Asian individuals had a reduced risk of heart failure (RR 0.61, [95% CI 0.41-0.91], P = 0.0134) and hospitalisation (RR 0.76, [95% CI 0.66-0.87], P = 0.0001) compared to White individuals. Initial combination treatment within the first year of T2D diagnosis confers favourable cardio-metabolic outcomes when compared to standard therapy, even in patients without established cardiovascular disease. Black and Asian individuals in particular demonstrate a greater degree of benefit compared to White individuals. Further prospective studies with a focus on ethnicity are now required to validate these findings.


An investigation of liquid carryover and sample residual for a high-throughput flow cytometer sample delivery system.
The phenomenon of intersample contamination in air-segmented continuous-flow assays has been studied for many years, and new uses are being found for these sampling techniques every day. One application that has been developed recently employs a flow cytometer to conduct high-throughput screening assays of biological compounds. We have explored the sources of intersample contamination in the system and shown how methods developed previously can be applied to describe these phenomena. Using a simple model, we were able to accurately measure liquid film thickness in the sample tubing and demonstrate the effects of intersample contamination in a flow cytometer assay. Also, measures have been taken to reduce the level of intersample contamination in cytometric screening assays, helping to make the system a more viable tool for drug screening applications.


Systemic Lupus Erythematosus Presenting as Myopericarditis with Acute Heart Failure: A Case Report and Literature Review.
Acutely decompensated dilated cardiomyopathy in a middle-aged patient without the typical risk factor profile presents a clinical dilemma. While cardiomyopathy is a known aspect of systemic lupus erythematosus (SLE), initial clinical presentation as decompensated dilated cardiomyopathy (DCM) is exceedingly rare in the literature. We share the case of a 49-year-old African-American female with no past medical history who presented with overt heart failure of 4 weeks evolution. Workup showed acute onset decompensated dilated cardiomyopathy, with a serologic profile compatible with SLE. She responded well to immunosuppressive steroid therapy. Literature review for SLE presenting as dilated cardiomyopathy with acute heart failure revealed a paucity of clinical evidence and consensus. Therefore, a comprehensive review of case reports was undertaken. A total of 10 cases were identified. Patients were 90% female and averaged 31 years of age. Dyspnea was the most common clinical presentation, and dilated cardiomyopathy with severely compromised left ventricular function was universally appreciated. Clinical presentation to diagnosis averaged 2 weeks. Immunosuppressive therapy regimens were universally employed; however, the regimens varied significantly. High-dose steroid therapy was most commonly used, and clinical and functional recovery was reported in 90% of individual case reports. Within the limited evidence and experience of therapeutic approaches, the efficacy of different singular or combined therapy is based solely on anecdotal case reports. Given the near-complete response to a short course of high-dose steroid therapy as much in the clinical recovery as in the resolution of DCM, the limited evidence based on review of these observational case studies and series supports the initial use of high-dose steroid therapy in acute lupus myocarditis.


[Revision of failed acetabular cups with extensive structural allografts].
Structural allografts are used with encouraging results for revision of failed total hip arthroplasty and in the surgery of bone tumours. The aim of the present study is to describe the clinical and radiological results achieved with structural allografts in revision of a total hip arthroplasty. 15 patients (12 female and 3 male patients) were revised with an acetabular defect situation of type 3 A or 3 B according to the Paprosky classification. Five fresh-frozen acetabula, nine distal femora and one proximal tibia were used for acetabular reconstruction. The rigid graft fixation was performed with 2 > or = AO screws. In one case a cemented acetabular ring was implanted, four cementless cups and ten cemented polyethylene acetabular components were used. The mean follow-up was 7.9 years (1.6-11.0 years). A stable osseointegration of fifteen transplanted structural allografts was achieved in thirteen cases. Two allografts (one aseptic loosening, one deep infection) failed to osseointegrate. In one case the migration of a cementless cup was registered. Revision surgery of this female patient was performed successfully with a cemented reconstruction ring. The mean Harris hip score at the latest follow-up was 81.4 points (70-99 points). For reconstruction of acetabular bone stock and restoration of the bone anatomy structural allografts can be recommended. The use of cementless cups in combination with structural grafts is to be evaluated as critical.


