Hemophilus Septicemia Meningitis in an 11-Month-Old Vaccinated Infant.
Haemophilus influenzae is a gram-negative pleomorphic coccobacillus associated with many diseases, such as meningitis, pneumonia, septicemia, cellulitis, and otitis media. The most virulent and most common serotype is H. influenzae type b (Hib), which was responsible for the majority of meningitis cases until the development of vaccines that led to a decrease in its incidence worldwide. Here, we report the case of an 11-month-old female infant who was previously healthy and fully vaccinated against Hib and developed sepsis and meningitis. The patient was managed as a case of partially treated bacterial meningitis but failed to respond to a short-duration course of antibiotics and had focal seizures of the left hand. Non-contrast brain MRI revealed multiple and bilateral brain abscesses more evident on the left side. The patient was then followed up with imaging every 10-14 days to monitor the response and resolution of the brain abscesses. She was successfully treated with a full course of intravenous ceftriaxone for six weeks until imaging was clear and the brain abscesses were nearly undetected. Invasive H. influenzae infections are considered emerging cases, and there is a need to consider and suspect the disease even in fully vaccinated patients.


Functional genes for cellobiose utilization in natural isolates of Escherichia coli.
The genes for utilization of cellobiose are normally cryptic in both laboratory strains and natural isolates of Escherichia coli. A survey of natural isolates of E. coli reveals that functional genes for cellobiose utilization, while rare, are present. The fraction of E. coli that utilized cellobiose ranged from less than 0.01% in human fecal samples to 7% in fecal samples obtained from horses. Samples obtained from sheep, cows, dogs, and pigs contained 0.1 to 0.5% cellobiose-positive E. coli. Neither the previously identified cel genes nor the bgl genes from E. coli K-12 were expressed during growth on cellobiose by any of the 14 naturally occurring Cel+ isolates that were tested. All of the naturally occurring Cel+ isolates possessed a cel operon, but all were deleted for the major portion of the bgl operon. The functional cel+ genes from these natural isolates differed from the mutationally activated cel+ genes obtained in earlier studies in that (i) the mutationally activated cel+ genes were temperature sensitive, while the functional genes were not, and (ii) transport of cellobiose was inducible in the strains carrying functional cel+ genes, while it was expressed constitutively in strains carrying mutationally activated genes.


HIF-1α Stabilization Increases miR-210 Eliciting First Trimester Extravillous Trophoblast Mitochondrial Dysfunction.
Preeclampsia is associated with first trimester placental dysfunction. miR-210, a small non-coding RNA, is increased in the preeclamptic placenta. The effects of elevated miR-210 on placental function remain unclear. The objectives of this study were to identify targets of miR-210 in first trimester primary extravillous trophoblasts (EVTs) and to investigate functional pathways altered by elevated placental miR-210 during early pregnancy. EVTs isolated from first trimester placentas were exposed to cobalt chloride (CoCl2), a HIF-1α stabilizer and hypoxia mimetic, and miR-210 expression by qPCR, HIF1α protein levels by western blot and cell invasion were assessed. A custom TruSeq RNA array, including all known/predicted miR-210 targets, was run using miR-210 and miR-negative control transfected EVTs. Mitochondrial function was assessed by high resolution respirometry in transfected EVTs. EVTs exposed to CoCl2 showed a dose and time-dependent increase in miR-210 and HIF1α and reductions in cell invasion. The TruSeq array identified 49 altered genes in miR-210 transfected EVTs with 27 genes repressed and 22 enhanced. Three of the top six significantly repressed genes, NDUFA4, SDHD, and ISCU, are associated with mitochondrial function. miR-210 transfected EVTs had decreased maximal, complex II and complex I+II mitochondrial respiration. This study suggests that miR-210 alters first trimester trophoblast function. miR-210 overexpression alters EVT mitochondrial function in early pregnancy. Mitochondrial dysfunction may lead to increased reactive oxygen species, trophoblast cell damage and likely contributes to the pathogenesis of preeclampsia.


Blastocyst rate of in vitro embryo production in sheep is affected by season.
It has been reported that the number and quality of in vitro produced embryos is season related. This study was conducted to assess the effect of season on cleavage, blastocyst and lambing rates of in vitro produced ovine embryos during 3 years of collection data. Ovaries of Sarda sheep were collected from a slaughterhouse. In total, 5035 oocytes were recovered and matured in TCM-199 with 4 mg/ml bovine serum albumin (BSA), 100 μM cysteamine, 0.3 mM Na pyruvate, 0.1 UI/ml recombinant follicle-stimulating hormone (r-FSH), 0.1 UI/ml recombinant luteinising hormone (r-LH), and 1 μg/ml estradiol-17β. Matured oocytes were fertilized with fresh semen in synthetic oviductal fluid (SOF) with 20% heat inactivated estrous sheep serum. The presumptive zygotes were cultured for 6-7 days (blastocyst stage) in SOF medium supplemented with 1% Basel Medium Eagle (BME), 1% Minimum Essential Medium, 1 mM glutamine and 8 mg/ml fatty acid-free BSA. The embryos produced were vitrified and a total of 165 blastocysts (80 from the breeding season and 85 from the anoestrous season) were transferred in pairs into recipient ewes during the reproductive period. There were no significant differences in cleavage rates between seasons in any of the 3 years examined (84% versus 83%, 81% versus 80% and 80% versus 79%, respectively). The blastocyst rate varied significantly between seasons in 2005 and 2007 (P < 0.05), and in 2006 (P < 0.001). There were no differences in pregnancy and lambing rates between embryos during anoestrous versus during the breeding season. In conclusion, only the blastocyst rate appeared to have been affected by season, possibly due to variation in the number of developmentally competent oocytes.


Enhancement of the properties of a drug by mono-deuteriation: reduction of acid-catalysed formation of a gut-motilide enol ether from 8-deuterio-erythromycin B.
Erythromycin B is structurally very similar to erythromycin A, and also shares its clinically important antibacterial activity. Its potential advantage is that it is much more stable to acid. Both compounds are susceptible to 6-9-enol ether formation, involving loss of a proton from C-8. The enol ethers lack antibacterial activity and can give rise to unpleasant gut motilide side-effects. Our previous work on degradation kinetics revealed that the formation of erythromycin B enol ether from erythromycin B is subject to a large deuterium isotope effect. We therefore synthesized 8-d-erythromycin B (in 87% yield) in the hope that acid-catalysed enol ether formation would be reduced, relative to erythromycin B. In a range of microbiological and biochemical assays, deuteriation did not appear to compromise the efficacy of the drug. Degradation studies showed, however, that incorporation of deuterium into erythromycin B reduces (though does not completely suppress) enol ether formation, providing the possibility of using a facile mono-deuteriation to reduce the gut motilide side-effects of the drug.


Role of Bruton's tyrosine kinase in myeloma cell migration and induction of bone disease.
Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Bruton's tyrosine kinase (BTK), of the TEC family, is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. We demonstrated BTK expression in clinical myeloma plasma cells, interleukin (IL)-6- or stroma-dependent cell lines and osteoclasts. SDF-1 induced BTK activation in myeloma cells and BTK inhibition by small hairpin RNA or the small molecule inhibitor, LFM-A13, reduced their migration toward stromal cell-derived factor-1 (SDF-1). Pretreatment with LFM-A13 also reduced in vivo homing of myeloma cells to bone using bioluminescence imaging in the SCID-rab model. Enforced expression of BTK in myeloma cell line enhanced cell migration toward SDF-1 but had no effect on short-term growth. BTK expression was correlated with cell-surface CXCR4 expression in myeloma cells (n = 33, r = 0.81, P < 0.0001), and BTK gene and protein expression was more profound in cell-surface CXCR4-expressing myeloma cells. BTK was not upregulated by IL-6 while its inhibition had no effect on IL-6 signaling in myeloma cells. Human osteoclast precursors also expressed BTK and cell-surface CXCR4 and migrated toward SDF-1. LFM-A13 suppressed migration and differentiation of osteoclast precursors as well as bone-resorbing activity of mature osteoclasts. In primary myeloma-bearing SCID-rab mice, LFM-A13 inhibited osteoclast activity, prevented myeloma-induced bone resorption and moderately suppressed myeloma growth. These data demonstrate BTK and cell-surface CXCR4 association in myeloma cells and that BTK plays a role in myeloma cell homing to bone and myeloma-induced bone disease. Am. J. Hematol. 88:463-471, 2013. © 2013 Wiley Periodicals, Inc.


Heterogeneity of murine erythroleukemia cells with respect to tumor promoter-mediated inhibition of cell differentiation.
Spontaneous and induced differentiation of murine erythroleukemia cells (strain 745A DS19 ) is reversibly inhibited by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent promoter of mouse skin carcinogenesis, and by other tumor-promoting macrocyclic plant diterpenes, but it is not by nonpromoting diterpenes. Twelve clones randomly isolated from this strain vary in their response to TPA. All clones are induced to differentiate by several compounds, the most potent of which is hexamethylene bisacetamide. In six clones TPA (100 ng/ml) caused greater than 90% inhibition of differentiation, as measured by the appearance of benzidine-reactive cells. In two clones cell differentiation was not inhibited by TPA even at concentrations as high as 1 microgram/ml. In four clones, differentiation was only partially inhibited (16 to 47%) by TPA. Clones resistant to TPA inhibition of differentiation were also resistant to structurally related tumor-promoting agents. The isolation of variant cell lines, sensitive and resistant to TPA, provides a tool for elucidating the mechanism of tumor promoter-mediated inhibition of cell differentiation.


Fludarabine phosphate in the treatment of chronic lymphocytic leukemia.
Fludara I.V. (fludarabine phosphate) is a purine analogue that has been synthesized and found to have activity in lymphoid neoplasms in phase I and II studies. Fludara I.V. has been used extensively in the management of chronic lymphocytic leukemia in the last 5 years. In studies of Fludara I.V. as a single agent, the response rate was 59% in 78 patients. The true complete remission (CR) rate (no evidence of disease) was 13% with 16% having a CR with persistent lymphoid nodules. These patients are considered to be in CR using the National Cancer Institute Working Group Guidelines. The other patients (31%) achieved a partial remission (PR). Fludara I.V. has also been used as a single agent in previously untreated patients. Thirty (83%) of the 36 patients obtained a complete or partial response. Thirty-six percent of the patients achieved a true CR and 39% a CR with persistent lymphoid nodules in the bone marrow. Thus, the complete remission rate was 75%. Fludara I.V. has now been combined with prednisone in the management of 101 previously treated patients with chronic lymphocytic leukemia. Fourteen percent of patients have achieved a true CR, 24% a nodular CR, and 19% a PR. The results were very similar to those obtained with Fludara I.V. as a single agent. Other investigators have explored Fludara I.V. by continuous infusion. Twenty-two of 42 evaluable patients, in that study, achieved a PR. Fludara I.V. had minimal evidence of toxicity except for episodes of fever. The episodes of fever were more common in patients who had received previous treatment and had stage III or IV disease according to the Rai staging system. Some of these episodes of fever were associated with pneumonia. It appears that the spectrum of organisms causing the febrile episodes is that usually associated with immune deficiency (monocyte or T-cell deficiency). Future studies with Fludara I.V. will explore different schedules and combination approaches.


