Calciphylaxis: pathogenesis and therapy.
Calciphylaxis is a rare, painful and debilitating disease in which calcification of the skin and subcutaneous tissues or of internal organs can lead to skin necrosis, discolouration, and other skin lesions. The typical patient has end-stage renal disease (ESRD) and hyperparathyroidism. Selye originally characterized this syndrome in rats and distinguished it from other syndromes of abnormal calcification by the following sequence: sensitizers, latent period, and challengers. There has been recent debate regarding misdiagnosis and failure to differentiate this category of patients even in clinical studies. In this article the clinical manifestations of calciphylaxis are described; the importance of distinguishing this condition from other calcification syndromes is explained; risk factors, sensitizers, and challenges are reviewed; treatments of choice are discussed; and the merits of parathyroidectomy are evaluated. It is important to consider calciphylaxis in a differential diagnosis of calcification syndromes and in treating patients with ESRD and hyperparathyroidism, because early diagnosis and treatment can interrupt the progression of the disease process; the disease is painful and debilitating; and inappropriate treatment such as corticosteroid administration may aggravate the condition. Skin biopsy is an important diagnostic tool when the condition is suspected. Parathyroidectomy may be justified because the untreated disease itself has significant rates of morbidity and mortality and because this treatment occasionally leads to dramatic clinical improvement.


Emtricitabine triphosphate in dried blood spots is a predictor of viral suppression in HIV infection and reflects short-term adherence to antiretroviral therapy.
Emtricitabine triphosphate (FTC-TP), the phosphorylated anabolite of emtricitabine, can be quantified in dried blood spots (DBS). We evaluated FTC-TP in DBS as a predictor of viral suppression and evaluated self-reported adherence as a predictor of FTC-TP. Persons living with HIV (PLWH) on an FTC-containing regimen were prospectively recruited. A DBS and HIV viral load were obtained during routine clinical visits. Self-reported adherence for 3 days, 30 days and 3 months was captured. Generalized estimating equations were used to estimate the adjusted odds ratio (aOR) of viral suppression for quantifiable FTC-TP versus below the limit of quantification (BLQ). The utility of self-reported adherence to predict quantifiable FTC-TP was assessed by calculating the area under receiver operating characteristic (ROC) curve. One thousand one hundred and fifty-four person-visits from 514 participants who had DBS assayed for FTC-TP were included in the analysis. After adjusting for age, gender, race, BMI, ART class, ART duration, estimated glomerular filtration rate and CD4+ T cell count, the aOR (95% CI) for viral suppression for quantifiable FTC-TP versus BLQ was 7.2 (4.3-12.0; P < 0.0001). After further adjusting for tenofovir diphosphate, the aOR was 2.1 (1.2-4.0; P < 0.015). The area under the ROC curve for 3 day self-reported adherence was 0.82 (95% CI 0.75-0.88) compared with 0.70 (95% CI 0.62-0.77, P = 0.004) and 0.79 (95% CI 0.71-0.86, P = 0.32) for 3 month and 30 day self-reported adherence, respectively. In PLWH, FTC-TP from DBS is a strong predictor of viral suppression, even after adjusting for tenofovir diphosphate, and was best predicted by 3 day self-reported adherence.


Improved prostate delineation in prostate HDR brachytherapy with TRUS-CT deformable registration technology: A pilot study with MRI validation.
Accurate prostate delineation is essential to ensure proper target coverage and normal-tissue sparing in prostate HDR brachytherapy. We have developed a prostate HDR brachytherapy technology that integrates intraoperative TRUS-based prostate contour into HDR treatment planning through TRUS-CT deformable registration (TCDR) to improve prostate contour accuracy. In a perspective study of 16 patients, we investigated the clinical feasibility as well as the performance of this TCDR-based HDR approach. We compared the performance of the TCDR-based approach with the conventional CT-based HDR in terms of prostate contour accuracy using MRI as the gold standard. For all patients, the average Dice prostate volume overlap was 91.1 ± 2.3% between the TCDR-based and the MRI-defined prostate volumes. In a subset of eight patients, inter and intro-observer reliability study was conducted among three experienced physicians (two radiation oncologists and one radiologist) for the TCDR-based HDR approach. Overall, a 10 to 40% improvement in prostate volume accuracy can be achieved with the TCDR-based approach as compared with the conventional CT-based prostate volumes. The TCDR-based prostate volumes match closely to the MRI-defined prostate volumes for all 3 observers (mean volume difference: 0.5 ± 7.2%, 1.8 ± 7.2%, and 3.5 ± 5.1%); while CT-based contours overestimated prostate volumes by 10.9 ± 28.7%, 13.7 ± 20.1%, and 44.7 ± 32.1%. This study has shown that the TCDR-based HDR brachytherapy is clinically feasible and can significantly improve prostate contour accuracy over the conventional CT-based prostate contour. We also demonstrated the reliability of the TCDR-based prostate delineation. This TCDR-based HDR approach has the potential to enable accurate dose planning and delivery, and potentially enhance prostate HDR treatment outcome.


Superconductivity and strong interactions in a tunable moiré quasicrystal.
Electronic states in quasicrystals generally preclude a Bloch description1, rendering them fascinating and enigmatic. Owing to their complexity and scarcity, quasicrystals are underexplored relative to periodic and amorphous structures. Here we introduce a new type of highly tunable quasicrystal easily assembled from periodic components. By twisting three layers of graphene with two different twist angles, we form two mutually incommensurate moiré patterns. In contrast to many common atomic-scale quasicrystals2,3, the quasiperiodicity in our system is defined on moiré length scales of several nanometres. This 'moiré quasicrystal' allows us to tune the chemical potential and thus the electronic system between a periodic-like regime at low energies and a strongly quasiperiodic regime at higher energies, the latter hosting a large density of weakly dispersing states. Notably, in the quasiperiodic regime, we observe superconductivity near a flavour-symmetry-breaking phase transition4,5, the latter indicative of the important role that electronic interactions play in that regime. The prevalence of interacting phenomena in future systems with in situ tunability is not only useful for the study of quasiperiodic systems but may also provide insights into electronic ordering in related periodic moiré crystals6-12. We anticipate that extending this platform to engineer quasicrystals by varying the number of layers and twist angles, and by using different two-dimensional components, will lead to a new family of quantum materials to investigate the properties of strongly interacting quasicrystals.


Anidulafungin Vicuron.
Anidulafungin, a 1,3-beta-glucan synthesis inhibitor and the pentyloxyterphenyl side chain derivative of echinocandin B, is being developed by Vicuron Pharmaceuticals Inc, under license from Eli Lilly & Co, for the potential treatment of fungal infection.


Systematic Analysis of Neurotransmitter Receptors in Human Breast Cancer Reveals a Strong Association With Outcome and Uncovers HTR6 as a Survival-Associated Gene Potentially Regulating the Immune Microenvironment.
Many epidemiological reports have indicated an increase in the incidence of breast cancer among psychotic patients, suggesting that the targets of antipsychotics, neurotransmitter receptors, may have a role in tumorigenesis. However, the functions of neurotransmitter receptors in cancer are barely known. Here, we analyzed 44 neurotransmitter receptors in breast cancer and revealed that the expression of 34 receptors was positively correlated with relapse-free survival rates (RFS) of patients using the public database (n = 3951). Among all these receptors, we revealed decreased expression of HTR6 in human advanced breast cancer versus tumors in situ using our original data (n = 44). After a pan-cancer analysis including 22 cancers (n = 11262), we disclosed that HTR6 was expressed in 12 tumors and uncovered its influence on survival in seven tumors. Using multi-omics datasets from Linkedomics, we revealed a potential regulatory role of HTR6 in MAPK, JUN, and leukocyte-differentiation pathways through enriching 294 co-expressed phosphorylated proteins of HTR6. Furthermore, we proclaimed a close association of HTR6 expression with the immune microenvironment. Finally, we uncovered two possible reasons for HTR6 down-regulation in breast cancer, including deep deletion in the genome and the up-regulation of FOXA1 in breast cancer, which was a potential negatively regulatory transcription factor of HTR6. Taken together, we revealed a new function of neurotransmitter receptors in breast cancer and identified HTR6 as a survival-related gene potentially regulating the immune microenvironment. The findings in our study would improve our understanding of the pathogenesis of breast cancer and provided a theoretical basis for personalized medication in psychotic patients.


Adolescent development of interethnic attitudes following a social intervention to increase intergroup contact: The moderating role of affective forecasting.
This longitudinal, quasi-experimental field study investigated affective forecasting as a moderator of positive intergroup contact effects among adolescents. We also examined a novel mediating mechanism that underlies this effect, namely accuracy of perceived outgroup willingness for intergroup contact. Three annual waves of survey data were used from 1,169 adolescents (Mage = 13.88 at Wave 1; 50% girls; 66% White British, 44% Asian British) whose schools were merged, in a unique intervention that resulted in one school where ethnic groups were evenly mixed (i.e., balanced school) and two White British majority schools (i.e., majority skewed schools). Results showed that positive intergroup contact and attitudes improved more in the balanced school than in the majority skewed schools. In all schools, change in adolescents' positive intergroup contact predicted change in positive intergroup attitudes indirectly via (a) increased accuracy of perceived outgroup willingness for contact and (b) reduced intergroup anxiety. Indirect effects via accuracy of perceived contact willingness were stronger for adolescents who made more negative affective forecasts than for other adolescents. These moderated mediation effects were stronger in the balanced school than in the majority skewed schools. Thus, more balanced ethnic mixing in schools seemed to directly enhance positive intergroup relations and attitudes for all adolescents, but to particularly benefit adolescents who made more negative affective forecasts about positive contact before the school merger. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Metabolism of stevioside by healthy subjects.
Stevioside (250-mg capsules) was given thrice daily for 3 days to 10 healthy subjects. Blood samples were collected and blood pressure measured after nocturnal fasting, before and at different time points during the third day of the administration of stevioside. No significant differences were found between the control and the stevioside condition for blood pressure and blood biochemical parameters. The 24-hr urinary volume and urinary excretion of electrolytes were not significantly different. Likewise, no significant difference was found for mean blood glucose and insulin between control and stevioside conditions. Thus, oral stevioside is not directly effective as a hypotensive or hypoglycemic agent in healthy subjects at the dose administered in this study. Stevioside, free steviol, and steviol metabolites were analyzed in blood, feces, and urine after 3 days of stevioside administration. No uptake was found of stevioside by the gastrointestinal tract or the amounts taken up were very low and below the detection limit of the UV detector. Stomach juice did not degrade stevioside. All the stevioside reaching the colon was degraded by micro-organisms into steviol, the only metabolite found in feces. In blood plasma, no stevioside, no free steviol or other free steviol metabolites were found. However, steviol glucuronide (SV glu) was found in maximum concentrations of 33 micro g/ml (21.3 micro g steviol equivalents/ml). In urine, no stevioside or free steviol were present, but SV glu was found in amounts of up to 318 mg/24-hr urine (205 mg steviol equivalents/24 hrs). No other steviol derivatives were detected. In feces, besides free steviol, no other steviol metabolites or conjugates were detected. Steviol was excreted as SV glu in urine.