A central role for the nuclear factor-kappaB pathway in anti-inflammatory and proinflammatory actions of mechanical strain.
Mechanical signals play an integral role in bone homeostasis. These signals are observed at the interface of bone and teeth, where osteoblast-like periodontal ligament (PDL) cells constantly take part in bone formation and resorption in response to applied mechanical forces. Earlier, we reported that signals generated by tensile strain of low magnitude (TENS-L) are antiinflammatory, whereas tensile strain of high magnitude (TENS-H) is proinflammatory and catabolic. In this study, we examined the mechanisms of intracellular actions of the antiinflammatory and proinflammatory signals generated by TENS of various magnitudes. We show that both low and high magnitudes of mechanical strain exploit nuclear factor (NF)-kappaB as a common pathway for transcriptional inhibition/activation of proinflammatory genes and catabolic processes. TENS-L is a potent inhibitor of interleukin (IL)-1 beta-induced I-kappaBbeta degradation and prevents dissociation of NF-kB from cytoplasmic complexes and thus its nuclear translocation. This leads to sustained suppression of IL-1beta-induced NF-kappaB transcriptional regulation of proinflammatory genes. In contrast, TENS-H is a proinflammatory signal that induces I-kappaBbeta degradation, nuclear translocation of NF-kappaB, and transcriptional activation of proinflammatory genes. These findings are the first to describe the largely unknown intracellular mechanism of action of applied tensile forces in osteoblast-like cells and have critical implications in bone remodeling.


Epigenetic silencing of argininosuccinate synthetase confers resistance to platinum-induced cell death but collateral sensitivity to arginine auxotrophy in ovarian cancer.
Evidence indicates that acquired resistance of cancers to chemotherapeutic agents can occur via epigenetic mechanisms. Down-regulation of expression of argininosuccinate synthetase (ASS1), the rate-limiting enzyme in the biosynthesis of arginine, has been associated with the development of platinum resistance in ovarian cancer treated with platinum-based chemotherapy. The aim of the present study was to analyse epigenetic regulation of ASS1 in ovarian cancer tissue taken at diagnosis and relapse and determine its significance as a predictor of clinical outcome in patients treated with platinum-based chemotherapy. In addition, expression and epigenetic regulation of ASS1 were analysed in human ovarian cancer cell lines, and ASS1 expression correlated with the ability of the lines to grow in media containing cisplatin, carboplatin or taxol or in arginine-depleted media. Our results show that aberrant methylation in the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines. ASS1 silencing conferred selective resistance to platinum-based drugs and conferred arginine auxotrophy and sensitivity to arginine deprivation. In ovarian cancer, ASS1 methylation at diagnosis was associated with significantly reduced overall survival (p = 0.01) and relapse-free survival (p = 0.01). In patients who relapse, ASS1 methylation was significantly more frequent at relapse (p = 0.008). These data establish epigenetic inactivation of ASS1 as a determinant of response to platinum chemotherapy and imply that transcriptional silencing of ASS1 contributes to treatment failure and clinical relapse in ovarian cancer. The collateral sensitivity of cells lacking endogenous ASS1 to arginine depletion suggests novel therapeutic strategies for the management of relapsed ovarian cancer.


Optical diffraction studies of crystalline structures in electron micrographs. II. Crystalline inclusions in mitochondria of human hepatocytes.
Unit cell dimensions of mitochondrial crystals were determined by optical diffraction analysis of electron micrographs of human liver biopsy specimens. Identical unit cells were found in pathologic material obtained from six patients with Wilson's disease, from one patient with sickle-cell hepatitis, and from two normal subjects. These measurements led to the conclusion that the crystals observed in patients and in normal subjects were probably chemically identical. Furthermore, the relatively large size of the unit cell limits the choices for its constituents to phospholipid micelles or to relatively large protein molecules.


[Phasmids. Properties and the use in genetic engineering. I. Construction of the phasmid vector].
A phasmid vector molecule designated pMYF11 has been constructed. The vector combines some useful features of plasmid and phage vector molecules. lambda pMYF11 is a hybrid of lambda 47.1 vector and pBR322 plasmid. CI- marker of pMYF11 is replaced with cI+ marker by recombination between the plasmid and prophage 434. The phasmid molecule can be used as a replacement vector for BamHI, HindIII, SalGI endonucleases. The maximum size of fragments to be cloned is 21 kilobase pairs. Positive selection for hybrid molecules is possible because of the Spi phenotype expression after replacement of the central HindIII or BamHI DNA fragment with foreign DNA. A library of Escherichia coli genes is constructed with the help of lambda pMYF11 as a vector molecule. A hybrid phage harboring genes of the proline operon is detected by means of complementation.


