Direct characterization of beta-adrenoceptors in membranes of immature red blood cells from rats.
By means of the radioactive antagonist ligand (3H)(-) dihydroalprenolol (DHAP) specific binding sites were identified in membrane preparations from red blood cells from rats. These specific sites were characterized as beta-adrenoceptors because of the following reasons: Specific binding of DHAP (in contrast to unspecific binding) was dependent on temperature and time of incubation. Furthermore, specific binding of DHAP showed saturability, temperature-dependent reversibility and high affinity (KD-value of DHAP = 6.51 nM). Specific binding of DHAP was competitively inhibited by beta-adrenergic antagonists (pindolol greater than alprenolol greater than or equal to propranolol greater than practolol) and agonists (isoprenaline greater than adrenaline). The (-) enantiomers of pindolol and isoprenaline showed pronounced higher affinities for the receptor sites than the respective (+) enantiomers. The receptor density in the membrane preparations (pmoles/mg protein) was strongly dependent on the degree of reticulocytosis: The Bmax-values increased more than 4 to 5 fold without alteration of the respective KD-values when reticulocyte counts were enhanced from 3 to 80% treatment of the animals with increasing doses of acetyl phenylhydrazine.


Nanoformulated copper/zinc superoxide dismutase reduces adipose inflammation in obesity.
An intimate association exists between oxidative stress and inflammation. Because adipose tissue (AT) inflammation is intricately linked to metabolic disorders, it was hypothesized that reducing oxidative stress would be effective in ameliorating AT inflammation in obesity. Wild-type mice were fed a high-fat diet (HF) for 8 weeks followed by a 2-week treatment with nanoformulated copper/zinc superoxide dismutase (NanoSOD). The mice were divided into: 1) chow diet, 2) HF, and 3) HF + NanoSOD. The HF + NanoSOD-treated mice showed a significant decrease in plasma and liver triglycerides when compared with HF-fed mice. Interestingly, NanoSOD reduced the expression of macrophage and inflammatory markers in visceral AT (VAT) and stromal cells derived from VAT. Moreover, the activation of proinflammatory signaling pathways, in particular, the extracellular signal-regulated kinases, was blunted in VAT on NanoSOD treatment. However, markers of oxidative stress were not altered significantly in the HF + NanoSOD group in the experimental conditions. Pretreatment of either macrophages or adipocytes significantly reduced the inflammatory response invoked in an in vitro coculture system, further supporting the role of NanoSOD in inhibiting obesity-linked inflammation. This data suggest that NanoSOD is effective not only in reducing AT macrophage accumulation and AT inflammation but also in promoting triglyceride metabolism in obesity.


Synthesis, Structural Characterization, and In Vitro and In Silico Antifungal Evaluation of Azo-Azomethine Pyrazoles (PhN2(PhOH)CHN(C3N2(CH3)3)PhR, R = H or NO2).
The azo-azomethine imines, R1-N=N-R2-CH=N-R3, are a class of active pharmacological ligands that have been prominent antifungal, antibacterial, and antitumor agents. In this study, four new azo-azomethines, R1 = Ph, R2 = phenol, and R3 = pyrazol-Ph-R' (R = H or NO2), have been synthesized, structurally characterized using X-ray, IR, NMR and UV-Vis techniques, and their antifungal activity evaluated against certified strains of Candida albicans and Cryptococcus neoformans. The antifungal tests revealed a high to moderate inhibitory activity towards both strains, which is regulated as a function of both the presence and the location of the nitro group in the aromatic ring of the series. These biological assays were further complemented with molecular docking studies against three different molecular targets from each fungus strain. Molecular dynamics simulations and binding free energy calculations were performed on the two best molecular docking results for each fungus strain. Better affinity for active sites for nitro compounds at the "meta" and "para" positions was found, making them promising building blocks for the development of new Schiff bases with high antifungal activity.