Risk estimates for neonatal myotonic dystrophy.
Children who inherit the autosomal dominant gene for myotonic dystrophy from their mother rather than their father may develop the severe neonatal type rather than the late onset type. The families of 22 neonatal type probands and 59 late onset type probands were studied to determine the risk of occurrence and recurrence of the neonatal type. The frequency of the neonatal type in sibs of neonatal type probands was 29%, or 37% if cases of neonatal deaths are counted as affected. This is significantly higher than the 6% of the neonatal type found in the offspring of affected women not ascertained through a child with the neonatal type. These data suggest that certain women carrying the gene for myotonic dystrophy are predisposed to have children affected with the neonatal type rather than the late onset type. The female near relatives of these women do not seem to share this predisposition. The data should be useful for genetic counseling.


The life cycle of platelet granules.
Platelet granules are unique among secretory vesicles in both their content and their life cycle. Platelets contain three major granule types-dense granules, α-granules, and lysosomes-although other granule types have been reported. Dense granules and α-granules are the most well-studied and the most physiologically important. Platelet granules are formed in large, multilobulated cells, termed megakaryocytes, prior to transport into platelets. The biogenesis of dense granules and α-granules involves common but also distinct pathways. Both are formed from the trans-Golgi network and early endosomes and mature in multivesicular bodies, but the formation of dense granules requires trafficking machinery different from that of α-granules. Following formation in the megakaryocyte body, both granule types are transported through and mature in long proplatelet extensions prior to the release of nascent platelets into the bloodstream. Granules remain stored in circulating platelets until platelet activation triggers the exocytosis of their contents. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, located on both the granules and target membranes, provide the mechanical energy that enables membrane fusion during both granulogenesis and exocytosis. The function of these core fusion engines is controlled by SNARE regulators, which direct the site, timing, and extent to which these SNAREs interact and consequently the resulting membrane fusion. In this review, we assess new developments in the study of platelet granules, from their generation to their exocytosis.


Providing care in isolation while awaiting SARS-CoV-2 test results: Considering differential diagnoses and avoiding anchoring bias.
Isolation of confirmed or suspected coronavirus disease 2019 (COVID-19) cases is essential but, as symptoms of COVID-19 are non-specific and test results not immediately available, case identification at admission remains challenging. To inform optimization of triage algorithms, patient flow and patient care, we analyzed characteristics of patients admitted to an isolation ward, both severe acute respiratory syndrome coronavirus 2019 (SARS-CoV-2) positive patients and patients in which initial suspicion was not confirmed after appropriate testing.Data from patients with confirmed or suspected COVID-19 treated in an isolation unit were analyzed retrospectively. Symptoms, comorbidities and clinical findings were analyzed descriptively and associations between patient characteristics and final SARS-CoV-2 status were assessed using univariate regression.Eighty three patients (49 SARS-CoV-2 negative and 34 positive) were included in the final analysis. Of initially suspected COVID-19 cases, 59% proved to be SARS-CoV-2-negative. These patients had more comorbidities (Charlson Comorbidity Index median 5(interquartile range [IQR] 2.5, 7) vs 2.7(IQR 1, 4)), and higher proportion of active malignancy than patients with confirmed COVID-19 (47% vs 15%; P = .004), while immunosuppression was frequent in both patient groups (20% vs 21%; P = .984). Of SARS-CoV-2 negative patients, 31% were diagnosed with non-infectious diseases.A high proportion of patients (59%) triaged to the isolation unit were tested negative for SARS-CoV-2. Of these, many suffered from active malignancy (47%) and were immunosuppressed (20%). Non-infectious diseases were diagnosed in 31%, highlighting the need for appropriate patient flow, timely expert medical care including evaluation for differential diagnostics while providing isolation and ruling out of COVID-19 in these patients with complex underlying diseases.


Detection of Prosthetic Joint Infection Based on Magnetically Assisted Surface Enhanced Raman Spectroscopy.
Accurate and rapid diagnosis of prosthetic joint infection (PJI) is vital for rational and effective therapeutic management of this condition. Several diagnostic strategies have been developed for discriminating between infected and noninfected cases. However, none of them can reliably diagnose the whole spectrum of clinical presentations of PJI. Here, we report a new method for PJI detection based on magnetically assisted surface enhanced Raman spectroscopy (MA-SERS) using streptavidin-modified magnetic nanoparticles (MNP@Strep) whose surface is functionalized with suitable biotinylated antibodies and then coated with silver nanoparticles by self-assembly. The high efficiency of this approach is demonstrated by the diagnosis of infections caused by two bacterial species commonly associated with PJI, namely, Staphylococcus aureus and Streptococcus pyogenes. The method's performance was verified with model samples of bacterial lysates and with four real-matrix samples of knee joint fluid spiked with live pathogenic bacterial cells. This procedure is operationally simple, versatile, inexpensive, and quick to perform, making it a potentially attractive alternative to established diagnostic techniques based on Koch's culturing or colony counting methods.


Immunotherapy of cancer: tumor suppression and regression by cell walls of Mycobacterium phlei attached to oil droplets.
Components of mycobacterial cell wall(s) (CW) attached to oil droplets were evaluated for their ability 1) to inhibit the growth of line-10 tumor transplants in the skin of syngeneic guinea pigs when inoculated together with 10(6) tumor cells (suppression experiments) and 2) to regress established 7-day-old intradermal tumors and eradicate microscopic lymph node metastases upon injection into the tumors (regression experiments). CW and cell-wall skeleton (CWS) preparations from Mycobacterium phlei, a fast-growing saprophyte of group IV of the atypical mycobacteria, suppressed tumor growth in essentially all animals when 37.5-mug doses were administered; at a dose of 300 mug, they cured 50-60% of the animals in regression tests. The addition of 300 mug of a purified trehalose mycolate, isolated from M. tuberculosis strain Aoyama B, to 300 mug M. phlei CW or CWS preparations significantly increased their tumor regressive potency to provide cure rates to about 90%. Because M. phlei can be propagated more readily, it can be used advantageously in place of BCG to prepare stable, non-living immunologic adjuvants of defined composition and consistently high potency to meet the need for standards with minimal residual malignant disease.


Purification and characterization of hepatic inorganic pyrophosphatase hydrolyzing imidodiphosphate.
A 56-kDa inorganic pyrophosphatase consisting of 33-kDa subunits was purified from bovine liver almost to homogeneity. This hydrolase required divalent cations such as MgCl2, CoCl2, and MnCl2 to hydrolyze PPi and was insensitive to 2 mM sodium fluoride. The purified hydrolase released 2.1 mumol Pi from PPi per minute per milligram of protein in the presence of 1 mM MgCl2, and the Km for PPi was 0.14 mM. It also hydrolyzed imidodiphosphate to yield Pi and ammonia even in the absence of a divalent cation. The purified hydrolase liberated 2.2 mumol Pi from imidodiphosphate per minute per milligram of protein and the Km for imidodiphosphate was 0.12 mM. Addition of 80 microM MgCl2, CoCl2, or MnCl2 to the reaction mixture increased the hydrolysis rate of imidodiphosphate by 1.5-, 2.0-, and 3.4-fold, respectively. In the absence of divalent cations, the enzymatic hydrolysis of imidodiphosphate was inhibited competitively by PPi (Ki = 0.13 mM). Moreover, one-half of the maximal hydrolysis of imidodiphosphate was inhibited by 10 microM trans-1,2-diaminocyclohexane N,N,N',N'-tetraacetic acid or 45 microM p-chloromercuriphenyl sulfonate. When the hydrolase was treated with heat or SDS, two activities capable of hydrolyzing PPi and imidodiphosphate gave similar inactivation profiles, indicating that one hydrolase participated in the hydrolysis of both substrates.


Evaluative laboratory testing practices of United States rheumatologists.
Several laboratory tests can be used to monitor disease activity in patients with rheumatic diseases. We sought to learn how rheumatologists use evaluative laboratory tests in the care of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We surveyed United States rheumatologists by mailed questionnaire. Of the 976 rheumatologists who received the questionnaire, 575 responded, for a response rate of 59%. Eighty-six percent of the respondents reported using either the erythrocyte sedimentation rate (ESR) or C-reactive protein level to monitor patients with RA, 92% used either the anti-DNA antibody level or complement C3 level to monitor patients with SLE, and 95% used either the ESR or ANCA levels to monitor patients with ANCA-associated vasculitis. The frequency of testing was distributed over a broad range, but testing was common. Testing on 50% of the visits or more was reported by 52% of respondents for RA, 59% of respondents for SLE, and 64% of respondents for ANCA-associated vasculitis. Between 7% and 11% of respondents reported testing patients on every visit, regardless of clinical disease activity. The majority of respondents reported not altering the treatment of clinically stable patients based on these test results. Evaluative laboratory testing is common, and is rarely used as an independent guide for treatment.


[Serum interferon level and (2'-5')-oligo(A) synthetase activity in malignant melanoma].
Both the serum levels of interferon and the activity of lymphocytic (2'-5')-oligoadenylate synthetase (OAS) of 37 patients suffering from malignant melanoma-15 with low (I,I-II,II) and 22 with higher (III,IV,V) Clark levels-were compared with those of a group of healthy controls in order to detect a possible involvement of the interferon system in the pathological process. Previous results obtained in studies on relatively small groups of patients had suggested that melanoma patients with low Clark levels (i.e. biologically early melanoma) show elevated activities of OAS, while those with higher levels show normal values. In our present investigation on a larger sample of patients, we did not find any differences between these two melanoma groups and healthy persons with regard to the OAS activity. Thus we were not able to confirm the provisional results set up by previous studies.