Update and projection on HIV/AIDS in Taiwan.
The HIV/AIDS epidemic in Taiwan started in 1986, with 5,221 cases of HIV infections, 1,596 cases of AIDS, and 911 deaths reported through 2003. National surveillance data indicate that men who have sex with men accounted for 48.2% of HIV infections, followed by heterosexual men (33.8%) and heterosexual women (6.1%). Only 353 (6.8%) of all HIV cases are females. The average age of HIV-infected persons, AIDS cases, and deaths was 31.2, 36.2, and 39.0 years, respectively. The incidence of HIV infection has increased by approximately 15% every year since 1997. The continuing epidemic will likely burden the national health care system and may result in an estimated socioeconomic loss of U.S. dollars 1.6 billion in 2010, as 15,125 HIV infections and 1,420 deaths from AIDS are projected. To respond to the HIV/AIDS epidemic in Taiwan, the government has been working with nongovernmental organizations to promote HIV testing, conduct various education programs, and reach out to high-risk groups. HIV/AIDS patients are linked to medical care and provided with free highly active antiretroviral treatment. The main challenge is to reduce HIV-related stigma. Prevention focused on preventing further transmission of HIV by seropositive persons to others is urgently needed in fighting the HIV/AIDS epidemic.


Exosome-based immunomodulation during aging: A nano-perspective on inflamm-aging.
Exosomes are nanovesicles formed by inward budding of endosomal membranes. They exert complex immunomodulatory effects on target cells, acting both as antigen-presenting vesicles and as shuttles for packets of information such as proteins, coding and non-coding RNA, and nuclear and mitochondrial DNA fragments. Albeit different, all such functions seem to be encompassed in the adaptive mechanism mediating the complex interactions of the organism with a variety of stressors, providing both for defense and for the evolution of symbiotic relationships with others organisms (gut microbiota, bacteria, and viruses). Intriguingly, the newly deciphered human virome and exosome biogenesis seem to share some physical-chemical characteristics and molecular mechanisms. Exosomes are involved in immune system recognition of self from non-self throughout life: they are therefore ideal candidate to modulate inflamm-aging, the chronic, systemic, age-related pro-inflammatory status, which influence the development/progression of the most common age-related diseases (ARDs). Not surprisingly, recent evidence has documented exosomal alteration during aging and in association with ARDs, even though data in this field are still limited. Here, we review current knowledge on exosome-based trafficking between immune cells and self/non-self cells (i.e. the virome), sketching a nano-perspective on inflamm-aging and on the mechanisms involved in health maintenance throughout life.


Anxiety, stress and coping strategies among University of South Pacific students.
This study set out to examine the relationship between stressors and coping strategies utilized by students, as well the prevalence of depression, anxiety and social dysfunction amongst this group within the cross-cultural framework of the University of the South Pacific (USP). Respondents included students from 10 countries served the University of the South Pacific. The research instrument constituted a questionnaire based on demographic variables plus three scales to elicit responses pertaining to stressors, depression and coping strategies. The findings highlight a number of variables that should be of at least some concern to the University with respect to the aforesaid areas mentioned. Regarding demographics, the data reveal a close parity between gender proportions, a relatively young student population and most of them transiting between the first and third years of studies. In terms of stress and depression, a minority of respondents reported stress-related problems and furthermore, small numbers made use of mental and counseling services provided by the University and other parties concerned. In terms of coping, quite a large number of coping variables were utilized by respondents in coming to terms with problems. The study concludes with implications regarding the role of USP in the light of stress and depression-related concerns revealed in the findings.


Reutilization pathway of purine nucleotides in human erythrocytes.
Human erythrocytes can operate the pyrophosphorolysis of IMP and utilize the phosphoribosyl moiety of this compound for the synthesis of AMP and of GMP from exogenous purine bases. Erythrocyte purine phosphoribosyltransferases seem to have a role in this interconversion pathway.


Relations between cardiovascular risk estimates and subclinical atherosclerosis in naive HIV patients: results from the HERMES study.
The aim of the study was to evaluate the cardiovascular risk factors associated with subclinical carotid atherosclerosis in antiretroviral therapy-naïve HIV-infected patients. The HERMES (HIV Exposure and Risk of Metabolic Syndrome) study enrolled therapy-naïve patients attending hospitals in the Italian coordination group for the study of allergies and HIV infection (CISAI [Coordinamento Italiano per lo Studio Allergia e Infezione da HIV]) in 2007. It was designed to identify metabolic syndrome (MS) and cardiovascular risk factors. The present analysis is a nested cross-sectional study with a subset of patients examined by carotid ultrasonography. Consecutive antiretroviral therapy-naïve HIV patients attending the facilities involved in the CISAI were included. Their 10-year probability of cardiovascular events was calculated using the Framingham Risk Score (FRS) and three other cardiovascular algorithms (the Global Framingham Risk Score - GFRS, 'Progetto Cuore' and 'SCORE'). Vascular age was estimated using a new model derived from GFRS and was compared with chronological age. The diagnosis of MS was based on the National Cholesterol Education Programme and International Diabetes Federation (IDF) definitions. Subclinical atherosclerosis was determined as ultrasound carotid intima-media thickness >0.9 mm. Out of 140 patients enrolled in the HERMES study by the four centres participating in the nested study, a total of 72 (51.4%) subjects, with no overt cardiovascular disease, were examined using carotid ultrasonography. The median age was 40 years, 79.2% men. The vascular age was 7.6 years higher than the chronological age. The factors associated with subclinical atherosclerosis were age (P < 0.0001), vascular age (P = 0.0002), body mass index (P = 0.003), waist circumference (P = 0.0002), MS (IDF definition, P = 0.004) and all the cardiovascular (CV) models (FRS, P = 0.01, GFRS, P = 0.002, Progetto Cuore, P = 0.018, SCORE, P = 0.03). Independent of other significant factors, waist circumference was significantly associated with pathological results (P = 0.007). The GFRS (area under the receiver-operating characteristic curves, 0.78; P < 0.001) had slightly better predictive accuracy than the other three CV models (FRS, areas under the curve [AUC] = 0.71, P = 0.003; Progetto Cuore, AUC = 0.74, P = 0.0005; SCORE, AUC = 0.77, P < 0.0001); 55% of patients at intermediate risk (6-20%) had subclinical carotid lesions. Subclinical carotid lesions had a highly significant direct association with all the CV risk predictors. The GFRS and vascular age were highly predictive. We recommend a carotid ultrasonographic examination at least among HIV patients with GFRS > or =6% or with an elevated waist circumference.


A numerical study of nonlinear infrasound propagation in a windy atmosphere.
Direct numerical simulations of the two-dimensional unsteady compressible Navier-Stokes equations are performed to study the acoustic field generated by an infrasonic source in a realistic atmosphere. Some of the main phenomena affecting the propagation of infrasonic waves at large distances from the source are investigated. The effects of thermal and wind-related refraction on the signals recorded at ground level are highlighted, with particular emphasis on the phase shift induced by the presence of caustics in the acoustic field. Nonlinear waveform steepening associated with harmonic generation, and period lengthening, both of which are typical of large source amplitudes, are illustrated, and the importance of thermoviscous absorption in the upper atmosphere is clearly demonstrated. The role of diffraction in the shadow zone, around caustics and at stratospheric altitudes is also pointed out. The Navier-Stokes equations are solved using high-order finite-differences and a Runge-Kutta time integration method both originally developed for aeroacoustic applications, along with an adaptive shock-capturing algorithm which allows high-intensity acoustic fields to be examined. An improvement to the shock detection procedure is also proposed in order to meet the specificities of nonlinear propagation at long range. The modeling as well as the numerical results are reported in detail and discussed.


Transfer of contextual cueing in full-icon display remapping.
Invariant spatial context can expedite visual search, an effect that is known as contextual cueing (e.g., Chun & Jiang, 1998). However, disrupting learned display configurations abolishes the effect. In current touch-based mobile devices, such as the iPad, icons are shuffled and remapped when the display mode is changed. However, such remapping also disrupts the spatial relationships between icons. This may hamper usability. In the present study, we examined the transfer of contextual cueing in four different methods of display remapping: position-order invariant, global rotation, local invariant, and central invariant. We used full-icon landscape mode for training and both landscape and portrait modes for testing, to check whether the cueing transfers to portrait mode. The results showed transfer of contextual cueing but only with the local invariant and the central invariant remapping methods. We take the results to mean that the predictability of target locations is a crucial factor for the transfer of contextual cueing and thus icon remapping design for mobile devices.


Angiotropic (intravascular) large cell lymphoma. A clinicopathologic study of seven cases with unique clinical presentations.
The authors recently reported the antigenic phenotypes of three cases of so-called "malignant angioendotheliomatosis" and suggested that angiotropic large cell lymphoma (ALCL) is a more appropriate designation for this disease. The authors now report an additional seven cases of ALCL with unique clinical presentations. One patient presented with prostate enlargement, the second with lytic bone lesions and thickened nasal sinus mucosa, the third had diffuse myalgia, the fourth had dyspnea and pulmonary infiltrates, the fifth had gangrene of the lower extremities, total-body skin involvement, and pancytopenia, the sixth had a lesion of the foreskin mimicking squamous cell carcinoma, and the seventh had a mediastinal mass. In all cases histologic features were characteristic of ALCL with, in two cases, extravascular spread into soft tissue. Immunohistologic studies showed a B-cell phenotype in five cases and a T-cell phenotype in one case. Two patients received combination chemotherapy using established treatment protocol for large cell lymphoma, and remain in complete clinical remission and two patients are responding clinically to combination chemotherapy. Two patients died shortly after receiving combination chemotherapy. One patient has only recently been diagnosed as having ALCL and no long-term follow-up is available. These data indicate that, although ALCL affects predominantly the central nervous system and skin, unusual clinical presentations may occur, and patients with ALCL may respond to combination chemotherapy for large cell lymphoma.