Local government venues' sponsorship and signage policies to limit the promotion of harmful products: A Western Australian public health audit.
Identify and assess publicly available local government sponsorship and signage policies related to harmful products in Western Australia (WA). An audit of WA Local Government Authority (LGAs) websites (n=139) was conducted. Sponsorship, signage, venue hire and community grants' policies were located and assessed against set criterion. Policies were scored for the inclusion of statements regarding the display and promotion of harmful commodities (alcohol, tobacco, gambling products, unhealthy food and beverages). Across WA local governments, 477 relevant policies were identified. Six percent (n=28) included statements restricting the promotion of at least one harmful commodity via sponsorships, signage, venue hire, and sporting and/or community grants policy. Twenty-three local governments had at least one policy that restricted unhealthy signage or sponsorship. Most WA local governments do not have publicly available policies that specifically limit the advertising and promotion of harmful commodities in their government-owned facilities. There is a dearth of research identifying LGA interventions addressing advertising of harmful commodities within council-owned sporting venues. This research indicates opportunities for West Australian LGAs to develop and implement policy to protect public health by restricting the promotion of harmful commodities to their communities, improving the healthfulness of environments.


Effect of fluconazole on the pharmacokinetics and pharmacodynamics of oral and rectal bromazepam: an application of electroencephalography as the pharmacodynamic method.
Quantitative analysis of electroencephalography (EEG) is used increasingly to evaluate the pharmacodynamics of benzodiazepines. The present study aimed to apply the EEG method as well as more traditional approaches to an interaction study of bromazepam and fluconazole. Twelve healthy male volunteers participated in a randomized, double-blind, four-way crossover study. The subjects received single oral or rectal doses of bromazepam (3 mg) after 4-day pretreatment of oral fluconazole (100 mg daily) or its placebo. Plasma bromazepam concentrations were measured before and 0.5, 1, 2, 3, 4, 6, 12, 22, 46, and 70 hours after bromazepam administration. Pharmacodynamic effects of bromazepam were assessed using self-rated drowsiness, continuous number addition test, and EEG. Fluconazole caused no significant changes in pharmacokinetics and pharmacodynamics of oral or rectal bromazepam. Rectal administration significantly increased AUC (1.7-fold, p < 0.0001) and Cmax (1.6-fold, p < 0.0001) of bromazepam. These changes following rectal dose may be due to avoidance of degradation occurring in the gastrointestinal tract. Rectal bromazepam also increased the area under the effect curves assessed by EEG (p < 0.05) and subjective drowsiness (p < 0.05). EEG effects were closely correlated with mean plasma bromazepam concentrations (r = 0.92, p < 0.001 for placebo; r = 0.89, p < 0.0001 for fluconazole). Thus, the EEG method provided pharmacodynamic data that clearly reflected the pharmacokinetics of bromazepam.


Remote patient monitoring for COVID-19 patients: comparisons and framework for reporting.
COVID-19 has challenged health services throughout the world in terms of hospital capacity and put staff and vulnerable populations at risk of infection. In the face of these challenges, many health providers have implemented remote patient monitoring (RPM) of COVID-19 patients in their own homes. However systematic reviews of the literature on these implementations have revealed wide variations in how RPM is implemented; along with variations in particulars of RPM reported on, making comparison and evaluation difficult. A review of reported items is warranted to develop a framework of key items to enhance reporting consistency. The aims of this review of remote monitoring for COVID-19 patients are twofold: (1) to facilitate comparison between RPM implementations by tabulating information and values under common domains. (2) to develop a reporting framework to enhance reporting consistency. A review of the literature for RPM for COVID-19 patients was conducted following PRISMA guidelines. The Medline database was searched for articles published between 2020 to February 2023 and studies reporting on items with sufficient detail to compare one with another were included. Relevant data was extracted and synthesized by the lead author. Quality appraisal was not conducted as the the articles considered were evaluated as informational reports of clinical implementations rather than as studies designed to answer a research question. From 305 studies retrieved, 23 studies were included in the review: fourteen from the US, two from the UK and one each from Africa, Ireland, China, the Netherlands, Belgium, Australia and Italy. Sixteen generally reported items were identified, shown with the percentage of studies reporting in brackets: Reporting Period (82%), Rationale (100%), Patients (100%), Medical Team (91%) Provider / Infrastructure (91%), Communications Platform (100%), Patient Equipment (100%), Training (48%), Markers (96%), Frequency of prompt / Input (96%),Thresholds (82%), Discharge (61%), Enrolled (96%), Alerts/Escalated (78%), Patient acceptance (43%), and Patient Adherence (52%). Whilst some studies reported on patient training and acceptance, just one reported on staff training and none on staff acceptance. Variations in reported items were found. Pending the establishment of a robust set of reporting guidelines, we propose a reporting framework consisting of eighteen reporting items under the following four domains: Context, Technology, Process and Metrics.