[Infections of cutaneous wounds].
Infection of cutaneous wounds can be defined as proliferation of microorganisms at an interruption in the mucocutaneous covering. The phenomenon depends on an association of local and general factors which disturb the balance in host-pathogen interactions, in favor of the latter. In addition to infections by nonspecific pyogenic germs, whether posttraumatic or postsurgical, there are specific infections where the wound is the departure point for a systemic infection. Even today, tetanus and gaseous gangrene should be apprehended and systematically prevented. Similarly, the high incidence of infection of bite or scratch wounds (animal or human) should suggest prophylactic antibiotic treatment as well as evaluation of the risk of rabies in the case of animal bites or scratches. In any case, even if antibiotic treatment must be undertaken as an emergency measure, previous bacteriological investigation should be carried out if possible since it permits subsequent adaptation in case of failure of the initial antibiotic treatment.


Precipitation of 19S IgM rheumatoid factor-IgG circulating immune complexes in patients with juvenile arthritis by polyethylene glycol and separation by immobilized protein A.
Immune complexes (IC) in sera and synovial fluid (SF) from patients with juvenile (rheumatoid) arthritis (JA) were isolated by making use of polyethylene glycol (PEG) to precipitate IC and then using staphylococcal protein A to separate the IC. The isolated IC were compared to IC in sera analysed by sucrose density gradients and measured by the C1q solid phase assay (ClqSPA). Isolated IC from sera of 10 of 16 JA patients demonstrated significant 19S IgM rheumatoid factor (RF) titres in their acid elutes utilizing the haemolytic assay. IgM and IgG were detected by low level radial immunodiffusion in the acid eluate of sera in all 10 patients who had significant RF titres. In isolated IC from SF, three of five JA patients had significant 19S IgM RF titres detected in their acid eluates. By sucrose density gradient analysis of these sera, elevated levels of IC detected by ClqSPA were found in the fractions of greater than or equal to 19S comparable to the previous isolated 19S IgM-IgG complexes. This detection of IC like material containing 19S IgM and IgG by the present method further supports the participation of classic and hidden 19S IgM RF in IC formation in JA patients.


Solid pancreatic lesions: The choice of fine-needle aspiration-needle to optimize the diagnosis.
Endoscopic ultrasonography (EUS)-guided fine-needle aspiration (FNA) have a better accuracy for the detection of pancreatic tumors compared with others images modalities. We assessed if the image criteria of elastography and contrast harmonic echo-endoscopic ultrasound could help in choosing the appropriate FNA-needle in the evaluation of focal pancreatic mass in other to maximize the diagnostic yield. This study prospectively included all new patients with focal pancreatic masses referred to be examined by EUS from October to December/2013. A total of 21 patients performed EUS with sequentially elastography and intravenous injection of a second-generation contrast agent (2.4 mL of SonoVue, Braco International, The Netherlands). The lesions which appear hipovascular were assessed with 22 gauge or 25 gauge FNA-needles. The hipervascular masses were biopsied with 19 gauge needles. The topography of the lesions varied on 13 at the head, 4 at the body and 1 on the tail. The finding of a hypoenhanced mass was found in 57% (12/21 patients). Hyperenhanced was detected in 28% (6/21 patients). There were 14% (three patients) which the data were not recorded. The cytological diagnosis was achieved in 81% (17/21 patients) on the first biopsy. The others four patients have reached the diagnosis on the second examination. Of those four patients, in one was used the ProCore 25 gauge (lesion on the uncinatus process), and another one was used both 22 gauge and 25 gauge in the first examination. A characterization of the pancreatic lesions with elastography and contrast agents might be useful for clinical decision of which needle is better to improve biopsy quality and minimize EUS-FNA negatives results.


BOS is associated with decreased HDAC2 from steroid resistant lymphocytes in the small airways.
Immunosuppression therapies including corticosteroids fail to prevent bronchiolitis obliterans syndrome (BOS), primarily a disease of the small airways, following lung transplantation. We reported increases in steroid-resistant proinflammatory lymphocytes and their loss of histone deacetylase 2 (HDAC2), an important mediator of steroid action, in the blood of stable lung transplant recipients. We noted similar increases in the steroid-resistant lymphocytes in both the blood and small airways in BOS compared with the large airways. We hypothesized that these small airway cells would also exhibit a loss of HDAC2, and that these changes could be reversed by treatment with theophylline (HDAC2 activator). Blood, bronchoalveolar lavage and large and small airway brushings were collected from lung transplant patients with BOS (n = 12) or stable lung function (n = 18) and healthy aged-matched controls (n = 13). Intracellular proinflammatory cytokines [interferon (IFN-γ) and tumour necrosis factor (TNF)-α and HDAC2 were measured in CD8+ T, natural killer (NK) T-like and NK cells from cultured small airway brushings ± 5 mg/l theophylline ± 1 µM prednisolone using flow cytometry. Increased small airway CD8 T, NK T-like and NK cells were identified in BOS versus stable transplant and controls. In BOS, these cells exhibited increased IFN-γ/TNF-α and a loss of HDAC2. HDAC2 expression by small airway CD8+ T cells correlated with forced expiratory volume in 1 s (FEV1 ) (R = 0·880, P = 0·031). Theophylline and prednisolone synergistically up-regulated HDAC2 in CD8+ T cells. BOS is associated with loss of HDAC2 from steroid-resistant proinflammatory CD8+ T, NK T-like and NK cells in the small airways. Therapeutically increasing HDAC2 in these lymphocytes may reduce steroid resistance and improve graft survival.


Annexin-mediated matrix vesicle calcification in vascular smooth muscle cells.
In bone, osteoblasts and chondrocytes synthesize matrix vesicles (MVs) that interact with collagen to initiate calcification. MVs have been identified in human calcified arteries but are poorly characterized. The objective of this study is to determine the role of annexins and fetuin-A in MV formation and activity during calcification in bovine vascular smooth muscle cells (BVSMCs). BVSMCs were treated with control or calcification (high phosphorus) media, and cellular MVs were isolated by collagenase digestion and secreted MVs were isolated from cultured media by ultracentrifugation. The results showed that alkaline phosphatase (ALP) activity was significantly increased in MVs from calcified BVSMCs compared with noncalcified BVSMCs, as was annexin II and VI content and (45)Ca uptake. We also determined that MVs from calcifying BVSMCs could mineralize type I collagen but not type II collagen in the absence of cells in a dose- and time-dependent manner. Blockade of annexin calcium channel activity by K201 significantly decreased ALP activity and reduced the ability of the MVs to subsequently calcify on collagen, whether the K201 was added during or after MV formation. Furthermore, cellular MVs had significantly increased ability to calcify on collagen compared with secreted MVs, likely because of their increased ALP activity and annexin II content but low fetuin-A content. In conclusion, our results suggest that mineralization in VSMCs requires both active MVs and an interaction of the MVs with type I collagen, and both steps require annexin activity.


Pyrazole; A Privileged Scaffold of Medicinal Chemistry: A Comprehensive Review.
Pyrazole is considered an important active scaffold that possesses various types of pharmacological activities. The overwhelming literature reported earlier reflects the immense biological potential of pyrazole derivatives. The presence of this moiety in various FDA-approved drugs, including celecoxib (anti-inflammatory), apixaban (anticoagulant), rimonabant (anti-obesity), difenamizole (analgesic), and sildenafil (for erectile dysfunction), has proved its pharmacological potential. Owing to its diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the literature supporting the research of the past 10 years related to the structures of pyrazole derivatives with their corresponding biological activities. The findings of this review may open new avenues for an upcoming scientific breakthrough.


Circular RNAs: emerging players in brain aging and neurodegenerative diseases.
Brain aging is closely related to neurodegenerative diseases. Circular RNAs (circRNAs) are a type of conserved RNAs with covalently closed continuous loops. Emerging evidence has shown that circRNAs are implicated in the biology of brain aging and the pathology of age-related neurodegenerative diseases. Here, we summarize current studies on circRNAs associated with brain aging and neurodegenerative diseases by discussing their expression features, pathophysiological roles, and mechanisms of action. We also discuss the potential challenges of circRNA-based therapy against brain aging and neurodegenerative diseases, as well as their potential as diagnostic biomarkers of neurodegenerative diseases. The review provides insights into current progress in the functions of circRNAs in the process of brain aging and neurodegenerative diseases. © 2022 The Pathological Society of Great Britain and Ireland.


Interplatform reproducibility of liver and spleen stiffness measured with MR elastography.
To assess interplatform reproducibility of liver stiffness (LS) and spleen stiffness (SS) measured with magnetic resonance elastography (MRE) based on a 2D gradient echo (GRE) sequence. This prospective Health Insurance Portability and Accountability Act (HIPAA)-compliant and Institutional Review Board (IRB)-approved study involved 12 subjects (five healthy volunteers and seven patients with liver disease). A multislice 2D-GRE-based MRE sequence was performed using two systems from different vendors (3.0T GE and 1.5T Siemens) on the same day. Two independent observers measured LS and SS on confidence maps. Bland-Altman analysis (with coefficient of reproducibility, CR), coefficient of variability (CV), and intraclass correlation (ICC) were used to analyze interplatform, intra- and interobserver variability. Human data were validated using a gelatin-based phantom. There was excellent reproducibility of phantom stiffness measurement (CV 4.4%). Mean LS values were 3.44-3.48 kPa and 3.62-3.63 kPa, and mean SS values were 7.54-7.91 kPa and 8.40-8.85 kPa at 3.0T and 1.5T for observers 1 and 2, respectively. The mean CVs between platforms were 9.2%-11.5% and 13.1%-14.4% for LS and SS, respectively, for observers 1 and 2. There was excellent interplatform reproducibility (ICC >0.88 and CR <36.2%) for both LS and SS, and excellent intra- and interobserver reproducibility (intraobserver: ICC >0.99, CV <2.1%, CR <6.6%; interobserver: ICC >0.97, CV and CR <16%). This study demonstrates that 2D-GRE MRE provides platform- and observer-independent LS and SS measurements.


Kinematic parameters that influence the aesthetic perception of beauty in contemporary dance.
Some experiments have stablished that certain kinematic parameters can influence the subjective aesthetic perception of the dance audience. Neave, McCarty, Freynik, Caplan, Hönekopp, and Fink (2010, Biology Letters 7 221-224) reported eleven movement parameters in non-expert male dancers, showing a significant positive correlation with perceived dance quality. We aim to identify some of the kinematic parameters of expert dancers' movements that influence the subjective aesthetic perception of observers in relation to specific skills of contemporary dance. Four experienced contemporary dancers performed three repetitions of four dance-related motor skills. Motion was captured by a VICON-MX system. The resulting 48 animations were viewed by 108 observers. The observers judged beauty using a semantic differential. The data were then subjected to multiple factor analysis. The results suggested that there were strong associations between higher beauty scores and certain kinematic parameters, especially those related to amplitude of movement.