Characteristics of paediatric dental emergencies during the COVID-19 pandemic in Riyadh City, Saudi Arabia.
Except for emergencies and urgent cases, dental treatments have been suspended in Saudi Arabia. This report examines the pattern of emergency dental care provided to children and adolescents in Riyadh City, Saudi Arabia, which has been affected by the current COVID-19 pandemic. In late March 2020, the General Directorate of Dentistry, Ministry of Health (MOH), administered an online dental emergency investigation form, which was to be completed by all MOH (governmental) dental centres and sent to the MOH on daily basis. This report included patient information (such as gender and age), whether the patient had contacted the hotline service centre, dental diagnosis, specialty of the treating dental professional and treatment provided. Descriptive analyses were generated. Only few (n=95) patients under the age of 14 sought emergency dental treatment during the investigated period (six weeks). Findings showed very low utilisation of the hotline service (14.7%). Most had dental pain (n=85; 89.5%). Eighty four (88.4%) patients were seen by a general dental practitioner (GDP), while the rest (n=11; 11.6%) were seen by a specialised dental professional (SDP). The dental abscess (33.7%) and caries into pulp (29.5%) were the most common diagnoses for emergency dental visits among the children and adolescents. A high proportion of dental centres provided medication prescriptions and assumed inappropriate dental management during the COVID-19 pandemic. The COVID-19 pandemic had a significant impact on child and adolescent emergency dental services. The number of dental emergency visits was low, with a high percentage of dental infection. We urge dental professionals to pursue a consistent approach in treating emergency dental conditions during the COVID-19 pandemic era and following the national protocols.


The use of methylene blue in abdominal aortic surgery: a case report.
The open abdominal aortic surgery includes a well-known phase in which arterial blood flow is stopped by occluding clamps, resulting in peculiar physiologic changes usually superimposed on advanced pathologic conditions. An anesthetic plan should aim at providing hemodynamic stability and preserving organ function. Clamp removal leads to an acute fall in blood pressure following a decrease in systemic vascular resistance, caused by reactive hyperemia due to opening of the previously minimally perfused vascular beds. Several different mediators, including the nitrous oxide (NO) pathway, have been thought to be responsible for this hemodynamic effect. The massive production of NO by the inducible isoform of NO synthase could be partially responsible for the profound vasodilatation and myocardial dysfunction. The dye methylene blue (MB) has been used as to prevent vasodilatation in other clinical situations like sepsis, cardiopulmonary bypass and liver transplantation. We describe its use in a patient with poor hemodynamic status, who was submitted to aortic aneurism repair with infrarenal cross clamp. The intervention was also associated with a severe bleeding. In this case MB allowed us to control hypotension with relatively low doses of vasopressors.


Protein hydration observed by X-ray diffraction. Solvation properties of penicillopepsin and neuraminidase crystal structures.
Solvation in macromolecular crystal structures was studied by analyzing X-ray diffraction data of two proteins, penicillopepsin and neuraminidase. The quality of several solvent models was assessed by complete cross-validation in order to prevent overfitting the diffraction data. Radial solvent distribution functions were computed from electron density maps using phases obtained from multiple isomorphous replacement and from the protein's atomic model combined with the best solvent model. Distribution functions were computed around hydrophilic and hydrophobic groups on the protein's surface. Averaging of the distribution functions was performed in order to reduce the influence of noise. The first solvation shell is characterized by a peak in the average distribution functions. At 1.8 A resolution, polar groups show a sharp peak while non-polar groups show a broad one. The distinction between hydrophobic and hydrophilic solvation sites is lost when using lower resolution (2.8 A) diffraction data. Higher-order solvation shells are not observed in the average distribution functions. We hope that site-specific radial distribution functions obtained from high-quality diffraction data will produce a picture of macromolecular solvation consistent with available experimental data and computational results.


Disruption of serine/threonine protein phosphatase 5 inhibits tumorigenesis of urinary bladder cancer cells.
Serine/threonine protein phosphatase 5 (PPP5C) is a member of the protein serine/threonine phosphatase family and has been shown to participate in multiple signaling cascades and tumor progression. We found that PPP5C was highly expressed in bladder cancer tissues compared to normal urothelial tissues, and positively correlated to tumor stages through ONCOMINE microarray data mining. Knockdown of PPP5C via a lentivirus-mediated short hairpin RNA (shRNA) markedly inhibited cell proliferation and colony formation. Flow cytometric analysis showed that PPP5C-deficient T24 and BT5637 bladder cancer cells were arrested in G0/G1 phase and induced apoptosis. In addition, tumor growth was inhibited in vivo in a xenograft nude mouse model. Further studies indicated that knockdown of PPP5C downregulated c-myc and CDK4, whereas upregulated p27, BAD and Beclin1. These results suggest that PPP5C is associated with bladder cancer (BCa) and plays an oncogenic role in the development and progression of bladder cancer.


Redo mitral valve surgery-a long-term experience.
Our experience with reoperative mitral valve (MV) surgery over a 27-year period is presented here. From January 1975 to June 2002, 11,908 operations were performed for MV disease. Out of these 744 were reoperations. The mean age at primary operation was 23.6 +/- 10.1 years (range 2 to 53 years) and at reoperation was 36.0 +/- 11.0 years (range 6 to 65 years) with a mean interval of 11.5 +/- 2.5 years. Mitral valve replacement (MVR) was performed following previous closed mitral valvotomy (CMV) in 408 patients, open mitral commissurotomy (OMC) in 21 patients, and MV repair in 58 patients, MVR in 80 patients, homograft mitral valve replacement (HMVR) in 11 patients. The reasons for reoperation were mainly progression of lesions. Valve thrombosis and endocarditis were indications for reoperation following MVR. Twenty-eight patients underwent redo CMV, 53 patients underwent OMC, and 14 patients underwent MV Repair. Early mortality was 5.64% (n = 42). Hemorrhage and low cardiac output were the major causes. Follow-up was 124.8 +/- 30.5 months (2 to 300 months). Follow-up was 88%. There were no late deaths in the valve repair group. There were three episodes of thromboembolism in this group (0.3% per patient-year). In the valve replacement group there were six late deaths; three due to valve thrombosis, one due to infective endocarditis, and two due to anticoagulant-related hemorrhage. There were 13 episodes of thromboembolism in this group (0.6% per patient-year). Redo MV surgery is safe and can be undertaken with acceptable mortality and morbidity.


Glucocorticoids and 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome.
Central obesity is associated with type 2 diabetes mellitus, hypertension and dyslipidaemia. This cluster of risk factors is known as the metabolic syndrome, and also occurs in people with primary glucocorticoid excess (Cushing's syndrome). Exogenous glucocorticoid use also increases the risk of cardiovascular disease. Circulating glucocorticoid concentrations are tightly controlled by the hypothalamic-pituitary-adrenal axis, however tissue glucocorticoid levels are also enhanced by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Transgenic overexpression of 11beta-HSD1 in either adipose tissue or the liver in mice causes components of the metabolic syndrome, while transgenic deletion of 11beta-HSD1 prevents adverse metabolic complications of obesity. Although plasma glucocorticoid levels are not elevated in obesity, dysregulation of 11beta-HSD1 is observed with decreased activity in the liver and increased activity in adipose tissue. 11beta-HSD1 is highly regulated, and dietary composition may be a powerful determinant of activity. Polymorphisms in the 11beta-HSD1 gene are also associated with components of the metabolic syndrome. Inhibition of this enzyme appears to be an attractive option to treat metabolic disease. Selective 11beta-HSD1 inhibitors in rodents cause weight loss, improve insulin sensitivity and delay progression of cardiovascular disease. Trials in humans though will be the ultimate test to determine if inhibition of 11beta-HSD1 offers a new tool in the treatment of metabolic disease.


The influence of cold shock proteins on transcription and translation studied in cell-free model systems.
Cold shock proteins (CSPs) form a family of highly conserved bacterial proteins capable of single-stranded nucleic acid binding. They are suggested to act as RNA chaperones during cold shock inhibiting the formation of RNA secondary structures, which are unfavourable for transcription and translation. To test this commonly accepted theory, isolated CSPs from a mesophilic, thermophilic and a hyperthermophilic bacterium (Bacillus subtilis, Bacillus caldolyticus and Thermotoga maritima) were studied in an Escherichia coli based cell free expression system on their capability of enhancing protein expression by reduction of mRNA secondary structures. The E. coli based expression of chloramphenicol acetyltransferase and of H-Ras served as model systems. We observed a concentration-dependent suppression of transcription and translation by the different CSPs which makes the considered addition of CSPs for enhancing the protein expression in in vitro translation systems obsolete. Protein expression was completely inhibited at CSP concentrations present under cold shock conditions. The CSP concentrations necessary for 50% inhibition were lowest (140 microm) for the protein of the hyperthermophilic and increased when the thermophilic (215 microm) or even the mesophilic protein (451 microm) was used. Isolated in vitro transcription under the influence of CSPs showed that the transcriptory effect is independent from the rest of the cell. It could be shown in a control experiment that the inhibition of protein expression can be removed by addition of hepta-2'-desoxy-thymidylate (dT7); a heptanucleotide that competitively binds to CSP. The data are in line with a hypothesis that CSPs act on bulk protein expression not as RNA chaperones but inhibit their transcription and translation by rather unspecific nucleic acid binding.


Postfeeding radial dispersal in larvae of Chrysomya albiceps (Diptera: Calliphoridae): implications for forensic entomology.
Blowflies utilize discrete and ephemeral breeding sites for larval nutrition. After the exhaustion of food, larvae begin dispersing in search of sites to pupate or additional food sources, a process referred as postfeeding larval dispersal. Some of the most important aspects of this process were investigated in the blowfly Chrysomya albiceps, employing a circular arena to allow radial dispersion of larvae from the center. The results showed a positive correlation between burial depth and distance, and a negative correlation between distance and pupal weight. These results can be used in forensic entomology for the postmortem interval estimation of human corpses in medico-criminal investigations.