Overexpression of TIMP-2 mediated by recombinant adenovirus in rat abdominal aorta inhibits extracellular matrix degradation.
To investigate the effects of a tissue inhibitor of the matrix metalloproteinase-2 (TIMP-2) gene on the extracellular matrix of the abdominal aorta, models of rat abdominal aortic aneurysm were utilized and a solution of AdTIMP-2 was perfused into the abdominal aorta. The models of rat abdominal aortic aneurysm were constructed with intraluminal perfusion of the abdominal aorta with porcine pancreatic elastase, and an adenovirus solution carrying the TIMP-2 gene was transferred into the aorta by local perfusion. After 14 days, aortic wall elastin and collagen concentrations were measured with an image analysis system and fixed aortic tissues were examined by light microscopy for inflammation. No abdominal aortic aneurysms developed in TIMP-2 gene-transferred rat models, representing a marked decreased from control rats (p < 0.01). The elastic fibers and collagenous fibers were preserved with greater integrity in the AdTIMP-2 group than in the control group and inflammatory cells were seen in adventitial areas. The TIMP-2 gene mediated by adenovirus can renew the balance of degradation of the extracellular matrix caused by elastase and inhibit the formation of an abdominal aortic aneurysm. This finding provides a new strategy for treatment of abdominal aortic aneurysms.


Molecular Evolution of MERS Coronavirus: Dromedaries as a Recent Intermediate Host or Long-Time Animal Reservoir?
While dromedary camels are the immediate animal source of MERS coronavirus (MERS-CoV) infection, the evolutionary origin of MERS-CoV remains obscure. We analyzed 219 camel and human MERS-CoV genome sequences available in GenBank. Phylogenetic analysis showed that 5 and 214 strains belong to clade A and B, respectively, with clade A further divided into lineage A1 (3 human strains) and lineage A2 (2 camel strains), and clade B divided into B1 to B6 (each containing both human and camel strains). Recombination analysis showed potential recombination events in five strains from dromedaries in Saudi Arabia, with recombination between lineage B5 and B3 in four strains, and between lineage B3 and B4 in one strain. The spike protein showed the highest number of amino acid substitutions, especially between A2 and other lineages, and contained positively selected codons. Notably, codon 1020 was positively selected among B and B5 strains, and can distinguish between clade A (Q1020) and B (R1020/H1020) strains, suggesting that this residue may play a role in the evolution of S protein during divergence of different lineages. The time of the most recent common ancestor of all MERS-CoV was dated to approximately 2010. The implications on the role of camels in the evolution of MERS-CoV are discussed.


CircPTCH1 Promotes Migration in Lung Cancer by Regulating MYCN Expression Through miR-34c-5p.
The incidence rate and mortality rate of lung cancer are the highest in the world. Therefore, further studies are needed to reveal the molecular mechanism of lung cancer progression and development. Previous study demonstrated that the deregulation of circRNAs can regulate cell biological functions in tumorigenesis and development. However, the roles of circPTCH1 in lung cancer have not yet been revealed. The expression levels of circPTCH1, miR-34c-5p, and MYCN were measured by RT-PCR in lung cancer tissues and cells; dual-luciferase reporter and RIP assay showed that circRNA served as a sponge for miRNA, and miRNA could target mRNA. In vitro, effects of si-circPTCH1 can regulate lung cancer cells' migration, invasion were detected by CCK-8 assay, wound healing assay, and transwell assay. Our research demonstrated that the expression of circPTCH1 was upregulated in lung cancer tissues and cell lines and increased in metastatic tissues compared to that of non-metastatic tissues. circPTCH1 sponging miR-34c-5p to target MYCN was revealed by dual-luciferase reporter and a RIP assay. In addition, the expression level of miR-34c-5p was reduced in lung cancer tumor tissues, and MYCN was significantly increased in lung cancer tumor tissues. Pearson correlation analysis showed that miR-34c-5p with circPTCH1 and MYCN had a moderately negative correlation, and there was a moderately positive correlation between circPTCH1 and MYCN. Further, cytological studies found that circPTCH1 reduced lung cancer cells' migration and invasion by targeting MYCN via miR-34c-5p. circPTCH1 plays a tumor enhancement role in lung cancer and that can effectively promote migration, invasion and EMT by targeting the miR-34c-5p/MYCN axis. circPTCH1 may be a novel potential treatment and diagnosis biomarker for lung cancer.