Choroidal Thickness Changes in Rheumatoid Arthritis and the Effects of Short-term Hydroxychloroquine Treatment.
The objective of this study is to evaluate choroidal thickness (CT) in patients with rheumatoid artritis (RA) and the effects of short-term hydroxychloroquine (HCQ) treatment. Thirty RA patients (group 1) and 30 normal subjects (group 2) were enrolled in the study. Group 1 was further divided into two subgroups as follows: group 1A (Before HCQ treatment) and group 1B (1 year after HCQ treatment). The CTs were measured using optical coherence tomography (EDI-OCT). The mean subfoveal choroidal thickness (SFCT) (µm) was 335.70 ± 64.58 in group 1A, 341.85 ± 63.95 in group 1B, and 358.51 ± 63.83 in group 2. SFCT was significantly lower in groups 1A and 1B than in group 2 (p = 0.020 and p = 0.028, respectively). Group 1B presented statistically significant thicker SFCT than group 1A (p = 0.033). CT was significantly lower in RA patients than in normal subjects. HCQ treatment may, however, cause a statistically significant increase in SFCT. This increase is clinically negligible.


A Comprehensive Review of the Effect of Honey on Human Health.
Honey is a nutritious, healthy, and natural food, to which antioxidant, anti-inflammatory, and antimicrobial properties have been attributed, mainly due to its content of phenolic compounds. The aim of this review is to analyze the available evidence of the effect of honey on humans. Forty-eight clinical trials published between 1985 and 2022 were analyzed, with a total of 3655 subjects. More beneficial effects of honey intake than no or negative effects on different cardiovascular and metabolic risk factors, glucose tolerance, mucositis caused by chemo-radiotherapy, cough in children and wound healing, among others have been observed. Although the number of studies conducted to date is limited and the different investigations are not standardized, beneficial effects of honey intake have been observed, especially when its intake replaces the intake of other sweeteners. In addition, honey could be a safe adjuvant to be administered alongside drugs used for certain diseases.


Primary thymus tumors: retrospective case analysis at a reference center in Latin America, 2011-2019.
Thymic tumors are unusual neoplasms, representing 0.2 to 1.5% of tumors in humans, but correspond to 20% of mediastinal tumors and 50% of those that occur in the anterior mediastinum. They tend to appear around the fourth and fifth decades of life without gender predilection. Up to 30% of patients are asymptomatic, therefore many are incidentally diagnosed. Radical thymectomy is the treatment of choice with high survival rates when detected in the early stages. This was a retrospective descriptive study, including 18 adult patients' diagnosis of thymic neoplasm, who were managed with surgical resection from 2011 to 2019. Information about demographics, clinical characteristics, imaging findings, surgical and medical management, plus histological findings was obtained and reported. 18 patients with thymic tumors were included, of which specific histologic studies reveled thymomas, carcinomas, neuroendocrine tumors, thymolipoma and thymic cyst. Mean age was 52.7 years, with a predominance of male population. The main symptom was dyspnea, followed by cough and chest pain. Paraneoplastic syndromes such as myasthenia gravis, aplastic anemia and Cushing syndrome were reported. 89% of cases were treated by radical thymectomy alone, while only 2 cases required chemotherapy and radiotherapy. There were no surgical complications. Mean hospital stay length was 11. 9 days, with only 1 mortality during hospital admission. 5-year survival rate was 81%. The treatment of choice is radical thymectomy, which has been shown to positively impact patient mortality. Early detection is key to improve patient outcomes.


TIPS versus paracentesis for cirrhotic patients with refractory ascites.
Ten per cent of cirrhotic patients develop refractory ascites, which carries substantial morbidity and has a one-year survival of less than 50 per cent. Patients with refractory ascites may benefit from transjugular intrahepatic portosystemic stent-shunts (TIPS). To compare TIPS versus paracentesis standard treatment in patients with refractory ascites due to cirrhosis with regard to overall short- and long-term mortality, treatment efficacy, and complications. We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (July 2003), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 1, 2003), MEDLINE (1966 to July 2003), EMBASE (1980 to July 2003), and CINAHL (1982 to July 2003). We supplemented the searches with reading through scientific citations, review of citations in relevant primary articles, and hand-searched abstracts from national meetings. We included randomised clinical trials comparing TIPS and paracentesis with or without volume expanders for cirrhotic patients with refractory ascites. We evaluated the methodological quality of the randomised clinical trials by the generation of the allocation section, allocation concealment, and follow-up. Two independent observers extracted data from each trial. We contacted trial authors for additional information. Dichotomous outcomes were reported as odds ratio (OR) with 95% confidence interval (CI). Four randomised clinical trials, including 264 patients, met the inclusion criteria. Methodological quality was moderate. Thirty-day mortality (OR 1.00, 95% CI 0.10 to 10.06, P = 1.0) and 24-month mortality (OR 1.17, 95% CI 0.52 to 2.66, P = 0.70) did not differ significantly between TIPS and paracentesis treatment. TIPS significantly reduced ascites re-accumulation at three months (OR 0.07, 95% CI 0.03 to 0.18, P < 0.00001) and at 12 months follow-up (OR 0.14, 95% CI 0.06 to 0.28, P < 0.00001). Hepatic encephalopathy occurred significantly more often in the TIPS group (OR 2.11, 95% CI 1.22 to 3.66, P = 0.008). Gastrointestinal bleeding (OR 0.82, 95% CI 0.36 to 1.84, P = 0.63), acute renal failure (OR 0.64, 95% CI 0.15 to 2.72, P = 0.55), septicemia/infection (OR 1.05, 95% CI 0.22 to 4.94, P = 0.96), and disseminated intravascular coagulation (OR 0.82, 95% CI 0.26 to 1.84, P = 0.63) did not differ significantly between groups. TIPS removed ascites more effectively than paracentesis. After 12 months, the beneficial effects of TIPS on ascites was still present. Mortality, gastrointestinal bleeding, septicemia/infection, acute renal failure, and disseminated intravascular coagulation did not differ significantly between the two groups. Hepatic encephalopathy occurred significantly more often in the TIPS group.


[Acute dysphagia: often there is a readily treatable cause].
Three patients, one woman aged 45 years and two men aged 40 and 62 years, presented with acute dysphagia due to oesophageal obstruction by a piece of food. In the woman symptoms of oesophageal perforation developed after the piece of food was removed by rigid endoscopy; she recovered after treatment with a stent, antibiotics and acid inhibitors. The younger man had a stricture of the oesophagus that was dilated. The older man had a Barrett's oesophagus and also oesophagcal adenocarcinoma; he was free of symptoms three years after resection of the oesophagus and the creation of a tubular stomach. In adults, 60% of acute oesophageal obstructions are caused by food impaction, which is associated with a high incidence of secondary pathologic findings in the oesophagus (75-97%). Evaluation of the oesophagus by flexible endoscopy contributes to an adequate diagnosis. Moreover, it can be used to treat the cause of the obstruction. If dilation therapy is started early after detecting a benign stricture in the oesophagus, it reduces the likelihood of recurrence. The detection of early-stage oesophageal malignancies may improve the prognosis of patients with this disorder.


Hypothalamic control of anterior pituitary function: a history.
The concept of neurohumoral control of anterior pituitary function championed by Geoffrey Harris was based upon clinical and biological observation backed by rigorous experimental testing. The areas of the brain involved in the control of gonadotrophic hormone synthesis and release were identified by electrical stimulation, lesioning and fibre tract cutting. The medial preoptic area (MPOA) proved to be a major integrating centre, with axon terminals from this region terminating at the median eminence releasing factors into the portal vessels to give a direct route from brain to pituitary. It took over a decade before the gonadotrophic hormone-releasing hormone (GnRH) was isolated, sequenced and synthesised. With antibodies raised against this peptide, the MPOA was identified as a site rich in GnRH neurones and the hormone was detected at high levels in portal blood extracts. A natural knockout of the GnRH gene was discovered in a hypogonadal (hpg) mouse. Hormone injections, gene replacement methods and neural grafting in these mutants all confirmed the central role of GnRH in reproduction. The modern techniques of molecular biology have allowed us to extend our knowledge base. In the last few years the role of kisspeptin and its receptor (GPR54) in the control of the GnRH neurone has added a further level of hypothalamic involvement in the modulation of reproduction.


Effects of cholera toxin on in vitro models of immediate and delayed hypersensitivity. Further evidence for the role of cyclic adenosine 3',5'-monophosphate.
Cholera enterotoxin inhibits the antigen-induced. IgE-mediated release of histamine from human leukocytes and the lysis of allogeneic mastocytoma cells by splenic lymphocytes from specifically immunized mice. This effect requires a prolonged preincubation time of the toxin with the lymphocyte/leukocyte preparations: a demonstrable inhibition requires about 30 min of pre-incubation and the toxin activity is still increasing at 90-180 min. Cholera enterotoxin also stimulates adenyl cyclase and leads to increased levels of cyclic AMP in the lymphocyte/leukocyte preparations. The concentration of toxin required for both cyclic AMP accumulation and inhibition of the biologic responses is about the same (ca. 1 ng/ml), and the time course of cyclic AMP accumulation parallels the development of inhibitory activity. Both activities, inhibition of the in vitro hypersensitivity reactions and cyclic AMP accumulation, are blocked by cholera antitoxin and by a toxoid prepared from the toxin (choleragenoid). These are specific antagonists in that they do not block the inhibiting activity or rise in cyclic AMP levels caused by other adenyl cyclase stimulators. Because cholera enterotoxin has no known activity other than the stimulation of adenyl cyclase and because of its unusual time course and the availability of specific antagonists, this data considerably strengthens the hypothesis that the cyclic AMP system influences the expression of these two forms of hypersensitivity phenomena.


[Concurrent malaria and rickettsiosis in a patient returning from the Republic of South Africa].
Definitive diagnosis and therapy proved challenging in the case of a 60-year-old male with malaria and rickettsiosis. Returning travellers who are unwell can present practical difficulties in diagnosis and treatment and the focus here is on conditions relevant to the Republic of South Africa. Malaria, rickettsiosis and Q fever are discussed.