International Health Fellowship: a proposed curriculum for emergency physicians.
There are a growing number of emergency physicians (EPs) working in health care abroad. There are, however, no formal training programs for EPs in international health. An International Health Fellowship has been developed to provide training for EPs in public health and international medicine. The fundamental competencies of a fellow completing the International Health Fellowship include assessment of medical need, program development, integration of programs into the existing health care framework, and evaluation of projects. This article outlines the philosophy of a training program in international health, provides an overview of the goals and objectives for such a program, and describes the development of an existing fellowship. The International Health Fellowship will develop leaders in the field of global health by combining clinical expertise, practical field experience, formal public health training, and research and education in international health. Physicians completing a fellowship will be prepared to work within foreign health systems to develop, integrate, and evaluate health care programs on an international scale.


Binding of sodium dodecyl sulfate to linear and star homopolymers of the nonionic poly(methoxyhexa(ethylene glycol) methacrylate) and the polycation poly(2-(dimethylamino)ethyl methacrylate): electromotive force, isothermal titration calorimetry, surface tension, and small-angle neutron scattering measurements.
We investigated the binding of sodium dodecyl sulfate (SDS) to various linear and star polymers of the nonionic methoxyhexa(ethylene glycol) methacrylate (PMHEGMA) and the ionic 2-(dimethylamino)ethyl methacrylate (PDMAEMA), the latter being a polycation at low pH. The dodecyl sulfate ion selective electrode (EMF), isothermal titration calorimetry (ITC), and surface tension (ST) were applied to gain detailed information about interactions. In all cases there is evidence of significant binding of SDS over an extensive SDS concentration range spanning from ca. 10(-6) to 0.1 mol dm(-3). At pH 3, the polymer PDMAEMA is a strong polycation and here the binding is dominated by electrostatic 1:1 charge neutralization with the anionic surfactant. At their natural pH of 8.6, PMHEGMA and PDMAEMA polymers are essentially nonionic and bind SDS in the form of polymer-bound aggregates in the concentration range of ca. 1 x 10(-3) to 3 x 10(-2) mol dm(-3). All the polymers also bind SDS to a lesser extent at concentrations below 1 x 10(-3) mol dm(-3) reaching as low as 10(-7) mol dm(-3). This low concentration binding process involves the polymer and nonassociated SDS monomers. As far as we are aware, this is the first example that such a low concentration noncooperative binding process could be observed in SDS/neutral polymer systems by EMF and ST. We also showed that the nonionic surfactant hexa(ethylene glycol) mono-n-dodecyl ether (C12EO6) and the cationic cetyltrimethylammonium bromide (C16TAB) interact with star PDMAEMA. We believe that the interaction of C12EO6 and CTAB is of similar noncooperative type as the first SDS binding process in the range from ca. 10(-5) to 0.3 x 10(-3) mol dm(-3). At the high concentration binding limit Csat of SDS, the above polymers become fully saturated with bound SDS micelles. We applied small angle neutron scattering (SANS) to determine the structure and aggregation numbers of the star polymer/bound SDS micelles and calculated the stoichiometry of such supramolecular complexes. The SANS data on PDMAEMA star polymers in the presence of C12EO6 showed only a limited monomer binding in contrast to linear PDMAEMA, which showed monomer C12EO6 binding at low concentrations but micellar aggregates at 6 x 10(-3) mol dm(-3).


Hereditary Cancer Risk Assessment and Genetic Testing in the Community-Practice Setting.
To evaluate the feasibility and results of incorporating routine hereditary cancer risk assessment, counseling, and follow-up genetic testing in the community obstetrics and gynecology practice setting without referral to a genetic counselor. This prospective process intervention study was conducted with two obstetrics and gynecology practice groups (five sites). The intervention included baseline process assessment, refinement of clinic-specific patient screening workflows and tools, and training in hereditary cancer risk screening and follow-up. Outcomes related to hereditary cancer assessment and testing were measured during an 8-week postintervention period. Patients and health care providers were surveyed about satisfaction with the process. Data also were collected during the 8 weeks before the intervention to assess the effects of screening process improvements. A total of 4,107 patients were seen during the postintervention period, and 92.8% (3,811) were assessed for hereditary cancer risk. Among those assessed, 906 of 3,811 (23.8%) women met National Comprehensive Cancer Network guidelines for genetic testing, and 813 of 906 (89.7%) eligible patients were offered genetic testing. A total of 165 of 4,107 (4.0%) women completed genetic testing and received a final test result. This represents a fourfold increase over genetic testing immediately before the intervention (1.1%) and an eightfold increase over the previous year (0.5%). Testing identified pathogenic variants in 9 of 165 (5.5%) tested women. All health care providers (15/15) reported that they will continue to use the established hereditary cancer risk assessment process. In addition, 98.8% (167/169) of patients who submitted a sample for genetic testing and completed a patient satisfaction survey stated that they were able to understand the information provided, and 97.6% (165/169) expressed satisfaction with the overall process. It is feasible to incorporate hereditary cancer risk assessment, education, and testing into community obstetrics and gynecology practices. As a result, multigene panel testing identified significant cancer risks that otherwise would not have been recognized.


Ethical and legal considerations in social media research for health technology assessment: conclusions from a scoping review.
The objective was to identify and describe the published guidance and current academic discourse of ethical issues and standards related to the use of Social Media Research for generating patient insights for the use by health technology assessment (HTA) or health policy decisions. A scoping review of the literature was conducted in PubMed and Embase and identified 935 potential references published between January 2017 and June 2021. After title and abstract screening by three reviewers, 40 publications were included, the relevant information was extracted and data were collected in a mind map, which was then used to structure the output of the review. Social Media Research may reveal new insights of relevance to HTA or health policies into patient needs, patient experiences, or patient behaviors. However, the research approaches, methods, data use, interpretation, and communication may expose those who post the data in social media channels to risks and potential harms relating to privacy, anonymity/confidentiality, authenticity, context, and rapidly changing technologies. An actively engaged approach to ensuring ethical innocuousness is recommended that carefully follows best practices throughout planning, conduct, and communication of the research. Throughout the process and as a follow-up, there should be a discourse with the ethical experts to maximally protect the current and future users of social media, to support their trust in the research, and to advance the knowledge in parallel to the advancement of the media themselves, the technologies, and the research tools.


Mdmx and Mdm2: brothers in arms?
The p53 tumor suppressor pathway is inactivated in most if not all human tumors. In about 50% of the cases this is accomplished directly by gene mutations. The tumors that retain wild type p53 frequently show defects either in effector target genes, or in the expression of p53 regulatory proteins. The Mdm2 protein is generally considered THE master regulator of the p53 tumor suppressor activity. Recently, however, the Mdm2-related protein Mdmx is taking the stage in the p53-Mdm2-Mdmx play. We summarize here observations unambiguously assigning a critical role for the Mdmx protein in the regulation of p53 function during development and tumor formation.


Sympathoadrenal modulation of stress-activated signaling in burn trauma.
Burn injury stimulates stress-responsive components, p38 mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinases (JNK)/nuclear factor (NF)-kappaB. p38 MAPK plays a role in postburn cardiomyocyte tumor necrosis factor-alpha secretion and cardiac dysfunction. Since burn trauma increases circulating catecholamine levels, which in turn modulate inflammatory cytokine production, we hypothesized that increased sympathetic activity after major burn trauma may trigger postburn cardiac p38 MAPK activation via an adrenergic receptor-mediated phenomenon. We examined adrenergic receptor populations involved in burn-activated cardiac stress signaling. Sprague Dawley rats were divided into six groups: 1) control, 2) control plus alpha1-adrenergic agonist phenylephrine (2 microg/kg, intravenous), 3) control plus beta-adrenergic agonist isoproterenol (1 microg/kg, intravenous), 4) burn (fluid resuscitation with lactated Ringer's 4 ml/kg/% burn), 5) burn plus alpha1-adrenergic antagonist prazosin (1 mg/kg, by mouth), and 6) burn plus beta-adrenergic antagonist propranolol (3.3 mg/kg, by mouth). Phenylephrine, but not isoproterenol, increased cardiac p38 MAPK/JNK/NF-kappaB activation. Burn trauma activated p38 MAPK, JNK, and NF-kappaB, and this stress response was blocked by either prazosin or propranolol. Thus, stimulation of the adrenergic pathway may constitute one upstream activator of stress response in burn.


Associations of Organizational Safety Practices and Culture With Physical Workload, Perceptions About Work, and Work-Related Injury and Symptoms Among Hospital Nurses.
The study aim was to examine the relationships of organizational safety practices with nurses' perceptions about job and risk and experiences of work-related injury and symptoms. Nursing professions report high rates of work-related injuries. Organizational safety practices have been linked to workers' safety outcomes and perceptions about work. This study analyzed data from a random sample of 280 California RNs in a cross-sectional statewide survey. Data were collected by both postal and online surveys. Higher perceptions of organizational safety practices (safety climate, ergonomic practices, people-oriented culture) were significantly associated with lower physical workload, lower job strain, higher job satisfaction, lower risk perception, and lower work-related injury and symptom experiences. Ergonomic practices and people-oriented culture were associated with less intention of leaving job. Organizational safety practices may play a pivotal role in improving positive perceptions about jobs, reducing injury risks, and promoting nurse retention.


Obesity-related glomerulopathy and the nephron complement.
Obesity-related glomerulopathy (ORG) is a secondary form of glomerular disease that can occur in individuals with obesity. However, the absolute risk for an obese individual to develop progressive renal deterioration is low. Therefore, obesity alone appears to be insufficient to develop such severe renal injury, and there are likely other factors that contribute to the development of this entity. The glomerular hyperfiltration found in patients with ORG has been postulated to lead to structural abnormalities in glomeruli, such as glomerulomegaly and focal segmental glomerular sclerosis, in a manner analogous to that described in patients with reduced renal mass. In fact, recent studies suggest that a reduction in nephron mass is implicated in patients with ORG and synergistically contributes to the development of this renal complication together with obesity-induced changes in renal hemodynamics.


[Nailfold capillaroscopy and ankylosing spondylarthritis: incidence of anomalies, but absence of diagnostic and prognostic value].
Vascular involvement is seldom reported in ankylosing spondylitis (AS). In this study, microcirculation was evaluated by nailfold capillaroscopy in 32 defined AS patients compared to a control group (C) of 14 sciatica. Capillary findings were divided into five groups: normal, minor dystrophies, edema, microangiopathy, stagnation. Capillaroscopic abnormalities were more frequent in SA as compared to C, for edema (40% vs 7%) and microangiopathy (15% vs 0%). P = 0.01. There were neither clinical nor biological differences between AS patients with and without microangiopathy. Capillaroscopy abnormalities seem frequent in AS and may be secondary to an immune complex mechanism.