Steviol glycosides modulate glucose transport in different cell types.
Extracts from Stevia rebaudiana Bertoni, a plant native to Central and South America, have been used as a sweetener since ancient times. Currently, Stevia extracts are largely used as a noncaloric high-potency biosweetener alternative to sugar, due to the growing incidence of type 2 diabetes mellitus, obesity, and metabolic disorders worldwide. Despite the large number of studies on Stevia and steviol glycosides in vivo, little is reported concerning the cellular and molecular mechanisms underpinning the beneficial effects on human health. The effect of four commercial Stevia extracts on glucose transport activity was evaluated in HL-60 human leukaemia and in SH-SY5Y human neuroblastoma cells. The extracts were able to enhance glucose uptake in both cellular lines, as efficiently as insulin. Our data suggest that steviol glycosides could act by modulating GLUT translocation through the PI3K/Akt pathway since treatments with both insulin and Stevia extracts increased the phosphorylation of PI3K and Akt. Furthermore, Stevia extracts were able to revert the effect of the reduction of glucose uptake caused by methylglyoxal, an inhibitor of the insulin receptor/PI3K/Akt pathway. These results corroborate the hypothesis that Stevia extracts could mimic insulin effects modulating PI3K/Akt pathway.


The amyloid precursor protein of Alzheimer disease in human brain and blood.
Studies of the metabolism and function of the amyloid precursor protein (APP) and its proteolytic fragment A beta in cultured cells, transgenic mice, and post-mortem brain tissue have advanced our understanding of Alzheimer disease (AD). However, the molecular pathogenesis of the disease is still not clear, and we are a long way from finding a cure for the disease. Studies carried out on human platelets and leukocytes have also helped shed light on APP and A beta metabolism and function. Platelet and leukocyte APP isoforms are processed using mechanisms similar to those in neuronal cells to generate A beta and soluble forms of APP. The activation of platelets and leukocytes leads to the secretion of APP and A beta, resulting in higher levels of these proteins in serum. APP and A beta in the circulation may be involved in the regulation of platelet function and in the modulation of immune responses. Because human platelets and lymphocytes produce all forms of APP and secrete amyloidogenic A beta peptides, these tissues may be useful in monitoring responses to therapeutic interventions directed at APP metabolism. Although not of neuronal origin, further studies on the more accessible ex vivo tissues, including platelets and leukocytes and other blood components, may reveal potential peripheral markers for AD and will further our understanding of the molecular pathogenesis of AD.


Comprehensive molecular characterization of gastric cancer patients from phase II second-line ramucirumab plus paclitaxel therapy trial.
Gastric cancer (GC) is a heterogenous disease consisted of several subtypes with distinct molecular traits. The clinical implication of molecular classification has been limited especially in association with treatment efficacy of ramucirumab or various targeted agents. We conducted a prospective non-randomized phase II single-arm trial of ramucirumab plus paclitaxel as second-line chemotherapy in 62 patients with metastatic GC who failed to respond to first-line fluoropyrimidine plus platinum treatment. For integrative molecular characterization, all patients underwent pre-ramucirumab treatment tissue biopsy for whole-exome/whole-transcriptome sequencing to categorize patients based on molecular subtypes. We also systematically performed integrative analysis, combining genomic, transcriptomic, and clinical features, to identify potential molecular predictors of sensitivity and resistance to ramucirumab treatment. Sixty-two patients were enrolled in this study between May 2016 and October 2017. Survival follow-up in all patients was completed as of the date of cut-off on January 2, 2019. No patient attained complete response (CR), while 22 patients achieved confirmed partial response (PR), resulting in a response rate (RR) of 35.5% (95% CI, 23.6-47.4). According to TCGA molecular classification, there were 30 GS, 18 CIN, 3 EBV, and 0 MSI tumors. The RR was 33% in GS (10/30), 33% in CIN (6/18), and 100% in EBV-positive GC patients with significant statistical difference for EBV(+) against EBV(-) tumors (P = 0.016; chi-squared test). Moreover, responsive patients were marked by activation of angiogenesis, VEGF, and TCR-associated pathways, while non-responder patients demonstrated enrichments of sonic hedgehog signaling pathway and metabolism activity. Integrative multi-layer data analysis further identified molecular determinants, including EBV status, and somatic mutation in GNAQ to ramucirumab activity. Prospective molecular characterization identified a subset of GC patients with distinct clinical response to ramucirumab therapy, and our results demonstrate the feasibility of personalized therapeutic opportunities in gastric cancer. The study was registered on ClinicalTrial.gov ( NCT02628951 ) on June 12, 2015.