The association of dietary phytochemical index and nonalcoholic fatty liver disease.
Consumption of phytochemical-rich foods relates to the prevention of chronic diseases. In this study we assessed the dietary phytochemical index (PI) in metabolic parameters, liver enzymes, and severity of fibrosis among nonalcoholic fatty liver disease patients. This cross-sectional study was conducted on 210 patients with NAFLD. Fibrosis-4 index (FLB4), nonalcoholic fatty liver disease fibrosis score (NFS), FBS, lipids profile, AST, ALT, ALP, and GGT were measured. PI was calculated through the information obtained from a validated semi-quantitative food frequency. Multiple regression models were used to estimate mean difference changes in the evaluated variables associated with various dietary PI. Participants' mean ± SD of age and BMI were 39.23 ± 10.52 and 24.40 ± 2.64, respectively. We found that DPI is inversely associated with serum TG, TC, and LDL-C and directly associated with serum HDL-C and a higher score in DPI is associated with lower scores in NFS and FIB-4. Multivariate linear regression showed that there is an inverse association between DPI and AST, ALT, ALP, GGT, NFS, and FIB-4. Higher dietary PI could impact on reduction of NAFLD progression and improvement of metabolic parameters.


Role of host cytokine responses in the pathogenesis of avian H5N1 influenza viruses in mice.
Highly pathogenic avian H5N1 influenza viruses are now widespread in poultry in Asia and have recently spread to some African and European countries. Interspecies transmission of these viruses to humans poses a major threat to public health. To better understand the basis of pathogenesis of H5N1 viruses, we have investigated the role of proinflammatory cytokines in transgenic mice deficient in interleukin-6 (IL-6), macrophage inflammatory protein 1 alpha (MIP-1alpha), IL-1 receptor (IL-1R), or tumor necrosis factor receptor 1 (TNFR1) by the use of two avian influenza A viruses isolated from humans, A/Hong Kong/483/97 (HK/483) and A/Hong Kong/486/97 (HK/486), which exhibit high and low lethality in mice, respectively. The course of disease and the extent of virus replication and spread in IL-6- and MIP-1alpha-deficient mice were not different from those observed in wild-type mice during acute infection with 1,000 50% mouse infective doses of either H5N1 virus. However, with HK/486 virus, IL-1R-deficient mice exhibited heightened morbidity and mortality due to infection, whereas no such differences were observed with the more virulent HK/483 virus. Furthermore, TNFR1-deficient mice exhibited significantly reduced morbidity following challenge with either H5N1 virus but no difference in viral replication and spread or ultimate disease outcome compared with wild-type mice. These results suggest that TNF-alpha may contribute to morbidity during H5N1 influenza virus infection, while IL-1 may be important for effective virus clearance in nonlethal H5N1 disease.


Postpartum cerebral angiopathy with intracerebral hemorrhage in a patient receiving lisuride.
Postpartum cerebral angiopathy is a recognized but infrequent complication of ergot alkaloid derivatives. We describe a patient who experienced reversible cerebral vasoconstriction with intracerebral hemorrhage (ICH) after ingesting lisuride in the postpartum period. Lisuride is likely to cause postpartum cerebral angiopathy, and ICH must now be considered a possible cerebrovascular complication of postpartum cerebral angiopathy. Our observation calls for further study to verify these findings.


[Untargeted metabolomics study of dexamethasone-induced congenital cleft palate in New Zealand rabbits].
Objective: To investigate the metabolic disorders in placental tissues of dexamethasone induced cleft palate mode. Methods: Twelve pregnant rabbits were randomly divided into dexamethasone group (experimental group, 8) and saline control group (4), and a certain amount of dexamethasone and saline were administered intramuscularly to the experimental and control groups respectively from embryonic days (ED) 13 to 16, and placental tissue samples were collected on day 21 of gestation. The corresponding profiles of the embryonic placental tissue samples were obtained by liquid chromatography-triple tandem quadrupole(LC-MS), and the metabolites of the embryonic placental tissues were characterized by principal component analysis among the dexamethasone-treated group with cleft palate (D-CP group), the dexamethasone-treated group without cleft palate (D-NCP group) and the control group. Results: There were significant metabolic differences among the D-CP group, D-NCP group and control group, with a total of 133 differential metabolites (VIP>1, P<0.05) involving in important metabolic pathways including vitamin B6 metabolism, lysine metabolism, arginine anabolic metabolism, and galactose metabolism. The four metabolites, vitamin B6, galactose, lysine and urea, differed among the three groups (P<0.05). There were significant differences in vitamin B6 (0.960±0.249, 0.856±0.368, 1.319±0.322), galactose (0.888±0.171, 1.033±0.182, 1.127±0.127), lysine (1.551±0.924, 1.789±1.435, 0.541±0.424) and urea (0.743±0.142, 1.137±0.301, 1.171±0.457, respectively) levels among control group, D-NCP group and D-CP group (F=5.90, P=0.008; F=5.59, P=0.009; F=4.26, P=0.025; F=5.29, P=0.012). Conclusions: The results indicated that dexamethasone induced cleft palate may be highly correlated with metabolic disorders including vitamin B6 metabolism, lysine metabolism, arginine anabolic metabolism and galactose metabolism.


Forehead flap periorbital reconstruction.
To evaluate functional and aesthetic results of periorbital defect repair using forehead flaps. Retrospective review of patients who received periorbital defect repair by 3 of us with a paramedian forehead flap alone or in conjunction with other local or regional flaps, bone grafts, or cartilage grafts. Flap survival, functional results, and postoperative complications were determined by physical examination at regular follow-up. Three experienced surgeons other than us quantified aesthetic outcomes using a 10-cm visual analog scale. Eighteen patients underwent periorbital defect repair between August 1, 1989, and December 31, 2000. Defects ranged from 8 to 300 cm(2) (mean, 46.8 cm(2)) in area. The most commonly involved primary structures were the medial canthus, lacrimal drainage system, and medial upper eyelid. The mean improvement on a 10-cm visual analog scale was 1.6 from before resection to after reconstruction and 3.8 from tumor resection to after reconstruction. In all relevant cases, globe coverage and lacrimal drainage system patency were excellent. No patients experienced fistula formation or eyelid retraction. The reliability, versatility, and relative technical simplicity of the forehead flap provide excellent cosmetic and functional results in reconstruction of intermediate-sized periorbital defects, especially those associated with nasal defects.


[A new loading bioreactor for bone tissue-engineering applications].
Bone cells live in an environment heavily influenced by mechanical force. The development of bone tissue is dependent on the environment that surrounds it, both in vivo and in vitro. A loading stimulator on research of bone tissue-engineering was developed based on the mechanism of mechanosensation, scaffolding composites with mechanical strains with more physiologic magnitude, frequency components, and waveform. It also achieves the mechanical environment particularly in hard scaffold enough strong like cancellous bone. The device was tested using a reference scaffold made of better elastic plastic material. The experiment results showed that the device could be used in precision strain controls. Since the drive of the stimulator comes from the usage of smart material, piezoceramics, the strain at physiological level is controlled precisely. The stimulator provides a mechanical condition under which the effects of loading applied on bone tissue-engineering culture are conveniently investigated. Furthermore, after the stimulator is improved, it will be an appropriate bioreactor for bone tissue-engineering culture.


Tankyrase Mediates K63-Linked Ubiquitination of JNK to Confer Stress Tolerance and Influence Lifespan in Drosophila.
Tankyrase (Tnks) transfers poly(ADP-ribose) on substrates. Whereas studies have highlighted the pivotal roles of Tnks in cancer, cherubism, systemic sclerosis, and viral infection, the requirement for Tnks under physiological contexts remains unclear. Here, we report that the loss of Tnks or its muscle-specific knockdown impairs lifespan, stress tolerance, and energy homeostasis in adult Drosophila. We find that Tnks is a positive regulator in the JNK signaling pathway, and modest alterations in the activity of JNK signaling can strengthen or suppress the Tnks mutant phenotypes. We further identify JNK as a direct substrate of Tnks. Although Tnks-dependent poly-ADP-ribosylation is tightly coupled to proteolysis in the proteasome, we demonstrate that Tnks initiates degradation-independent ubiquitination on two lysine residues of JNK to promote its kinase activity and in vivo functions. Our study uncovers a type of posttranslational modification of Tnks substrates and provides insights into Tnks-mediated physiological roles.


The Use of Vacuum-Assisted Closure in Purulent Complications and Difficult-To-Heal Wounds in Cardiac Surgery.
Sternal wound infections are a serious and potentially fatal complication of cardiac surgery. The aim of the study was to analyze the results of using the vacuum-assisted closure (VAC) system over a 4-year period. Quantitative VAC performance data from a retrospective review of a consecutive cohort of 47 patients treated with VAC for post-cardiac surgery wound complications were collected and statistically analyzed. In the study group 35 patients developed infections of the post-operative chest wound. In 12 other patients wound dehiscence was observed, but repeated cultures did not reveal the presence of any bacteria. The statistical analysis identified the following as significant risk factors: age, female sex, being overweight, a high total logistic EuroScore, the use of both internal thoracic arteries for bypass grafting, and diabetes. In the wound negative culture group the total length of hospital stay was significantly shorter than in the wound positive culture group. Mortality in this group was 0.0% vs. 5.7% in the wound positive culture group. In the study material, Gram-negative bacteria were responsible for 77% of the post-operative wound infections, with only 14% Gram-positive wound cultures. No complications were related to VAC use. The use of negative-pressure wound therapy with other concomitant surgical procedures is a good method of treating infected wounds as well as non-contaminated dehiscence of the wound and sternum. Considering that most of the infections within the authors' department are caused by Gram-negative bacteria, it would be beneficial to consider modifying the model of preventive antibiotic treatment to cover the Gram-negative spectrum in addition to the Gram-positive bacteria currently targeted.