Reducible expansions and related sharp crossovers in Feigenbaum's renormalization field.
We discuss reducible aspects of Mao and Hu's multiple scaling expansion [J. Stat. Phys. 46, 111 (1987); Int. J. Mod. Phys. B 2, 65 (1988)] in the framework of renormalization theory. After establishing a suitable form of reduced expansion, we present numerical evidence showing sharp crossovers from Feigenbaum's constant (delta) to Mao and Hu's constant (delta (')) in the first-order reduced expansion. We find that the crossover is caused by the universal scaling relation existing in constant coefficients of Mao and Hu's expansion. Special attention is paid to constant coefficients corresponding to scaling terms including delta ('). We show numerically that they converge to zero in universal ways with convergence ratios larger than delta. Here, the convergence direction is transversal to the unstable eigendirection of the linearized renormalization operator. From this observation, we propose a concise form of expansion for Feigenbaum's universal function g(r)(x).


Laparoscopic treatment of superior mesenteric artery syndrome.
Superior mesenteric artery syndrome is caused by compression of the third portion of the duodenum by the superior mesenteric artery. Many disease states predispose one to this condition. We present a case report of a young female patient who presented with gastro-duodenal obstruction from superior mesenteric artery syndrome and subsequently underwent surgical treatment with minimally invasive techniques. Pathophysiology of SMA syndrome is reviewed. The cause of superior mesenteric artery syndrome is variable but always results in duodenal obstruction. Surgery is one treatment option that is effective and can be performed laparoscopically. Laparoscopic duodenojejunostomy is an acceptable method of treating superior mesenteric artery syndrome.


The motivation-opportunity-capability model of behavioural therapy - the vital component of effective patient centric obesity management.
Obesity has reached pandemic proportions globally and its management requires a multipronged approach to ensure an effectual and sustainable response. Integrating behavioural therapy is an important component in obesity management and would often lead to improvement in the quality of care provided to patients with obesity. Though important, it is often complex and difficult to administer in a busy outpatient department. We propose a Motivation-Opportunity-Capability(MOC) model, using Michie et al's COM-B ideation as an inspiration. This provides a simple framework to understand the behaviour of a patient with obesity and suggest therapeutic strategies more likely to be effective in a person centric manner. Integration of the MOC model in existing obesity management protocols would further help in improving outcomes of therapy and help in providing sustained weight loss.


Dissecting the stress metabolic alterations in in vitro Cyrtanthus regenerants.
Metabolic plasticity in plants allows for continuous adjustments of defence strategies in suboptimal environments. Proline and other metabolites figure prominently in most stress-mediated responses. This study examined the expression of salinity and osmotic adjustments in the enzymatic activity and accumulation of solutes and metabolites in response to imposed water and salt stress in Cyrtanthus contractus N.E. Br. and Cyrtanthus guthrieae L. Bolus regenerants. In vitro-derived plantlets were cultured on solid Murashige and Skoog (MS) media with three different polyethylene glycol (PEG)-induced osmotic levels and four NaCl stress-induced levels at 25 °C. The levels of proline and phenolic compounds measured at intervals of three, four and five weeks from initial plantlet culture increased in a stress-dependent pattern. The levels of these metabolites also showed a significant increase with an increase in the duration of plantlets under stress conditions. The highest proline concentration (9.98 μmol g(-1) FW) was recorded in C. contractus at 300 μM NaCl after five weeks. A corresponding high level of total phenolic compounds (147 mg GAE g(-1) DW) was also recorded in the same treatment for the same species. The activity of proline dehydrogenase (PDH) (EC 126.96.36.199) was shown to decrease with an increase in proline levels from week three to week five in almost all the stress conditions. The high levels, particularly of phenolic compounds obtained under osmotic and salinity stress conditions in this study present a promising potential of manipulating culture and/or growing conditions for improved secondary compound production and hence medicinal benefits.


Distinct subcellular localization of beta-tubulin epitopes in the adult mouse brain.
A panel of monoclonal antibodies specific of alpha-tubulin (TU-01, TU-09) and beta-tubulin (TU-06, TU-13) subunits was used to study the location of N-terminal structural domains of tubulin in adult mouse brain. The specificity of antibodies was confirmed b immunoblotting experiments. Immunohistochemical staining of vibratome sections from cerebral cortex, cerebellum, hippocampus, and corpus callosum showed that antibodies TU-01, TU-09, and TU-13 reacted with neuronal and glial cells and their processes, whereas the TU-06 antibody stained only the perikarya. Dendrites and axons were either unstained or their staining was very weak. As the TU-06 epitope is located on the N-terminal structural domain of beta-tubulin, the observed staining pattern cannot be interpreted as evidence of a distinct subcellular localization of beta-tubulin isotypes or known post-translational modifications. The limited distribution of the epitope could, rather, reflect differences between the conformations of tubulin molecules in microtubules of somata and neurites or, alternatively, a specific masking of the corresponding region on the N-terminal domain of beta-tubulin by interacting protein(s) in dendrites and axons.


Xenopus metamorphosis as a model to study thyroid hormone receptor function during vertebrate developmental transitions.
A hormone-dependent developmental transition from aquatic to terrestrial existence occurs in all tetrapod vertebrates, such as birth, hatching, and metamorphosis. Thyroid hormones (TH) and their receptors (TRs) are key players in the tissue transformations comprising vertebrate developmental transitions. The African clawed frog, Xenopus, is a premier model for the role of TRs in developmental transitions because of the numerous and dramatic TH-dependent tissue transformations during metamorphosis and because of the endocrine, molecular, and genomic resources available. TRs are nuclear receptors that repress TH-response genes when plasma TH is minimal and that activate those same genes to induce tissue-specific gene regulation cascades when TH plasma levels increase. Tissue-specific TR expression levels help determine tissue sensitivity and responsivity to TH thereby regulating the initiation and rate of developmental change in TH-sensitive tissues which govern the tissue developmental asynchrony observed during metamorphosis. This review highlighting Xenopus presents the key experimental findings underpinning the roles TRs play in control of vertebrate developmental transitions.


[Acute pulmonic valve endocarditis].
Right heart endocarditis mainly affects tricuspid valve, especially in drug users. Isolated pulmonary valve infection is rare. We here report the case of a 32-year old young woman whose diagnosis of community-acquired pulmonary valve endocarditis was confirmed. This study is even more interesting because pulmonary valve endocarditis has occurred in a patient without a history of drug addiction; nevertheless, it wasn't associated with restrictive interventricular communication. The patient underwent emergency surgery due to the visualization of large and mobile vegetation on transthoracic heart ultrasound. Surgery was carried out under extracorporeal circulation and pulmonary valve has been replaced with a bioprosthesis. Bloodcultures and valve culture showed methicillin-sensitive staphylococcus aureus. Postoperative evolution was favorable, with a follow-up of 06 months without recurring infections.


Relation of EGFR Mutation Status to Metabolic Activity in Localized Lung Adenocarcinoma and Its Influence on the Use of FDG PET/CT Parameters in Prognosis.
The purposes of this study were to assess the relation between epidermal growth factor receptor (EGFR) mutation status and FDG PET/CT findings and to evaluate the influence of this relation on the use of FDG PET/CT parameters to establish a prognosis in cases of localized lung adenocarcinoma. Patients with stage I and II lung adenocarcinomas were retrospectively enrolled. At the initial FDG PET/CT examination, maximum and peak standardized uptake, tumor-to-background ratio, and volumetric parameters of metabolic tumor volume and total lesion glycolysis were measured. The values of all the metabolic and volumetric FDG PET/CT parameters were significantly lower in EGFR mutant than in EGFR wild-type lung adenocarcinomas. All parameters were statistically significant for predicting recurrence-free survival. In multivariate analyses, peak standardized uptake and total lesion glycolysis were more significant prognostic factors than was TNM stage (p < 0.001). Optimal cutoff values of parameters for predicting recurrence-free survival were slightly different between the two groups. EGFR mutation is related to low metabolic activity of localized lung adenocarcinoma at FDG PET/CT. Because of differences in the metabolic activity of EGFR mutant and wild-type tumors, EGFR mutation status must be considered when FDG PET/CT parameters are used for prognosis.


A comparative study of release of interleukin-6 and tumour necrosis factor during normothermic and hypothermic cardiopulmonary bypass.
The institution of cardiopulmonary bypass generates many pro-inflammatory cytokines and several clinical variables, including temperature, have been shown to influence cytokine release during and after cardiopulmonary bypass. The release of tumour necrosis factor and interleukin-6 are the best predictors of post-cardiopulmonary bypass related morbidity. Their release during normothermic and hypothermic cardiopulmonary bypass and the correlation with clinical parameters of organ injury was studied. This prospective study was carried out in 52 adult patients, scheduled for cardiac surgery, exposed to normothermic and 27 to hypothermic cardiopulmonary bypass. Samples for estimation of tumour necrosis factor and interleukin-6 were collected preoperatively, 1 hour and 24 hours post cardiopulmonary bypass and analysed by ELISA. Haemodynamic parameters and respiratory parameters were noted and lung injury scores calculated. Interleukin-6 levels were raised in both the groups at 1 hour and 24 hours post cardiopulmonary bypass and the response was higher in the normothermic group. Tumour necrosis factor response was, however, similar in both the groups, with a rise at 1 hour returning back to baseline by 24 hours post cardiopulmonary bypass. The normothermic group had a better respiratory index in the postoperative period, early extubation was possible, had better clinical haemodynamics, a shorter cardiopulmonary bypass time and had reduced requirement of defibrillation after the release of aortic cross clamp. We conclude that the release of interleukin-6 was thermo-dependent but did not correlate with the clinical signs of organ injury. Tumour necrosis factor levels were significantly raised after the cardiopulmonary bypass but the rise was not thermo-dependent.


Evaluation of temporomandibular joint disc displacement as a risk factor for osteoarthrosis.
Temporomandibular joint (TMJ) disc displacement is a clinical sign often found in patients with temporomandibular disorders (TMDs) and associated with TMJ osteoarthrosis. Osteoarthrosis is a degenerative joint disease that may be associated with pain and functional disability. The aim of this study was to evaluate the odds ratio (OR) of joints with disc displacement presenting osteoarthrosis via magnetic resonance imaging (MRI) analysis. In total, 224 TMJ images from patients with signs and symptoms of a TMD were evaluated. The OR, a measure of association, was used to calculate the likelihood of TMJ disc displacement (with or without reduction) with osteoarthrosis. Joints with anterior disc displacement with reduction (ADDwR) and anterior disc displacement without reduction (ADDwoR) were 2.73- and 8.25-times, respectively, more likely to have osteoarthrosis. A nine-times greater likelihood of osteophyte occurrence was observed in cases of ADDwoR, whereas a lower OR for their occurrence (OR 2.96) was observed in cases of ADDwR. The significant OR of joints with disc displacement presenting osteoarthrosis, particularly in cases of ADDwoR, emphasizes the importance of accurate assessment of changes in disc position, which may be associated with other painful and functional disorders of the TMJ.