Cerebral and lower limb near-infrared spectroscopy in adults on extracorporeal membrane oxygenation.
Percutaneous femoral venoarterial (VA) or jugular venovenous (VV) extracorporeal membrane oxygenation (ECMO) can result in delivery of hypoxic blood to the brain, coronaries, and upper extremities. Additionally, VA-ECMO by percutaneous femoral artery cannulation may compromise perfusion to the lower limbs. Use of near-infrared spectroscopy (NIRS) detects regional ischemia and warns of impending hypoxic damage. We report the first known series with standardized monitoring of this parameter in adults on ECMO. This is an institutional review board-approved single institution retrospective review of patients with NIRS monitoring on ECMO from July 2010 until June 2011. Patients were analyzed for drops in NIRS tracings below 40 or >25% from baseline. VA-ECMO and VV-ECMO were initiated by percutaneous cannulation of the femoral vessels and the internal jugular vein, respectively. Sensors were placed on the patients' foreheads and on the lower limbs. NIRS tracings were recorded, analyzed, and correlated with clinical events. Twenty patients were analyzed (median age: 47.5 years): 17 patients were placed on VA-ECMO, and three patients on VV-ECMO. The median duration on ECMO was 7 days (range 2-26). One hundred percent of patients had a significant drop in bilateral cerebral oximetry tracings resulting in hemodynamic interventions, which involved increasing pressure, oxygenation, and/or ECMO flow. In 16 patients (80%), these interventions corrected the underlying ischemia. Four patients (20%) required further diagnostic intervention for persistent decreased bilateral and/or unilateral cerebral oximetry tracings, and were found to have a cerebrovascular accident (CVA). Six (30%) patients had persistent unilateral lower limb oximetry events, which resolved upon placement or replacement of a distal perfusion cannula. No patient was found to have either lower limb ischemia or a CVA with normal NIRS tracings. Use of NIRS with ECMO is important in detecting ischemic cerebral and peripheral vascular events. This allows for potential correction of the underlying process, thus preventing permanent ischemic damage.


Parent-Child Relationship Quality as a Mediator of the Association between Perceived Stress and Diabetes Self-Management in Adolescents With Type 1 Diabetes.
Diabetes self-management is suboptimal in adolescents with type 1 diabetes (T1D), including those in China. The aim of the study was to investigate the impact of parent-child relationship quality on diabetes self-management. Data were collected by a self-report survey among 122 Chinese adolescents from April to July 2017. The data were analyzed using a one-way analysis of variance, descriptive analyses, correlation analyses, and mediation analyses. The mean age was 13.8 (range, 10-18) years, and the mean diabetes duration was 4.1 (±3.1) years. About half of the adolescents with T1D experienced high levels of perceived stress. Parent-child relationship quality mediated the associations between perceived stress and collaboration with parents, diabetes care activities, and diabetes communication on aspects of diabetes self-management (ps < 0.05). To reduce the negative impacts of perceived stress on diabetes self-management in this population, parent-child relationship quality should be considered an important element of family-based interventions and clinical practice.