Ex Vivo and In Vivo Characterization of Interpolymeric Blend/Nanoenabled Gastroretentive Levodopa Delivery Systems.
One approach for delivery of narrow absorption window drugs is to formulate gastroretentive drug delivery systems. This study was undertaken to provide insight into in vivo performances of two gastroretentive systems (PXLNET and IPB matrices) in comparison to Madopar® HBS capsules. The pig model was used to assess gastric residence time and pharmacokinetic parameters using blood, cerebrospinal fluid (CSF), and urine samples. Histopathology and cytotoxicity testing were also undertaken. The pharmacokinetic parameters indicated that levodopa was liberated from the drug delivery systems, absorbed, widely distributed, metabolized, and excreted. Cmax were 372.37, 257.02, and 461.28 ng/mL and MRT were 15.36, 14.98, and 13.30 for Madopar HBS capsules, PXLNET, and IPB, respectively. In addition, X-ray imaging indicated that the gastroretentive systems have the potential to reside in the stomach for 7 hours. There was strong in vitro-in vivo correlation for all formulations with r2 values of 0.906, 0.935, and 0.945 for Madopar HBS capsules, PXLNET, and IPB, respectively. Consequently, PXLNET and IPB matrices have pertinent potential as gastroretentive systems for narrow absorption window drugs (e.g., L-dopa) and, in this application specifically, enhanced the central nervous system and/or systemic bioavailability of such drugs.


Staff opinions about the components of a good death in long-term care.
The aim of this study was to identify differences of opinion about the relative importance of different components of a good death among care providers in a long-term care home serving Canadian war veterans. The Concept of a Good Death scale (Swartz et al, 2003), with slight adaptations to fit the long-term care context, was made available to all staff. Responses were accepted for a one-month period. Survey return rate was 30.4%. There was a majority (greater than 50%) opinion that 12 of the 20 items were essential or important to a good death, and that three items were not necessary: 'that death is sudden and unexpected' (64.5%), 'that there be control of bodily functions to the end' (61.8%) and 'that there be mental alertness to the end' (55.3%). There was not a majority opinion on the five remaining items: 'that the dying period be short', 'that death occurs naturally without technical equipment', 'that the person lived until a key event', 'that the ability to communicate be present until death', and 'that death occurs during sleep'. Detailed analysis of survey results identified differences of opinion that could have implications for consistency and quality of care. The findings suggest ways in which the unique characteristics of the long-term care environment and population influence opinions about the components of a good death.


CM redesign cuts LOS, readmissions.
University Hospitals Case Medical Center in Cleveland revamped its case management process, resulting in drops in length of stay and readmissions. A three-person care management team is assigned to each unit, with each member having a specific focus. The case management team holds rounds each day with the interdisciplinary team, which includes representatives from post-acute providers. An electronic board tracks patients and includes expected length of stay and discharge disposition, ancillary services, and discharge needs.


[Advances on anatomic study and clinical application of submental artery island flap].
After more than 20 years of development, submental artery island flap (SMAIF) has become a versatile flap for head and neck reconstruction of the defects after tumor resection,trauma or facial deformity.The design of SMAIF is flexible and diverse. According to repair requirements,various types of flap can be harvested based on the different composition. SMAIF mainly used as an orthograde pedicled flap.It also can be used as a retrograde, free or hybrid variant.More modifications such as bipaddled, bipedicled, pre-expanded,deepithelialized were evolved. SMAIF shows some advantages including reliable blood supply, convenient preparation, well matched color with the facial skin, and the similar or even better repair effect compared with free flaps.In addition,the submental artery perforator flap and the submental vascularized lymph node flap are the latest clinical application achievements derived from the progress of anatomic research.They further improve the level of preparation skill and expand the indications of SMAIF.


Domestic violence and abuse in local child safeguarding policy: How is the problem represented?
Within the United Kingdom, domestic violence and abuse (DVA) is the most commonly identified factor within child in need assessments, with rates increasing in recent years in addition to 'lockdown'-related spikes. This article examines the representation of DVA in local child safeguarding policies using Bacchi's (2009) 'What is the problem represented to be?' approach. Policies were collected from the websites of all the child safeguarding partnerships of England in July 2021. In total, we identified 59 policies. These policies are designed to guide local responses to DVA across services and thus have potential for substantial impact on practice across health and social care. Our results suggest that local DVA policy in England exists within a conceptual framework which spotlights the individual and lacks attention to their context. We argue that these policies focus on adults, neglecting attention to children within their own safeguarding policies. This is through children being peripheralized within the conceptualisation of 'victim' and the assessed adult risk being used as a proxy measure for the risk to child. Demographic discussions build an image of DVA as an issue that can affect anyone, but with little acknowledgement of the vulnerabilities facing proportions of the population and their complexities - when such vulnerabilities are discussed, they are individualised and viewed in absence of their societal causes, potentially eclipsing critical elements of a child's experience of DVA. The implications of our results are wide-ranging but suggest a need to refocus on children and their context within local DVA policy.


Authentication of medicinal herbs using PCR-amplified ITS2 with specific primers.
Different parts of medicinal herbs have long been used as traditional Chinese drugs for treating many diseases, whereas materials of similar morphology and chemical fingerprints are often misidentified. Analyses of sequence variations in the nuclear ribosomal DNA (rDNA) internal transcribed spacer (ITS) have become a valid method for authentication of medicinal herbs at the intergenic and interspecific levels. DNA extracted from processed materials is usually severely degraded or contaminated by microorganisms, thus generates no or unexpected PCR products. The goal of this study is to apply the ITS fragments selectively amplified with two designed primer sets for efficient and precise authentication of medicinal herbs. The designed primers led to an accurate PCR product of the specific region in ITS2, which was confirmed with DNA extracted from 55 processed medicinal herbs belonging to 48 families. Moreover, the selectively amplified ITS2 authenticated five sets of easily confusable Chinese herbal materials. The designed primers were proven to be suitable for a broad application in the authentication of herbal materials.


The Mechanical Properties of Direct Metal Laser Sintered Thin-Walled Maraging Steel (MS1) Elements.
The aim of this study was to explore the mechanical properties of thin-walled maraging steel (MS1) elements fabricated using direct metal laser sintering (DMLS). This article first explains the fabrication procedure and then analyzes the results of the static tensile strength tests and microscopic (SEM) examinations. From this study, it is evident that the mechanical properties of such objects, particularly their tensile strength, are not affected by the build direction; no significant anisotropy was found. The experiments confirm, however, that the mechanical properties of thin-walled elements fabricated from MS1 by DMLS are largely dependent on thickness. The microscopic images of such elements show local discontinuities in the macrostructure of the molten material (powder). Although the research described here mainly contributes to the field of additive manufacturing, it also considers some aspects of Lean manufacturing.


[Chronic hepatitis C in hemodialysis patients].
Hepatitis C virus (HCV) is an important cause of chronic hepatitis in dialysis patients. With regard to epidemiology, the time on haemodialysis, the (previous) use of intravenous drugs as well as the number of blood transfusions received are important risk factors. There are strong indications suggesting nosocomial transmission of HCV. Strict application of infection prevention procedures in haemodialysis units is mandatory to restrain spread of HCV infection. Preliminary results show equal efficacy of alpha-interferon in normalisation of serum transaminases in dialysis patients and in patients with normal kidney function. However, in both groups relapses occur often, despite induction of remission. Antiviral therapy (with interferon and ribavirin) is emerging as a valid option to induce HCV eradication in dialysis patients. Thereafter, transplantation may be considered.


All-Factor Analysis and Correlations on the Transmembrane Process for Arginine-Rich Cell-Penetrating Peptides.
Currently, arginine-rich cell-penetrating peptides (CPPs), due to their little cytotoxicity and high transmembrane efficiency, are considered as one of the important intracellular carriers. Although the mechanism of the transmembrane process for arginine-rich CPPs was proposed, the quantitative correlations and the key factors involved in this process still deserve further investigation. In this study, all-atom molecular dynamics and the umbrella sampling technique were employed to study the arginine-rich CPPs transmembrane process. In the adsorption process of CPPs from solution to the surface of the lipid bilayer, the adsorption free energy (ΔGA) is found to be linearly related to the interaction energy change (ΔEA): ΔGA = 0.0426ΔEA + 36.7, R2 = 0.92. In the CPPs transmembrane process, the transmembrane free energy barrier (ΔGB) is roughly correlated with the corresponding interaction energy change (ΔEB): ΔGB = 0.108ΔEB +135, R2 = 0.73. The multiple salt bridges of guanidinium-PO4 account for 65% of the overall interaction energy, so the increased negative charges of the lipid bilayer or more salt bridges would facilitate CPPs adsorption and transmembrane processes. Also, the increased negative charges of the lipid bilayer would reduce the amount of water to be carried into the pore and further reduce the ΔGB. The peptide backbone would not have a direct impact on transmembrane efficiency. The ΔGB is also found to be related to the length of the pore (L): ΔGB = 46.2L - 31.3, R2 = 0.92, which makes the transmembrane efficiency estimable. This work is expected to deliver an in-depth understanding and help the optimization of CPPs.


Method Comparison (Agreement) Studies: Myths and Rationale.
Unprecedented technological growth in the last quarter of twentieth century has resulted in improved health care and opened new domains of health care research. This technological leap also facilitated the paradigm shift from hospital care to home care through development of 'point of care' devices. As early diagnoses and timely referral is a key to health management, these devices play an important role in improving health. Validation of the new technology in different settings is necessary before adopting it to practice. For a binary result like pregnancy test, it is trivial to use statistical tools like sensitivity, specificity etc. For a continuous variable like blood glucose level the analysis is not straightforward. Many of us misinterpret 'association' as 'agreement'. This misinterpretation is reflected in studies which have compared two different technologies. The findings of well conducted studies do not contribute to the evidence base just because of wrong analysis strategy. We delineate on finer nuances of analysis and interpretation of method comparison studies.


A phase 1 study of bendamustine and melphalan conditioning for autologous stem cell transplantation in multiple myeloma.
Bendamustine has efficacy in multiple myeloma with a toxicity profile limited to myelosuppression. We hypothesized that adding bendamustine to autologous stem cell transplant conditioning in myeloma would enhance response without significant additional toxicity. We conducted a phase 1 trial adding escalating doses of bendamustine to the current standard conditioning of melphalan 200 mg/m(2). Twenty-five subjects were enrolled into 6 cohorts. A maximum tolerated dose was not encountered and the highest dose level cohort of bendamustine 225 mg/m(2) + melphalan 200 mg/m(2) was expanded to further evaluate safety. Overall, there was no transplant related mortality and only one grade 4 dose-limiting toxicity was observed. Median number of days to neutrophil and platelet engraftment were 11 (range, 9 to 14) and 13 (range, 10 to 21), respectively. Disease responses at day +100 posttransplantation were progression in 5 (21%), partial response in 1 (4%), very good partial response in 7 (33%), complete response in 1 (4%), and stringent complete response in 9 (38%). Six patients (24%) with pre-existing high-risk disease died from progressive myeloma during study follow-up, all at or beyond 100 days after autologous stem cell transplant. Bendamustine up to a dose of 225 mg/m(2) added to autologous stem cell transplantation conditioning with high-dose melphalan in patients with multiple myeloma did not exacerbate expected toxicities.