Experimental study of the migration of charcoal particles in the human mouth.
Suspensions of charcoal in water, placed in the vestibule on one side of the mouth, spread within about 5 min to the dorsum of the tongue and the hard palate on the same side but did not cross the mid-line. When placed centrally under the tongue, the movement of charcoal was equally rapid but it spread over the whole surface of the mouth.


Impact of positive microscopic resection margins (R1) after gastrectomy in diffuse-type gastric cancer.
Diffuse-type gastric cancer (DTGC) is associated with poor outcome. Surgical resection margin status (R) is an important prognostic factor, but its exact impact on DTGC patients remains unknown. The aim of this study was to assess the prognostic value of microscopically positive margins (R1) after gastrectomy on survival and tumour recurrence in DTGC patients. All consecutive DTGC patients from two tertiary centers who underwent curative oncologic gastrectomy from 2005 to 2018 were analyzed. The primary endpoint was overall survival (OS) for R0 versus R1 patients. Secondary endpoints included disease-free survival (DFS), recurrence patterns as well as the overall survival benefit of chemotherapy in this DTGC patient cohort. Overall, 108 patients were analysed, 88 with R0 and 20 with R1 resection. Patients with negative lymph nodes and negative margins (pN0R0) had the best OS (median 102 months, 95% CI 1-207), whereas pN + R0 patients had better median OS than pN + R1 patients (36 months 95% CI 13-59, versus 7 months, 95% CI 1-13, p < 0.001). Similar findings were observed for DFS. Perioperative chemotherapy offered a median OS of 46 months (95% CI 24-68) versus 9 months (95% CI 1-25) after upfront surgery (p = 0.022). R1 patients presented more often early recurrence (< 12 postoperative months, 30% vs 8%, p = 0.002), however, no differences were observed in recurrence location. DTGC patients with microscopically positive margins (R1) presented poorer OS and DFS, and early tumour recurrence in the present series. R0 resection should be obtained whenever possible, even if other adverse biological features are present.


A new xenotransplantation model reveals tumor-initiating cells in cutaneous squamous cell carcinoma.
Two articles by Patel et al. in this issue demonstrate reproducible, high-frequency xenografting of both primary human cutaneous squamous cell carcinoma (SCC) tissue and single-cell suspensions, as well as the existence of a small population of CD133(+) tumor-initiating cells that are capable of regenerating the hierarchical organization and histology of the original tumor through multiple xenograft passages.


Clinical Stage B0 or T1c prostate cancer: nonpalpable disease identified by elevated serum prostate-specific antigen concentration.
A retrospective study was performed to evaluate the clinical and pathologic characteristics of 60 patients with a palpably benign prostate gland, but with biopsy-proved prostate cancer. All patients underwent prostate biopsy because of elevated serum prostate-specific antigen (PSA) concentration, and subsequently underwent radical retropubic prostatectomy (RRP). Similar analysis was performed for a randomly selected group of 60 clinical Stage B1 prostate cancers from the same period (control cohort). Patients with nonpalpable prostate cancers had a higher preoperative PSA level as compared with the clinical Stage B1 group (median value: 12.3 ng/mL versus 4.6 ng/mL, p < 0.001). There was no significant difference between the two groups with regard to clinical parameters (voiding symptoms, hematuria, age). The nonpalpable prostate cancers exhibited a significant tumor volume (mean: 7.4 cc; range: 0.3-56 cc), and 18 (30%) demonstrated capsular perforation to involve the periprostatic tissues. Of these, three (5%) had seminal vesicle invasion, and one (2%) had pelvic lymph node involvement. There was no difference between these pathologic characteristics and those of the clinical Stage B1 prostate cancers. These findings suggest that nonpalpable prostate cancers identified by an elevated serum PSA level can be of clinical significance and warrant therapeutic consideration. Although nonpalpable, these cancers are peripherally located and were clinically suspected prior to biopsy. Therefore, we propose that these cancers be classified as clinical Stage B0 in the Whitmore-Jewett staging system; in the new TNM staging system, they are designated as clinical Stage T1c.