Effect of cytokines on the production of endothelin by endothelial cells.
Circulating levels of endothelin (ET), a potent vasoconstrictor peptide and a mitogen for smooth muscle cells and fibroblasts, are reported to be increased in a variety of human diseases characterized by vascular pathology. In view of the probable immune bases for vascular injury in connective tissue disorders, we examined the effect of the cytokines IL-1 alpha, IL-4, IL-6, TNF-alpha and lymphotoxin on the production of ET-1 by cultured vascular endothelial cells. ET levels in endothelial cell conditioned media were measured by radioimmunoassay. IL-4 and lymphotoxin had no effect on ET release by endothelial cells, while IL-6, TNF-alpha and IL-1 alpha stimulated ET mRNA expression and ET release in a dose dependent fashion. IL-6 was the most potent stimulator and IL-1 was the least effective. The addition of neutralizing antibodies to the cytokines inhibited the observed increase in ET release. These results suggest that cytokines may play a significant role in the control of vascular tone. Furthermore, cytokines may indirectly contribute to the development of proliferative vascular lesions by stimulating smooth muscle and interstitial cell proliferation through their effects on endothelin release by the vascular endothelium.


Patient Reported Outcomes Measurements Information System in Stroke Patients in Full and Shortened Format.
Introduction: The modified Rankin Scale (mRS) after 90 days documents outcome in stroke patients, but focusses only on activities of daily living. Here we studied stroke outcome beyond these activities by the Dutch-Flemish version of the Patient Reported Outcomes Measurement Information System (PROMIS) questionnaire. Patients and Methods: We documented the mRS at day 90 in stroke patients who filled out a questionnaire on pain intensity and seven PROMIS domains: physical function, ability to participate in social roles, anxiety, fatigue, depression, sleep disturbance, pain interference. In a subgroup of patients this questionnaire was reduced to one overall question per PROMIS domain. We correlated these findings with the mRS. Results: We received 102 questionnaires and identified physical function as the most affected PROMIS domain. The strongest correlation with mRS was found for the health domains of physical function (ρs = 0.70, p < 0.001) and ability to participate in social roles (ρs = 0.61, p < 0.001). The other domains with substantial proportions of patients with worse scores compared to the general population (19-44%) correlated weakly with the mRS. We identified a strong correlation between the single question per health domain and the overall score per PROMIS domain. Discussion and Conclusion: PROMIS better reflects the overall health status of stroke patients beyond functional outcome as measured by the mRS. Simplification of the questionnaire with a single question per PROMIS domain could potentially replace the full questionnaire, but needs further validation.


Characterization of a cDNA sequence encoding the peroxisome proliferator activated receptor alpha in the chicken.
Peroxisome proliferator-activated receptors (PPAR) belong to the superfamily of the nuclear hormone receptors that play an important role in lipid homeostasis. A partial complementary deoxyribonucleic acid clone encoding a PPAR alpha from chicken liver was isolated and sequenced. Comparison with human, mouse, rat, and Xenopus PPAR alpha cDNA indicates a high degree of homology, especially at the level of the inferred peptide sequence (greater than 90%). The tissue pattern of expression indicates that PPAR alpha expression in the chicken is similar to that reported in other species, i.e., high expression levels in the liver, heart, and kidney, but also occurs in the lipogenic uropygial gland specific to birds.


Platelet-Rich Plasma Versus Hyaluronic Acid for Knee Osteoarthritis: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
Platelet-rich plasma (PRP) and hyaluronic acid (HA) are 2 nonoperative treatment options for knee osteoarthritis (OA) that are supposed to provide symptomatic relief and help delay surgical intervention. To systematically review the literature to compare the efficacy and safety of PRP and HA injections for the treatment of knee OA. Meta-analysis of level 1 studies. A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to identify level 1 studies that compared the clinical efficacy of PRP and HA injections for knee OA. The search phrase used was platelet-rich plasma hyaluronic acid knee osteoarthritis randomized. Patients were assessed via the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analog scale (VAS) for pain, and Subjective International Knee Documentation Committee (IKDC) scale. A subanalysis was also performed to isolate results from patients who received leukocyte-poor and leukocyte-rich PRP. A total of 18 studies (all level 1) met inclusion criteria, including 811 patients undergoing intra-articular injection with PRP (mean age, 57.6 years) and 797 patients with HA (mean age, 59.3 years). The mean follow-up was 11.1 months for both groups. Mean improvement was significantly higher in the PRP group (44.7%) than the HA group (12.6%) for WOMAC total scores (P < .01). Of 11 studies based on the VAS, 6 reported PRP patients to have significantly less pain at latest follow-up when compared with HA patients (P < .05). Of 6 studies based on the Subjective IKDC outcome score, 3 reported PRP patients to have significantly better scores at latest follow-up when compared with HA patients (P < .05). Finally, leukocyte-poor PRP was associated with significantly better Subjective IKDC scores versus leukocyte-rich PRP (P < .05). Patients undergoing treatment for knee OA with PRP can be expected to experience improved clinical outcomes when compared with HA. Additionally, leukocyte-poor PRP may be a superior line of treatment for knee OA over leukocyte-rich PRP, although further studies are needed that directly compare leukocyte content in PRP injections for treatment of knee OA.