Problem-Based Learning at the Faculty of Medicine of the Université de Montréal: A Situated Cognition Perspective.
This study describes the typical case of problem-based learning (PBL) application at the Faculty of Medicine of the Université de Montréal and its analysis from the perspective of situated cognition. I used a typical case study to determine the general model of PBL application and performed my analysis by a global processing of information, against to the conceptual model of situated cognition. A typical PBL tutorial case consists of a meeting of a group of about 8 students with a tutor to discuss a medical problem. Learning objectives are predetermined by faculty and recorded in the tutor's handbook. Broadly speaking, the analysis revealed a certain kind of scaffolding within a "zone of proximal development" (ZPD). The adaptation of PBL at the Faculty of Medicine of the University of Montreal is hybrid, original, and can be related to the model of cognitive apprenticeship, but the tutor's role, however, does not fit the model of cognitive apprenticeship completely.


A new prognostic risk model for acute myeloid leukemia patients based on telomere-related genes.
Telomere maintenance is critical to ensure unlimited cancer cell proliferation, but the role of telomere-related genes in acute myeloid leukemia (AML) has not yet been thoroughly discussed. This study aims to develop a new prognostic risk model based on telomere-related genes and analyze potential mechanisms and targets. Cox regression analyses were used to build the prognostic risk model. Kaplan-Meier (KM) survival analysis and receiver operating characteristic (ROC) curve were used to assess the model performance. At the same time, we analyzed the relationship between the risk score and chemotherapy and immunotherapy and preliminarily explored possible mechanisms of immune resistance. The real-time polymerase chain reaction (PCR) was used to detect the prognosis gene expression levels. Finally, a prognostic signature of six telomere-related genes (TGPS6) including ALDH2, CDK18, DNMT3B, FRAT2, LGALSL, and RBL2 was constructed. The TGPS6 score was confirmed as an independent prognostic factor (HR 2.74, CI [2.13-3.53], p < 0.001) in AML and the five-year area under the ROC curve (AUC) value of the score in the training and validation set reached 0.74, 0.81 respectively. In addition, the TGPS6 perfected the European LeukemiaNet (ELN) 2017 prognosis risk stratification and performed well in both AML and cytogenetically normal AML (CN-AML) cohorts. The TGPS6 score also provided a reference for chemotherapy and immunotherapy in patients with AML.


Brigatinib Approved, but Treatment Role Uncertain.
The FDA has approved the ALK inhibitor brigatinib for patients with metastatic non-small cell lung cancer who cannot take crizotinib or whose disease worsened despite its use. The decision was based upon results of a phase II study that assessed two drug doses, with overall response rates of 45% and 56% respectively. The drug's effect on overall survival remains unclear, as does the optimal sequence of brigatinib and the three other ALK inhibitors.


Reticulocytosis, hypochromia, and microcytosis: an unusual presentation of the preleukemic syndrome.
Two patients exhibiting a highly unusual preleukemic syndrome with marked reticulocytosis, hypochromia, and microcytosis are reported. This red cell phenotype has been investigated by means of HbF, HbA2, and i-antigen activity dosages, immunofluorescence labeling of F cells, reticulocyte survival, globin chain synthesis, and electron microscopy study. The marked reticulocytosis is explained by a delayed disappearance of the reticulum. Serum iron is normal, and a thalassemic syndrome is excluded because of a balanced alpha/non-alpha globin chain synthesis. Electron microscopy studies are consistent with a defect in iron uptake by erythroid cells. All the hematologic data and investigations are similar to those observed for the Belgrade laboratory rat. It is hypothesized that the low expression of HbF and i-Ag associated with microcytosis are related to a prolongation of erythroid maturation as reflected by abnormal reticulocyte survival.


Analysis and decoupling control of a permanent magnet spherical actuator.
This paper presents the analysis and decoupling control of a spherical actuator, which is capable of performing three degree-of-freedom motion in one joint. The proposed actuator consists of a rotor with multiple PM (Permanent Magnet) poles in a circle and a stator with circumferential coils in three layers. Based on this actuator design, a decoupling control approach is developed. Unlike existing control methods that each coil is responsible for both the spinning and tilting motion, the proposed control strategy specifies the function of each coil. Specifically, the spinning motion is governed by the middle layer coils with a step control approach; while the tilting motion is regulated by upper and lower coils with a computed torque control method. Experiments have been conducted on the prototype to verify the validity of the design procedure, and the experimental results demonstrate the effectiveness of the analysis and control strategy.


Does Breast Magnetic Resonance Imaging Combined With Conventional Imaging Modalities Decrease the Rates of Surgical Margin Involvement and Reoperation?: A Case-Control Comparative Analysis.
The objective of this study was to assess whether preoperative breast magnetic resonance imaging (MRI) combined with conventional breast imaging techniques decreases the rates of margin involvement and reexcision.Data on patients who underwent surgery for primary operable breast cancer were obtained from the Changhua Christian Hospital (CCH) breast cancer database. The rate of surgical margin involvement and the rate of reoperation were compared between patients who underwent conventional breast imaging modalities (Group A: mammography and sonography) and those who received breast MRI in addition to conventional imaging (Group B: mammography, sonography, and MRI).A total of 1468 patients were enrolled in this study. Among the 733 patients in Group A, 377 (51.4%) received breast-conserving surgery (BCS) and 356 (48.6%) received mastectomy. Among the 735 patients in Group B, 348 (47.3%) received BCS and 387 (52.7%) received mastectomy. There were no significant differences in operative method between patients who received conventional imaging alone and those that received MRI and conventional imaging (P = 0.13). The rate of detection of pathological multifocal/multicentric breast cancer was markedly higher in patients who received preoperative MRI than in those who underwent conventional imaging alone (14.3% vs 8.6%, P < 0.01). The overall rate of surgical margin involvement was significantly lower in patients who received MRI (5.0%) than in those who received conventional imaging alone (9.0%) (P < 0.01). However, a significant reduction in rate of surgical margin positivity was only observed in patients who received BCS (Group A, 14.6%; Group B, 6.6%, P < 0.01). The overall BCS reoperation rates were 11.7% in the conventional imaging group and 3.2% in the combined MRI group (P < 0.01). There were no significant differences in rate of residual cancer in specimens obtained during reoperation between the 2 preoperative imaging groups (Group A, 50%; Group B, 81.8%, P = 0.09). In multivariate analysis, multifocal/multicentric breast cancer (odds ratio = 2.38, P = 0.02) and without MRI use (odds ratio = 2.35, P < 0.01) were the major predisposing factors to margin involvement in patients received BCS.Preoperative breast MRI combined with conventional breast imaging results in a lower rate of surgical margin involvement and reoperations in patients who receive BCS.


Leptin deficiency reduces but does not eliminate the development of hepatic fibrosis in mice infected with Schistosoma mansoni.
Leptin, a product of the obese (ob) gene, was demonstrated previously in activated hepatic collagen-producing stellate cells, but not in quiescent retinol-storing stellate cells. The role of leptin in fibrogenesis is unknown. This study investigated the possible influence of leptin in the pathogenesis of fibrosis by determination of the amount of fibrosis produced by Schistosoma mansoni infection in leptin deficient male ob/ob mice as compared to control mice. The mice were infected percutaneously with cercaria of Schistosoma mansoni and the amount of liver fibrosis determined 12 weeks after infection. The amount of hepatic collagen deposited was quantified by morphometric analysis of liver sections stained with sirius red and by hydroxyproline content. The amount of histologically detectable fibrosis was greater in the infected controls than in the infected ob/ob mice. In the infected control mice, but not in the ob/ob mice, the fibrosis surrounding the granuloma was broad and extended beyond the portal tracts into the lobule with the formation of fibrous septa. This study shows that leptin is a potentiating, but not an essential factor, for the development of hepatic fibrosis, because leptin deficiency reduces but does not prevent the development of hepatic fibrosis.


Characterization of stargardt disease using polarization-sensitive optical coherence tomography and fundus autofluorescence imaging.
To identify disease-specific changes in Stargardt disease (STGD) based on imaging with polarization-sensitive spectral-domain optical coherence tomography (PS-OCT) and to compare structural changes with those visible on blue light fundus autofluorescence (FAF) imaging. Twenty-eight eyes of 14 patients diagnosed with STGD were imaged using a novel high-speed, large-field PS-OCT system and FAF (excitation 488 nm, emission > 500 nm). The ophthalmoscopic phenotype was classified into three groups. ABCA4 mutation testing detected 15 STGD alleles, six of which harbor novel mutations. STGD phenotype 1 (12 eyes) showed sharply delineated areas of absent RPE signal on RPE segmentation B-scans of PS-OCT correlating with areas of hypofluorescence on FAF. Adjacent areas of irregular fluorescence correlated with an irregular RPE segmentation line with absence of overlaying photoreceptor layers. Eyes characterized on OCT by a gap in the subfoveal outer segment layer (foveal cavitation) showed a normal RPE segmentation line on PS-OCT. Hyperfluorescent flecks on FAF in phenotype 2 STGD (8 eyes) were identified as clusters of depolarizing material at the level of the RPE. Distribution of flecks could be depicted on RPE elevation maps. An increased amount of depolarizing material in the choroid was characteristic for STGD Phenotype 3 (8 eyes). PS-OCT together with FAF identified characteristic patterns of changes in different stages of the disease. PS-OCT is a promising new tool for diagnosis and evaluation of future treatment modalities in STGD.