Pregnancy after lung and heart-lung transplantation: a French multicentre retrospective study of 39 pregnancies.
Pregnancy after lung and heart-lung transplantation remains rare. This French study deals with change in lung function after a pregnancy and the maternal and newborn outcomes. We retrospectively included 39 pregnancies in 35 women aged >20 years. Data on patients, course of pregnancies and newborns were collected from nine transplantation centres. Mean age at time of pregnancy was 28 years. Cystic fibrosis affected 71% of patients. Mean±sd time between transplantation and pregnancy was 63±44 months. 26 births occurred (67%) with a mean term of 36 weeks of amenorrhoea and a mean birthweight of 2409 g. Prematurity was observed in 11 cases (43%). Forced expiratory volume in 1 s was 83.9% of predicted before pregnancy and 77.3% of predicted 1 year after the end of pregnancy (p=0.04). 10 patients developed chronic lung allograft dysfunction after delivery. Nine patients died at a mean±sd time after transplantation of 8.2±7 years and a mean±sd time after pregnancy of 4.6±6.5 years. These data show that pregnancy remains feasible in lung and heart-lung transplant recipients, with more frequent maternal and newborn complications than in the general population. Survival in this cohort appears to be similar to the global survival observed in lung transplant recipients. Planned pregnancy and multidisciplinary follow-up are crucial.


Establishment of murine cell lines by constitutive and conditional immortalization.
Mouse cell lines were immortalized by introduction of specific immortalizing genes. Embryonic and adult animals and an embryonal stem cell line were used as a source of primary cells. The immortalizing genes were either introduced by DNA transfection or by ecotropic retrovirus transduction. Fibroblasts were obtained by expression of SV40 virus large T antigen (TAg). The properties of the resulting fibroblast cell lines were reproducible, independent of the donor mouse strains employed and the cells showed no transformed properties in vitro and did not form tumors in vivo. Endothelial cell lines were generated by Polyoma virus middle T antigen expression in primary embryonal cells. These cell lines consistently expressed relevant endothelial cell surface markers. Since the expression of the immortalizing genes was expected to strongly influence the cellular characteristics fibroblastoid cells were reversibly immortalized by using a vector that allows conditional expression of the TAg. Under inducing conditions, these cells exhibited properties that were highly similar to the properties of constitutively immortalized cells. In the absence of TAg expression, cell proliferation stops. Cell growth is resumed when TAg expression is restored. Gene expression profiling indicates that TAg influences the expression levels of more than 1000 genes that are involved in diverse cellular processes. The data show that conditionally immortalized cell lines have several advantageous properties over constitutively immortalized cells.


Combination of recombinant human growth hormone and propranolol decreases hypermetabolism and inflammation in severely burned children.
Recombinant human growth hormone (rhGH) is a salutary modulator of posttraumatic metabolic responses. However, rhGH administration is associated with deleterious side effects, such as hyperglycemia, increased free fatty acids, and triglycerides, which limit its use. Administration of beta-blocker attenuates cardiac work and resting energy expenditure after severe thermal injury and improves fat metabolism and insulin sensitivity. Therefore, the combination of rhGH plus propranolol appears ideal. The aim of the present study was to determine whether rhGH plus propranolol improves hypermetabolism and the inflammatory and acute phase response after severe burn without causing adverse side effects. Prospective randomized control trial. Shriners Hospitals for Children. Fifteen pediatric patients with burns > 40% total body surface area, 0.1-16 yrs of age, admitted within 7 days after burn. Fifteen children were matched for burn size, age, gender, inhalation injury, and infection and served as controls. Patients in the experimental group received rhGH (0.2 mg/kg/day) and propranolol (to decrease heart rate by 15%) for > or = 15 days. Outcome measurements included resting energy expenditure, body composition, acute phase proteins, and cytokines. Both cohorts were similar in age, burn size, gender, and accompanying injuries. Percent predicted resting energy expenditure significantly decreased in patients receiving rhGH/propranolol (Delta -5% +/- 8%) compared with controls (Delta +35% +/- 20%) (p < .05). rhGH/propranolol administration significantly decreased serum C-reactive protein, cortisone, aspartate aminotransferase, alanine aminotransferase, free fatty acids, interleukin-6, interleukin-8, and macrophage inflammatory protein-1beta when compared with controls, while growth hormone/propranolol increased serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, growth hormone, prealbumin, and interleukin-7 when compared with placebo (p < .05). rhGH in combination with propranolol attenuates hypermetabolism and inflammation without the adverse side effects found with rhGH therapy alone.