Effect of CD14 blockade in rabbits with Escherichia coli pneumonia and sepsis.
CD14, a pattern recognition receptor found on myeloid cells, is a critical component of the innate immune system that mediates local and systemic host responses to Gram-negative and Gram-positive bacterial products. Previous studies in normal animals have tested the effect of CD14 blockade on the systemic response to i.v. LPS. The goals of the study were to determine whether CD14 blockade protected against the deleterious systemic response associated with Escherichia coli pneumonia and to determine whether this strategy affected the pulmonary response to tissue infection. Rabbits were pretreated with either anti-CD14 mAb or isotype control mAb at 2.5 mg/kg. E. coli (1 x 109 CFU) was inoculated into the lungs, and the animals were observed for either 4 or 24 h. The blockade of CD14 improved the mean arterial blood pressure (p = 0.001) and decreased the i.v. fluid requirements (p = 0.01). Although this therapy protected the vascular compartment, rabbits treated with anti-CD14 mAb had increased bacterial burdens in the bronchoalveolar lavage fluid recovered from the instilled lung (p = 0.005) and widened alveolar-arterial oxygen difference. Blockade of CD14 prevents the deleterious systemic responses that occur in sepsis; however, other measures are necessary to control bacterial proliferation at the primary site of infection.


Executive systems constrain the flexibility of online control in children during goal-directed reaching.
We examined the influence of inhibitory load on online motor control in children. A sample of 129 school children was tested: younger, mid-age, and older children. Online control was assessed using a double-step perturbation paradigm across three trail types: non-jump, jump, and anti-jump. Results show that mid-aged children were able to implement online adjustments to jump trials as quickly as older children, but their performance on anti-jump trials regressed toward younger children. This suggests that rapid unfolding of executive systems during middle childhood may constrain the flexibility with which online control can be implemented, particularly when inhibitory demands are imposed.


[Participation of the visual projection and association cortical inputs in the formation of responses of neostriatal responses to visual stimuli in the alert cat].
Extracellular responses of caudate neurons to local light stimuli and to electrical stimulation of specific (area 17) and associative (the Clare-Bishop area) cortical zones were studied in awake cats. Stimulation of the Clare-Bishop area was found to be more effective for caudate cell responses in comparison with stimulation of area 17; it influenced more caudate cells (47%), whereas responses to area 17 stimulation occurred only in 8% of investigated cells. The mean latency values also were lower in the first case. Only a few neurons responded to stimulation of the both areas. Responses to visual stimuli and to electrical stimulation of these cortical areas were compared in the same caudate cells. Neurons which responded to visual stimuli were also better activated by the Clare-Bishop stimulation than by stimulation of area 17. Such cells were distributed preferably in the body of caudate nucleus. The possible role of the Clare-Bishop area in transmission of visual information to neostriatum is discussed.