Shining a light on the Arabidopsis circadian clock.
The circadian clock provides essential timing information to ensure optimal growth to prevailing external environmental conditions. A major time-setting mechanism (zeitgeber) in clock synchronization is light. Differing light wavelengths, intensities, and photoperiodic duration are processed for the clock-setting mechanism. Many studies on light-input pathways to the clock have focused on Arabidopsis thaliana. Photoreceptors are specific chromic proteins that detect light signals and transmit this information to the central circadian oscillator through a number of different signalling mechanisms. The most well-characterized clock-mediating photoreceptors are cryptochromes and phytochromes, detecting blue, red, and far-red wavelengths of light. Ultraviolet and shaded light are also processed signals to the oscillator. Notably, the clock reciprocally generates rhythms of photoreceptor action leading to so-called gating of light responses. Intermediate proteins, such as Phytochrome interacting factors (PIFs), constitutive photomorphogenic 1 (COP1) and EARLY FLOWERING 3 (ELF3), have been established in signalling pathways downstream of photoreceptor activation. However, the precise details for these signalling mechanisms are not fully established. This review highlights both historical and recent efforts made to understand overall light input to the oscillator, first looking at how each wavelength of light is detected, this is then related to known input mechanisms and their interactions.


[Comparison of two surgical methods as to early results in chronic subdural hematoma].
Despite general agreement among neurosurgeons concerning operative treatment in chronic subdural hematoma (CSDH), the optimal procedure remains controversial. Two surgical approaches are available: evacuation of hematoma fluid by trepanation; craniotomy and removal of hematoma with surrounding membranes. The main goal of this study was to compare the results of treatment in CSDH depending on the method of surgery. This retrospective study was done basing on case histories and computed tomography findings in 433 patients with CSDH operated between 1983 and 2003 at the Department ofNeurotraumatology, Jagiellonian University. Altogether, 495 neurosurgical procedures were done. Hematoma was managed by burr hole evacuation in 333 cases and by craniotomy in 162 cases. Neurological grading on discharge indicated that trepanation produced significantly better results than craniotomy. (1) In comparison with literature data and by separate evaluation, the results of treatment in CSDH at the Department of Neurotraumatology were good in trepanation and craniotomy groups alike. (2) Literature data and case histories of the present study demonstrate that burr hole evacuation is the preferred method of treatment in CSDH. (3) In the overwhelming majority of cases, computed tomography fails to identify CSDH patients necessitating craniotomy.


Children Born with Congenital Heart Defects and Growth Restriction at Birth: A Systematic Review and Meta-Analysis.
Newborns with congenital heart defects tend to have a higher risk of growth restriction, which can be an independent risk factor for adverse outcomes. To date, a systematic review of the relation between congenital heart defects (CHD) and growth restriction at birth, most commonly estimated by its imperfect proxy small for gestational age (SGA), has not been conducted. To conduct a systematic review and meta-analysis to estimate the proportion of children born with CHD that are small for gestational age (SGA). The search was carried out from inception until 31 March 2019 on Pubmed and Embase databases. Studies were screened and selected by two independent reviewers who used a predetermined data extraction form to obtain data from studies. Bias was assessed using the Critical Appraisal Skills Programme (CASP) checklist. The database search identified 1783 potentially relevant publications, of which 38 studies were found to be relevant to the study question. A total of 18 studies contained sufficient data for a meta-analysis, which was done using a random effects model. The pooled proportion of SGA in all CHD was 20% (95% CI 16%-24%) and 14% (95% CI 13%-16%) for isolated CHD. Proportion of SGA varied across different CHD ranging from 30% (95% CI 24%-37%) for Tetralogy of Fallot to 12% (95% CI 7%-18%) for isolated atrial septal defect. The majority of studies included in the meta-analysis were population-based studies published after 2010. The overall proportion of SGA in all CHD was 2-fold higher whereas for isolated CHD, 1.4-fold higher than the expected proportion in the general population. Although few studies have looked at SGA for different subtypes of CHD, the observed variability of SGA by subtypes suggests that growth restriction at birth in CHD may be due to different pathophysiological mechanisms.


Female sexual stimulation during antidepressant treatment.
Three women with several diagnoses, including depression and psychosis, personality disorder, attention deficit hyperactivity disorder, alcohol abuse, and physical disease, were treated with selective serotonin reuptake inhibitors (fluoxetine, paroxetine, fluvoxamine). One patient was prescribed paroxetine in addition to methylphenidate. While receiving these agents, two women experienced undesirable sexual arousal and the third had increased sexual desire, arousal, and hypersexuality.


Peopling of South Asia: investigating the caste-tribe continuum in India.
In recent years, mtDNA and Y chromosome studies involving human populations from South Asia and the rest of the world have revealed new insights about the peopling of the world by anatomically modern humans during the late Pleistocene, some 40,000-60,000 years ago, over the southern coastal route from Africa. Molecular studies and archaeological record are both largely consistent with autochthonous differentiation of the genetic structure of the caste and tribal populations in South Asia. High level of endogamy created by numerous social boundaries within and between castes and tribes, along with the influence of several evolutionary forces such as genetic drift, fragmentation and long-term isolation, has kept the Indian populations diverse and distant from each other as well as from other continental populations. This review attempts to summarize recent genetic studies on Indian caste and tribal populations with the focus on the information embedded in the socially defined structure of Indian populations.


Retrospective evaluation of the effects of traditional interscalene block alone versus combined with superior truncus block-associated diaphragm paralysis during arthroscopic shoulder surgery.
The aim of this study was to investigate the effects of traditional interscalene block (ISB) alone and ISB combined with superior truncus block (STB)-associated diaphragm paralysis evaluated by ultrasound, duration of analgesia, and rate of complication in patients undergoing arthroscopic shoulder surgery. Between January 2020 and December 2022, a total of 285 patients (158 males, 127 females; mean age: 48.0±15.1 years; range, 18 to 80 years) who underwent arthroscopic shoulder surgery under ISB, either alone or combined with STB, were retrospectively analyzed. The patients were operated under ISB alone using 30 mL 0.5% bupivacaine (n=140) or ISB using 10 mL (n=67) or 5 mL 0.5% bupivacaine (n=78) combined with STB using 20 mL 0.5% bupivacaine. Ultrasound reports of all patients' diaphragm function were also retrieved. Duration of analgesia, need for additional analgesics, and the type of analgesic drugs, and evaluations of patient and surgeon satisfactions were evaluated. Degree of diaphragm paralysis considered as complete (≥75%), partial (25.1 to 74.9%) and no paralysis (≤25%) were evaluated for comparison between the block types. The patients underwent operation due to rotator cuff rupture (n=218) or Bankart (n=67). Duration of analgesia, need for additional analgesia, and the type of analgesic drugs used were comparable between the block types. The most common complication was Horner syndrome (n=96, 33.68%) which was significantly lower in ISB (5 mL) +STB (20 mL) than the others (17.9% vs. 41.4% and 37.3%, p=0.002). The ISB (5 mL bupivacaine 0.5%) + STB (20 mL bupivacaine 0.5%) resulted in less complete diaphragm paralysis with adequate surgical anesthesia not requiring general anesthesia. The ISB using 5 mL of 0.5% bupivacaine + STB instead of traditional ISB alone can be preferred due to the low rate of complete hemi-diaphragm paralysis with adequate surgical anesthesia/analgesia and high patient and surgeon satisfaction.


Viral hepatitis. The alphabet game.
Differential diagnosis of viral hepatitis begins with a check for darkened urine and bile in the urine. These hallmarks of conjugated hyperbilirubinemia immediately rule out prehepatic liver disease. Next, studies are done for the elevated transaminase levels that are characteristic of hepatitis infection, and a thorough history is taken to rule out drug- and toxin-induced hepatitis that may mimic acute viral hepatitis. Elevated alkaline phosphatase is a good marker of cholestasis. Ultrasonography can clarify this diagnosis. The classic presenting symptoms of viral hepatitis are jaundice, nausea, vomiting, malaise, anorexia, and dull right upper quadrant pain. However, serologic studies are needed to detect the presence of specific viral agents.


Regional blood flow in human tumours with special reference to the effect of radiotherapy.
Blood flow in 41 superficial tumour nodules, of which nine were lymphomas, nine anaplastic carcinomas and 23 differentiated malignomas was measured using the 133Xe-clearance method. The lymphomas showed statistically higher blood flow (38-4 ml./min/100 g) than anaplastic (11-4 ml./min/100 g) and differentiated tumours (13-7 ml./min/100 g). After one week of radiation treatment the mean blood flow in anaplastic carcinomas was higher than the initial value. After an interval following the end of the radiation treatment the circulation diminished significantly compared with that observed immediately at the end of radiotherapy. The size of the tumours did not correlate with the blood flow.


Poor maternal nutrition during gestation alters the expression of genes involved in muscle development and metabolism in lambs.
Poor maternal nutrition during gestation can result in reduced muscle mass and increased adiposity of the muscle tissue in the offspring. This can have long-lasting consequences on offspring health and productivity. However, the mechanisms by which poor maternal nutrition affects postnatal muscle development are poorly understood. We hypothesized that poor maternal nutrition during gestation would alter expression of key pathways and genes involved in growth, development, and maintenance of the muscle of lambs. For this study, beginning at d 31 ± 1.3 of gestation, ewes were fed 100 (control), 60 (restricted), or 140% (overfed) of the NRC requirements. Within 24 h of birth, lambs were necropsied and semitendinosus muscle tissue was collected for gene expression analysis. Using RNA sequencing (RNA-seq) across dietary treatment groups, 35 and 10 differentially expressed genes were identified using the and reference annotations, respectively. Maternal overfeeding caused changes in the expression of genes involved in regulating muscle protein synthesis and growth as well as metabolism. Alternately, maternal nutrient restriction affected genes that are involved in muscle cell proliferation and signal transduction. That is, despite a similar phenotype, the genes identified differed between offspring born to restricted- or overfed, ewes indicating that the mechanism for the phenotypic changes in muscle are due to different mechanisms.


Correlation of karyotype and immunophenotype in childhood acute lymphoblastic leukemia; experience at the National Cancer Institute, Cairo University, Egypt.
To identify chromosomal pattern among the major immunophenotypic subgroups in Egyptian children with ALL, and its correlation with clinical presentation and disease free survival. Cytogenetic and immunophenotypic analysis were done for all patients. Patients received ALL-PNCI-III/98 chemotherapy protocol used at NCI, Cairo University. The frequency of pseudodiploidy and normal karyotype in the whole group was 42.9% and 33.3% respectively. The frequency of pseudodiploidy was 36.8% in CALLA positive early pre B, 30.7% in pre B cases, 71.4% in T cell cases and 100% in mature B cell cases. At 12 months, DFS was 50% for pseudodiploid group having pre B phenotype, compared to 16.6% for pseudodiploid group with CALLA positive early pre B ALL. Sixteen percent of the studied cases showed T cell phenotype, 71.4% of them showed pseudodiploid karyotype, all of them had high risk features. Hyperdiploidy was found in 31.5% of CALLA positive early pre B cases and was associated with favorable prognostic features and DFS of 66.6% at 12 months. Hyperdiploidy of >50 chromosome represented 62.5% of hyperdipoid cases, 80% of them were CALLA positive early pre B ALL carrying good risk features. Fifty percent of normal karyotypic patients showed pre B phenotype, while 42.8% showed CALLA positive early pre B ALL. Their age, TLC, DFS, were almost comparable. CALLA early pre B phenotype has a positive impact on chromosomal pattern having best outcome among patients with hyperdiploidy. The Pseudodiploid karyotype carries a better outcome with pre B phenotype.