Effect of chromocarb diethylamine on the permeability of the blood-brain barrier.
Intravenously injected collagenase, detectable in brain microvessels by immunological methods, partially degrades the constituents of the vascular wall and so increases the permeability of the blood-brain barrier (BBB). Intravenous administration of collagenase is a model for diseases in which the concentration of endogenous proteases is increased. Peroral treatment of rats with chromocarb diethylamine (CD) significantly reduced the degradation of the vascular wall by intravenous collagenase, as demonstrated by a lesser permeability increase of the BBB, a shorter recovery time, lower hydroxyproline levels in the cerebrospinal fluid and a lesser decrease of the collagen content of the brain capillary basal lamina.


Epithelioid hemangioma: morphological presentation on aspiration smears.
Epithelioid hemangioma (EH) or angiolymphoid hyperplasia with eosinophilia is an uncommon but distinctive lesion seen principally in the skin and subcutaneous tissue. The histopathology of this disease is very characteristic, but error in diagnosis is possible on cytopathology. There are very few case reports describing the cytomorphology of this lesion. We describe the findings of fine-needle aspiration of two cases of EH both arising in the subcutaneous tissue of the head and neck. Both the cases were misdiagnosed on cytology with one case being misinterpreted for an epithelioid sarcoma and the other for a reactive lymph node. The cytological findings of these cases are described and the problems encountered in the diagnosis of this entity are highlighted in this case report.


[Ni(tmen)(acac)][B(Ph)4] a probe for the anion basicity of ionic liquids.
An optical basicity scale of various ionic liquids (IL) anions has been determined by UV-Vis absorption spectroscopy. The indicator complex [Ni(tmen)(acac)][B(Ph)(4)] (tmen = tetramethylethylendiamine, acac = acetylacetonate) shows to be a sensitive probe as the position of the (3)A(2g)(F) --> (3)T(1g)(F) absorption maximum of square planar to octahedral Ni(2+) shifts distinctly depending on the electron donor ability of the respective ionic liquid anion. If the Lewis basicity of the anion becomes stronger a change to a tetrahedral coordination around Ni(2+) is observed. Here the (3)T(1)(F) --> (3)T(2)(F) and (3)T(1)(F) --> (3)T(1)(P) transitions are helpful for monitoring the IL anion basicity. Evaluating the optical spectra allows ordering the ionic liquids according to rising Lewis basicity: PF(6)(-) < BF(4)(-) < N(Tf)(2)(-) < OTf(-) << HCOO(-) << DCA(-) << CF(3)COO(-) << PO(2)(OEt)(2)(-) << Cl(-). No substantial influence of the ionic liquid counter cation on the Ni(2+) absorption spectra could be detected. In consequence, [Ni(tmen)(acac)][B(Ph)(4)] allows evaluation of the donor power, hence, the Lewis basicity of the ionic liquid anion independent from the IL cation and an optical basicity scale of ionic liquid anions could be successfully established. In addition, [Ni(tmen)(acac)][B(Ph)(4)] turns out to be a sensitive probe to detect even small chloride impurities in ionic liquids which are a commonly encountered contamination in ILs.


Local harmonic B(z) algorithm with domain decomposition in MREIT: computer simulation study.
Magnetic resonance electrical impedance tomography (MREIT) attempts to provide conductivity images of an electrically conducting object with a high spatial resolution. When we inject current into the object, it produces internal distributions of current density and magnetic flux density. By using a magnetic resonance imaging (MRI) scanner, we can measure B(z) data where z is the direction of the main magnetic field of the scanner. Conductivity images are reconstructed based on the relation between the injection current and B(z) data. The harmonic B(z) algorithm was the first constructive MREIT imaging method and it has been quite successful in previous numerical and experimental studies. Its performance is, however, degraded when the imaging object contains low-conductivity regions such as bones and lungs. To overcome this difficulty, we carefully analyzed the structure of a current density distribution near such problematic regions and proposed a new technique, called the local harmonic B(z) algorithm. We first reconstruct conductivity values in local regions with a low conductivity contrast, separated from those problematic regions. Then, the method of characteristics is employed to find conductivity values in the problematic regions. One of the most interesting observations of the new algorithm is that it can provide a scaled conductivity image in a local region without knowing conductivity values outside the region. We present the performance of the new algorithm by using computer simulation methods.


Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.
2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that for anandamide is mediated by fatty acid amide hydrolase (FAAH), and for 2-AG is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, which suggests a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL called JZL184 that, upon administration to mice, raises brain 2-AG by eight-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.


[The clinical therapeutic effects of arsenic trioxide combined with transcatheter arterial chemoembolization in treating primary liver cancer with pulmonary metastases].
To observe the therapeutic effects of arsenic trioxide combined with transcatheter arterial chemoembolization on treatment of primary liver cancer with pulmonary metastases. Sixty patients were randomly divided into two groups: group A (treatment group, n = 30) and group B (control group, n = 30). Group A was received periodic transcatheter arterial chemoembolization (TACE) and 10 mg arsenic trioxide by intravenous infusion for 5 hours per day, 3 days after TACE. Each cycle consisted of 14 days' administration, and repeated after 2 weeks. Each patient was received 3-4 successive cycles. Group B was received periodic TACE alone. efficiency, benefit rate, quality of life and the correlates with metastatic tumor size and number in the both groups were recorded. The objective efficiency was 26.7% (8/30), and the benefit rate was 60.0% (18/30) in group A, while they were 0 and 16.7% (5/30) in group B with significant statistics differences (χ(2) = 7.067, P = 0.008; χ(2) = 11.915, P = 0.001). The quality of life was improved in 4 patients and stable in 18 of group A, while no patient was improved and 13 were stable in group B (χ(2) = 9.669, P = 0.008). There was a significantly positive correlation between the tumor burden and therapeutic effect (Kendall r = -0.765, P < 0.001; Spearman r = -0.821, P < 0.001). Arsenic trioxide combined TACE is an effective treatment method in treating primary liver cancer with pulmonary metastases.


Biochemical and serological characteristics of children with membranous nephropathy due to hepatitis B virus infection: correlation with hepatitis B e antigen, hepatitis B DNA and hepatitis D.
Fourteen children with biopsy-proven membranous nephropathy associated with hepatitis B virus (HBV-MN) were evaluated biochemically and serologically and compared to 45 children with idiopathic nephrotic syndrome (INS). The mean ages of the two groups were similar (4.9 +/- 1.6 vs. 4.6 +/- 2.6 years). Serum albumin levels were similar in both groups, but serum cholesterol was significantly reduced in children with HBV-MN compared to INS. Serum C3 was also significantly depressed in children with HBV-MN compared to INS, but no differences in C4 levels were noted. Serum alanine transaminase as well as aspartate transaminase concentrations were significantly elevated in children with HBV-MN compared to those with INS, suggesting the presence of chronic hepatitis in children with HBV-MN. Hepatitis B surface and e antigens were present in serum of all children with HBV-MN, but only 54% had circulating HBV-DNA particles demonstrable in their serum. Serum C3 levels were higher in children with HBV-MN and circulating HBV-DNA, compared to those without circulating HBV-DNA. No other serological or biochemical differences occurred between these two groups. Glomerular deposition of IgG and C3 occurred in 91% of children with HBV-MN; but IgM deposition appeared to occur more frequently and with greater intensity in those children positive for circulating HBV-DNA. Antibody to delta antigen was negative in all children with HBV-MN. We conclude that biochemical and serological differences can be identified between HBV-MN and INS.(ABSTRACT TRUNCATED AT 250 WORDS)


Method specific Cholesky decomposition: coulomb and exchange energies.
We present a novel approach to the calculation of the Coulomb and exchange contributions to the total electronic energy in self consistent field and density functional theory. The numerical procedure is based on the Cholesky decomposition and involves decomposition of specific Hadamard product matrices that enter the energy expression. In this way, we determine an auxiliary basis and obtain a dramatic reduction in size as compared to the resolution of identity (RI) method. Although the auxiliary basis is determined from the energy expression, we have complete control of the errors in the gradient or Fock matrix. Another important advantage of this method specific Cholesky decomposition is that the exchange energy and Fock matrix can be evaluated with a linear scaling effort contrary to the RI method or standard Cholesky decomposition of the two-electron integral matrix. The methods presented show the same scaling properties as the so-called local density fitting methods, but with full error control.


Use of varenicline versus bupropion and risk of psychiatric adverse events.
To investigate whether varenicline use was associated with increased risk of psychiatric adverse events, compared with bupropion, another drug used for smoking cessation. We conducted a registry-based cohort study in Denmark, 2007-10, comparing new users of varenicline and bupropion in unmatched and 1 : 1 propensity score-matched analyses. Using Cox regression, we estimated the hazard ratio (HR) of any psychiatric adverse event (emergency department visit or in-patient admission with a psychiatric diagnosis) within 30 days following treatment initiation. The unmatched and matched analyses correspond to conventional crude and fully adjusted analyses, respectively. In unmatched analyses, there were 106 (0.18%) psychiatric adverse events among 59 790 varenicline users (rate 22 events per 1000 person-years), compared with 46 (0.26%) events among 17 936 bupropion users (rate 31 per 1000); the HR was 0.69 [95% confidence interval (CI): 0.49-0.98]. In propensity score-matched analyses, 39 (0.22%) events occurred among 17 935 varenicline users (rate 27 per 1000), compared with 46 (0.26%) events among 17 935 bupropion users (rate 31 per 1000); varenicline was not associated with increased risk of psychiatric adverse events (HR 0.85, 95% CI: 0.55-1.30). The overall rate of psychiatric adverse events was substantially higher among participants with a history of psychiatric disorder than in patients without such history; the risk associated with varenicline did not differ significantly by history of psychiatric disorder. In Denmark, the risk of psychiatric adverse events diagnosed during an emergency department visit or in-patient admission was not significantly higher with varenicline use compared with bupropion.