MR of carcinoma-specific monoclonal antibody conjugated to monocrystalline iron oxide nanoparticles: the potential for noninvasive diagnosis.
To determine if tumor-specific monoclonal antibodies conjugated to superparamagnetic monocrystalline iron oxide nanoparticles can be used to yield specific diagnoses with the use of MR imaging. Monoclonal antibodies conjugated to monocrystalline iron oxide nanoparticles were given to nude rats with intracranial tumors either by intravenous injection, intraarterial injection with osmotic blood-brain barrier disruption, or direct intratumoral inoculation. Either L6, a tumor-specific antibody, or P-1.17, a control isotype-matched antibody, was used. Coronal T1-weighted, T2-weighted, and spoiled gradient-recalled acquisition in the steady state images were obtained before, 30 minutes after, 6 hours after, and 24 hours after injection. Intravenous injection of greater than 2 mg of the tumor-specific antibody showed a specific pattern of enhancement of the tumors with the largest concentration of antibody in the area with the greatest density of tumor cells. The control antibody showed nonspecific changes. After intraarterial injection with barrier disruption to increase delivery globally or direct inoculation to increase delivery focally, no specific enhancement pattern was seen. Monoclonal antibodies conjugated with monocrystalline iron oxide particles may provide a method to obtain specific diagnoses with the use of MR imaging.


Type 4 acromion: a new classification.
The three types of acromial processes previously described in the literature include type 1, in which the undersurface is straight, and types 2 and 3, in which the undersurface is concave. In this report, a fourth type of acromion is described in which the undersurface is convex near its distal end. The frequency of a type 4 acromion in the normal population is discussed based on a retrospective review of the MR examinations of 30 patients that originally were read as normal.


Surprisingly little population genetic structure in a fungus-associated beetle despite its exploitation of multiple hosts.
In heterogeneous environments, landscape features directly affect the structure of genetic variation among populations by functioning as barriers to gene flow. Resource-associated population genetic structure, in which populations that use different resources (e.g., host plants) are genetically distinct, is a well-studied example of how environmental heterogeneity structures populations. However, the pattern that emerges in a given landscape should depend on its particular combination of resources. If resources constitute barriers to gene flow, population differentiation should be lowest in homogeneous landscapes, and highest where resources exist in equal proportions. In this study, we tested whether host community diversity affects population genetic structure in a beetle (Bolitotherus cornutus) that exploits three sympatric host fungi. We collected B. cornutus from plots containing the three host fungi in different proportions and quantified population genetic structure in each plot using a panel of microsatellite loci. We found no relationship between host community diversity and population differentiation in this species; however, we also found no evidence of resource-associated differentiation, suggesting that host fungi are not substantial barriers to gene flow. Moreover, we detected no genetic differentiation among B. cornutus populations separated by several kilometers, even though a previous study demonstrated moderate genetic structure on the scale of a few hundred meters. Although we found no effect of community diversity on population genetic structure in this study, the role of host communities in the structuring of genetic variation in heterogeneous landscapes should be further explored in a species that exhibits resource-associated population genetic structure.


Registered Nurses' beliefs about end-of-life care: A mixed method study.
To examine registered nurses' (RNs) behavioural, normative and control beliefs about end-of-life care for patients who are diagnosed with advanced and life-limiting illnesses; and to identify the barriers and facilitators they experience when providing end-of-life care. A sequential explanatory mixed methods study. An online cross-sectional survey was conducted using the Care for Terminally Ill Patient tool among 1293 RNs working across five hospitals in the Kingdom of Saudi Arabia. Online individual semi-structured interviews with a subgroup of survey respondents were then undertaken. Data were collected between October 2020 to February 2021. A total of 415 RNs completed the online survey, with 16 of them participating in individual interviews. Over half of the participants expressed the belief that end-of-life care is most efficiently delivered through multidisciplinary team collaboration. The majority of participants also believed that discussing end-of-life care with patients or families leads to feelings of hopelessness. Paradoxically, the study revealed that more than half of the participants held the negative belief that patients at the end of life should optimally receive a combination of both curative and palliative care services. The results showed that nurses' beliefs were significantly associated with their age, religion, ward type, level of education and frequency of providing end-of-life care. Data from the qualitative interviews identified four themes that explored RNs' beliefs and its related factors. The four themes were 'holistic care', 'diversity of beliefs', 'dynamics of truth-telling' and 'experiences of providing end-of-life care.' Wherever possible, patients at the end-of-life should be cared for in specialist settings by multidisciplinary teams to ensure effective, high-quality care. Where this is not possible, organisations should ensure that teams of multidisciplinary staff, including nurses, receive education and resources to support end-of-life care in non-specialist settings. Hospitals that employ foreign-trained nurses should consider providing targeted education to enhance their cultural competence and reduce the impact of different beliefs on end-of-life care.