A molecular study of heterozygous protein 4.1 deficiency in hereditary elliptocytosis.
Genomic DNA from five kindreds and two individuals with hereditary elliptocytosis [HE(4.1+)] and a partial deficiency of protein 4.1 [HE(4.1+)] was extracted and probed with a cDNA for protein 4.1. When using a fragment of the cDNA that encompassed the coding region of the gene, two restriction fragment length polymorphisms segregating with protein 4.1 deficiency were found in one kindred when using the enzymes BgIII and PvuII but were not seen in the other HE(4.1+) subjects or in 20 random control individuals. DNA digested with three other enzymes (HindIII, EcoRI, TaqI) produced restriction patterns similar to controls. The unique BgIII and PvuII polymorphisms probably reflect a rearrangement of the coding region of the protein 4.1 gene as the underlying cause of the partial protein 4.1 deficiency in this family. A less likely possibility is that these polymorphisms represent coincidental single base changes unrelated to the primary gene defect.


A peculiar case of HIV transmission within a family in north India.
We describe an unusual case of heterosexual HIV transmission between two brothers within a family, due to a locally prevalent social custom of remarriage of the elder brother's widow, to the younger brother. This case of HIV secondary transmission, which could possibly have been stopped at certain points by better understanding and awareness about HIV transmission emphasizes the need for extensive post-test counselling of affected individuals and their family members.


Predictors of outcomes in hospitalized patients undergoing pacemaker insertion: Analysis from the national inpatient database (2016-2017).
Pacemaker implantation in the U.S. is rising due to an aging population. The aim of this analysis was to identify risk factors associated with increased mortality and complications in hospitalized patients requiring pacemaker implantation. We performed a retrospective analysis using the National Inpatient Sample database, identifying hospitalized patients who underwent pacemaker implantation using International Classification of Disease, Tenth Revision, Clinical Modification codes. Independent predictors of inpatient mortality were identified using multivariate logistic regression analysis. There were 242,980 hospitalizations with pacemaker implantation during 2016 and 2017. The most frequently encountered indications for hospitalizations involving pacemaker insertion included sick sinus syndrome (SSS) (27.60%), complete atrioventricular (AV) block (21.57%), and second-degree AV block (7.83%). Chronic liver disease was associated with the highest adjusted odds of inpatient mortality (aOR = 5.76, 95% CI: 4.46 to 7.44, p < .001). Comorbid anemia had the highest statistically significant adjusted odds ratio (aOR) for predictors of post-procedural cardiac complications (aOR = 3.17, 95% CI: 2.81 to 3.58, p < .001). Mortality in hospitalized patients needing pacemaker implantation was 1.05%. About 3.36% of hospitalizations developed post procedural circulatory complications (PPCC), 2.45% developed sepsis, and 1.84% developed mechanical complications of cardiac electronic devices. We identified several predictors of inpatient mortality in hospitalized patients undergoing pacemaker implantation, including chronic liver disease, protein-calorie malnutrition, chronic heart failure, anemia, and history of malignancy. Anemia, chronic liver disease, and congestive heart failure were independent predictors of adverse outcomes in such patients.


Wnt-3a-activated human fibroblasts promote human keratinocyte proliferation and matrix destruction.
Aberrant Wnt regulation, detectable by nuclear translocation of beta-catenin, is a hallmark of many cancers including skin squamous cell carcinomas (SCCs). By analyzing primary human skin SCCs, we demonstrate that nuclear beta-catenin is not restricted to SCC cells but also detected in stromal fibroblasts, suggesting an important role for aberrant Wnt regulation also in the tumor microenvironment. When human keratinocytes and fibroblasts were treated with Wnt-3a, fibroblasts proved to be more responsive. Accordingly, Wnt-3a did not alter HaCaT cell functions in a cell-autonomous manner. However, when organotypic cultures (OTCs) were treated with Wnt-3a, HaCaT keratinocytes responded with increased proliferation. As nuclear beta-catenin was induced only in the fibroblasts, this argued for a Wnt-dependent, paracrine keratinocyte stimulation. Global gene expression analysis of Wnt-3a-stimulated fibroblasts identified genes encoding interleukin-8 (IL-8) and C-C motif chemokine 2 (CCL-2) as well as matrix metalloproteinase-1 (MMP-1) as Wnt-3a targets. In agreement, we show that IL-8 and CCL-2 were secreted in high amounts by Wnt-3a-stimulated fibroblasts also in OTCs. The functional role of IL-8 and CCL-2 as keratinocyte growth regulators was confirmed by directly stimulating HaCaT cell proliferation in conventional cultures. Most important, neutralizing antibodies against IL-8 and CCL-2 abolished the Wnt-dependent HaCaT cell hyperproliferation in OTCs. Additionally, MMP-1 was expressed in high amounts in Wnt-3a-stimulated OTCs and degraded the stromal matrix. Thus, our data show that Wnt-3a stimulates fibroblasts to secrete both keratinocyte proliferation-inducing cytokines and stroma-degrading metalloproteinases, thereby providing evidence for a novel Wnt deregulation in the tumor-stroma directly contributing to skin cancer progression.


Preventable deaths following emergency medical dispatch--an audit study.
Call taker triage of calls to the 112 emergency number, can be error prone because rapid decisions must be made based on limited information. Here we investigated the preventability and common characteristics of same-day deaths among patients who called 112 and were not assigned an ambulance with lights and sirens by the Emergency Medical Communication Centre (EMCC). An audit was performed by an external panel of experienced prehospital consultant anaesthesiologists. The panel focused exclusively on the role of the EMCC, assessing whether same-day deaths among 112 callers could have been prevented if the EMCC had assessed the situations as highly urgent. The panels' assessments were based on review of patient charts and voice-log recordings of 112 calls. All patient related material was reviewed by the audit panel and all cases where then scored as preventable, potentially preventable or non-preventable during a two day meeting. The study setting was three of five regions in Denmark with a combined population of 4,182,613 inhabitants, which equals 75% of the Danish population. The study period was 18 months, from mid-2011 to the end of 2012. Linkage of prospectively collected EMCC data with population-based registries resulted in the identification of 94,488 non-high-acuity 112 callers. Among these callers, 152 (0.16% of all) died on the same day as the corresponding 112 call, and were included in this study. The mean age of included patients was 74.4 years (range, 31-100 years) and 45.4% were female. The audit panel found no definitively preventable deaths; however, 18 (11.8%) of the analysed same-day deaths (0.02% of all non-high-acuity callers) were found to be potentially preventable. In 13 of these 18 cases, the dispatch protocol was either not used or not used correctly. Same-day death rarely occurred among 112 callers whose situations were assessed as not highly urgent. No same-day deaths were found to be definitively preventable by a different EMCC call assessment, but a minority of same-day deaths could potentially have been prevented with more accurate triage. Better adherence with dispatch protocol could improve the safety of the dispatch process.


Malignant Merkel cell neoplasm of the eyelid.
Malignant Merkel cell neoplasms of the eyelid are most commonly found in elderly patients. They occur most frequently on the upper eyelid and are seen as large, nontender , red or violaceous masses with intact overlying skin. Differential diagnosis includes lymphoma and oat cell carcinoma. Conventional light microscopic features are usually distinctive, but tissue should be saved for electron microscopy and immunocytochemical studies, since the presence of dense-core neurosecretory granules and perinuclear microfilaments on electron microscopic examination and positive staining for neuron-specific enolase, are strongly suggestive of malignant Merkel cell neoplasm. Because of the diffuse infiltrative growth pattern and early lymphatic spread of this tumor, treatment requires careful examination of regional lymph nodes and wide surgical excision of the tumor with frozen-section control of margins.


Multiple lymphangiomas of the neck, axilla, mediastinum, and bones in an adult.
Whereas lymphangiomas of the neck, axilla, or mediastinum are not uncommon in children, they are rarely found in the adult, and primary lymphangioma of bone is very rare. The authors report a case of multiple lymphangiomas of the neck, axilla, mediastinum, and bones in a 34-year-old man, which they believe to be only the second such case reported thus far.


Molecular detection of Coxiella burnetii in raw meat intended for pet consumption.
The discovery of antibodies against Coxiella burnetii in cattery-confined breeding cats indicating prior or current exposure (Shapiro et al., 2015) prompted an investigation into possible sources of infection. One hypothesis was that raw meat diets containing reservoir species may provide a source of C. burnetii transmission. The aim of this pilot study was to determine whether C. burnetii DNA was present in raw meat sold exclusively for companion animal consumption. The sample population consisted of raw meat packages (n = 58) of primarily kangaroo origin, with three to four aliquots (50-120 mg) randomly selected from each package. Genomic DNA was extracted from whole tissue in each of these aliquots using a modified protocol. Three quantitative PCR assays were used for the detection of C. burnetii targeting the IS1111 gene, the heat shock operon htpAB and the C. burnetii outer membrane protein-coding gene, com1. Coxiella burnetii DNA was detected in 25/58 samples (43%) using the IS1111, htpAB and/or com1 PCR assays and confirmed by DNA sequencing. All samples amplifying a product in the com1 assay also amplified a product in the htpAB and IS1111 assays. A total of 17/58 (29%) packets were positive with all three genes, 4/58 (7%) were positive with two genes (IS1111 and htpAB) and 4/58 (7%) were positive with the IS1111 gene only. Coxiella burnetii DNA was five times more likely to be found in offal than skeletal muscle meat samples. All meat samples in which C. burnetii DNA was found were from kangaroo tissues, while samples labelled as non-kangaroo meat (n = 4) were negative. Multi-locus variable number of tandem repeat analysis (MLVA) identified three different genotypes of C. burnetii that have all been identified previously from Australian human clinical Q fever cases. Further investigations are required to determine the potential role of certain raw meats in the transmission of C. burnetii to cats and humans.