Maternal occupational exposure to selected organic and chlorinated solvents and delivery of small-for-gestational age or preterm infants.
Potential reproductive effects of organic solvent exposure during pregnancy remain unclear. We investigated the association between maternal occupational exposure during pregnancy to six chlorinated solvents, three aromatic solvents, and Stoddard solvent, and delivery of preterm infants or those born small-for-gestational age (SGA). In this case-control study of SGA and preterm birth (PTB) nested within the National Birth Defects Prevention Study (NBDPS) from 1997 to 2011, we analyzed data from 7504 singleton live births without major birth defects and their mothers. Self-reported information on jobs held in the periconceptional period was assessed for solvent exposure. Unconditional logistic regression was used to estimate the association between maternal occupational exposure (any, none) during early pregnancy to organic solvents and PTB and SGA. Linear regression was used to examine changes in mean birthweight potentially associated with maternal occupational solvent exposure. Maternal occupational exposure to any organic solvents overall was not associated with an increased odds of PTB (adjusted odds ratio [aOR] = 0.94; 95% confidence interval [CI] 0.67-1.33) or SGA (aOR = 0.93; 95% CI 0.65-1.34). Point estimates increased modestly for higher estimated exposure versus lower, but confidence intervals were wide and not statistically significant. Maternal exposure to solvents was not associated with a statistically significant change in term birthweight among infants. Occupational exposure to organic solvents at the frequency and intensity levels found in a population-based sample of pregnant workers was not associated with PTB or SGA; however, we cannot rule out any effects among pregnant workers with uncommonly high exposure to organic solvents.


Menstrual Education and Personal Hygiene Supplies to Empower Young Women in Haiti.
Recent studies report that Haitian women are concerned about unmet women's health issues. The Days for Girls (DfG) International program features women's health education and personal hygiene kits to ensure women understand the process of menstruation and sanitary hygiene practices. The aim was to train Haitian seamstresses to produce the DfG kits during an in-country workshop and investigate the perceived benefit of the DfG program in young women who used the DfG kits. Posttest only design was used to measure the effectiveness of DfG workshop and postsurvey to study perception of women using DfG kits. It was found that the workshop participants demonstrated an understanding of the DfG program (90% average). Forty-four young women (89.8%) who used the DfG hygiene kits for 2 months agreed that there is a need for feminine hygiene programs in Haiti and that the kits were easy to use and clean (97.1% and 92.1%, respectively). The DfG program could provide a cost-effective feminine hygiene program for Haiti and decrease waste from traditional hygiene products.


Identification of multiple pathways in the Wolff-Parkinson-White syndrome. Diagnostic problems and therapeutic implications.
With advanced electrophysiological methods evaluation of functional properties and location of accessory pathways has become possible. Multiple pathways may, however, be difficult to outline with regard to localization and electrophysiological properties due to differences in refractoriness and/or fusion of conduction between the pathways. The investigational procedures in patients with multiple accessory pathways are described and discussed in connection with an illustrative patient with three accessory pathways, two of which are Kent's bundles and one most probably a Mahaim's bundle.


Fibrinolytic response to exercise in women using third-generation oral contraceptives.
The use of oral contraceptives (OC) is associated with an increased risk of thrombosis, suggesting OC exert procoagulant and/or antifibrinolytic effects. Given that physical exercise physiologically leads to an activation of blood coagulation and fibrinolysis, this study tested the hypothesis that OC might compromise the fibrinolytic response to exercise. Fibrinolytic variables were measured in 10 women (24 +/- 2 years) using OC (a formulation containing 30 micro g ethinylestradiol and 150 micro g desogestrel) and in 11 women without OC (mean +/- SD, 27 +/- 3 years) before, during and after a 1-h run on a treadmill at a velocity corresponding to an oxygen demand of 75-80% of maximum (anaerobic threshold). Exercise testing gave rise to considerable increases of tissue-type plasminogen activator antigen by seven-fold to eight-fold in women taking and not taking OC alike. In the presence of unchanged plasma levels of plasminogen activator inhibitor-1, exercise-induced release of tissue-type plasminogen activator led to enhanced plasmin formation with respect to plasmin-antiplasmin complexes, rising by (mean +/- standard error) 701 +/- 77 ng/ml (P < 0.001) in women using OC and by 695 +/- 117 ng/ml (P < 0.001 versus baseline; NS versus OC users) in controls. The fibrinolytic response to intensive physical exercise is preserved in women using OC and is similar to women not using OC.


The use of osseointegrated implants in orthodontic patients: I. Implants and their use in children.
Implants have been used successfully for the rehabilitation of edentulous adults. However, their use in children is limited because of the special problems of implants relating to continuing growth and development. This, the first of two articles, provides a review of the use of osseointegrated implants in the context of facial growth, and the role of the orthodontist in the management of implant-supported prosthodontic structures. A second article will discuss the role of implants in orthodontics in providing what has been termed 'absolute anchorage'.


Clinical and Echocardiographic Factors Associated with Right Ventricular Systolic Dysfunction in Hemodialysis Patients.
Chronic kidney disease is a disorder of epidemic proportions that impairs cardiac function. Cardiovascular diseases are the leading cause of death in hemodialysis patients, and the understanding of new nontraditional predictors of mortality could improve their outcomes. Right ventricular systolic dysfunction (RVSD) has recently been recognized as a predictor of cardiovascular death in heart failure and hemodialysis patients. However, the factors contributing to RVSD in hemodialysis patients remain unknown. The aim of this study was to evaluate the clinical and echocardiographic factors associated with RVSD in hemodialysis patients. A cross-sectional study was conducted in which 100 outpatients with end-stage renal disease on chronic hemodialysis were evaluated. A transthoracic echocardiographic examination was performed at optimal dry weight. Right ventricular systolic function was evaluated using tricuspid annular plane systolic excursion (TAPSE). Clinical and echocardiographic data were recorded for each patient. A multivariate linear logistic regression was created using RVSD (TAPSE <14 mm) as the dependent variable. Fifteen patients with RVSD and 85 patients without RVSD were analyzed. TAPSE had a positive correlation with left ventricular ejection fraction (LVEF) and myocardial relaxation velocity. Independent contributors to RVSD were LVEF (OR 1.14, 95% CI 1.05-1.26), left ventricular mass index (OR 1.02, 95% CI 1.00-1.04), and myocardial relaxation velocity (OR 1.81, 95% CI 1.18-3.19). Echocardiographic factors were significant contributors to RVSD. These measurements could be included as part of the routine workup in all end-stage renal disease patients on hemodialysis.


Silencing of human phosphatidylethanolamine-binding protein 4 enhances rituximab-induced death and chemosensitization in B-cell lymphoma.
Rituximab is the first line drug to treat non Hodgkin's lymphoma (B-NHL) alone or in combination with chemotherapy. However, 30-40% of B-NHL patients are unresponsive to rituximab or resistant after therapy. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of PEBP family and functions as an anti-apoptotic molecule. In this study, we found hPEBP4 to be expressed in up to 90% of B-cell lymphoma patients, but in only 16.7% of normal lymph nodes. Interestingly, hPEBP4 overexpression inhibited rituximab-mediated complement dependent cytotoxicity (R-CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in B-NHL cells while downregulation of hPEBP4 augmented the therapeutic efficacy of rituximab both in vitro and in vivo. Furthermore, hPEBP4 silencing sensitized the primary B-acute lymphocytic leukemia (B-ALL) cells to R-CDC. During rituximab-mediated complement dependent cytotoxicity, hPEBP4 was recruited to the cell membrane in a PE-binding domain dependent manner and inhibited R-CDC induced calcium flux and reactive oxygen species (ROS) generation. These events contributed to the decrease of cell death induced by R-CDC in B-cell lymphomas. Meanwhile, hPEBP4 knockdown potentiated the chemosensitization of the rituximab in B-cell lymphoma cells by regulating the expression of Bcl-xl, Cycline E, p21(waf/cip1) and p53 and the activation of caspase-3 and caspase-9. Considering that hPEBP4 conferred cellular resistance to rituximab treatment and was preferentially expressed in lymphoma tissue, it could be a potential valuable target for adjuvant therapy for B-cell lymphoma.


New genetic variants of TET2 and ASXL1 identified by next generation sequencing and pyrosequencing in a patient with MDS-RS-MLD and secondary acute myeloid leukemia.
Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by the presence of cytopenias, ineffective hematopoiesis and frequent transformation into secondary acute myeloid leukemia (secAML). Recent genomic studies provide unprecedented insight into the molecular landscape of clonal proliferation in MDS. Genetic diversity of both MDS and secAML subclones cannot be defined by a single somatic mutation. Mutations of the founding clone may survive over implemented chemotherapy and allogenic hematopoietic cell transplantation (alloHCT), but new subclonal mutations may also appear. Next generation sequencing (NGS) makes it possible to define the mutational profile of disease subclones during the treatment course and has a potential in pre- and post-alloHCT monitoring. Understanding the molecular pathophysiology of MDS may soon allow for monitoring the course of disease and personalized treatment depending on the mutational landscape. In the present paper we report, for the first time in MDS, ASXL1 c.1945G>T, TET2 c.4044+2dupT and c.4076G>T sequence variants. Moreover, we detected RUNX1 c.509-2A>C and SF3B1 c.1874G>T sequence variants. Furthermore, we verify the clinical utility of NGS and pyrosequencing in MDS and secAML.


Early intervention with Bifidobacterium lactis NCC2818 modulates the host-microbe interface independent of the sustained changes induced by the neonatal environment.
Inflammatory and metabolic diseases can originate during early-life and have been correlated with shifts in intestinal microbial ecology. Here we demonstrate that minor environmental fluctuations during the early neonatal period had sustained effects on the developing porcine microbiota and host-microbe interface. These inter-replicate effects appear to originate during the first day of life, and are likely to reflect very early microbiota acquisition from the environment. We statistically link early systemic inflammation with later local increases in inflammatory cytokine (IL-17) production, which could have important enteric health implications. Immunity, intestinal barrier function, host metabolism and host-microbiota co-metabolism were further modified by Bifidobacterium lactis NCC2818 supplementation, although composition of the in situ microbiota remained unchanged. Finally, our robust model identified novel, strong correlations between urinary metabolites (eg malonate, phenylacetylglycine, alanine) and mucosal immunoglobulin (IgM) and cytokine (IL-10, IL-4) production, thus providing the possibility of the development of urinary 'dipstick' tests to assess non-accessible mucosal immune development and identify early precursors (biomarkers) of disease. These results have important implications for infants exposed to neonatal factors including caesarean delivery, antibiotic therapy and delayed discharge from hospital environments, which may predispose to the development of inflammatory and metabolic diseases in later life.