Augmentation Mastopexy-An Algorithm to Demystify Surgical Planning.
As individual procedures breast augmentation and mastopexy are relatively simple and low-risk procedures. Simply, breast augmentation comprises of placing an implant under breast tissue or a combination or breast tissue and muscle (Spear and Giese in Aesth Surg J 20(2):155-164, 2020. https://doi.org/10.1067/maj.2000.106474 ). Mastopexy involves reshaping the breast and commonly raising the nipple1. Complications in the individual procedures are relatively low and generally reported as capsular contracture in breast augmentation or minor wound break down in mastopexy (Spear and Giese 2020). When combined as an augmentation mastopexy everything changes. Augmentation mastopexy is one of the most difficult challenges faced in plastic surgery2. We describe an easy-to-follow algorithm to assist the surgeon in their operative decision-making. LEVEL OF EVIDENCE V: This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Diagnostic Accuracy of the Xpert MTB/RIF Assay for Extrapulmonary Tuberculosis in Children With Musculoskeletal Infections.
Xpert MTB/RIF (Xpert) is useful for the diagnosis of extrapulmonary tuberculosis (TB) in adults, but there is limited evidence on its usefulness in children. We aimed to investigate the accuracy of Xpert for the diagnosis of extrapulmonary TB in children with musculoskeletal infections. The diagnostic accuracy of Xpert was compared with a reference standard of culture or histopathology in children hospitalized with suspected osteoarticular TB in Cape Town, South Africa from June 2013 to May 2015. One hundred and nine samples of 102 patients (60 male; 58.8%) with a median age of 5.6 years (interquartile range: 2.2-8.7) were included. There were 23 samples with confirmed TB by culture or histology (21.1%); histology was positive in all of these, while culture was positive in 14 samples (12.8%). Xpert was positive in 17 samples (15.6%), providing a sensitivity of 73.9% (95% confidence interval: 51.6-89.8) and specificity of 100% (95% confidence interval: 95.7-100). Xpert was positive at a mean of 0.8 days (0.46-1.4) compared with 21 days (19-30) for culture, P < 0.001. Multidrug-resistant TB was detected on culture in a single sample that was negative on Xpert testing. Xpert confirmed extrapulmonary TB of bone and joints more accurately and faster than culture and should be used as a first-line test. Histology remains a useful test for musculoskeletal TB in children.


Whey protein and high-volume resistance training in postmenopausal women.
To examine the combined effects of whey protein supplementation and low intensity, high-volume resistance training in healthy postmenopausal women. Postmenopausal women (n=12; age: 57 ± 4.7 years, weight: 75 ± 17.4 kg, height: 163 ± 5.5 cm, body mass index: 28.3 ± 7.0) consumed whey protein (4 x 10 gram aliquots) or placebo (maltodextrin) during unilateral resistance training sessions 2 days per week (Monday, Thursday) and consumed the opposite beverage during training the other side of the body on alternating days (Tuesday, Friday) for 10 weeks. Participants performed 3 sets at 30% baseline 1-repetition maximum (1RM) to volitional muscle fatigue for 4 exercises (leg curl, biceps curl, leg extension, triceps extension). Prior to and following training, assessments were made for upper and lower limb lean tissue mass (dual energy x-ray absorptiometry), muscle thickness of the elbow and knee flexors and extensors (ultrasound) and muscle strength (1RM leg curl, biceps curl, leg extension, triceps extension). There was a significant increase over time for muscle strength (biceps curl, leg extension, triceps extension; P = 0.006) and muscle thickness (elbow flexors and extensors; P = 0.022) with no differences between whey protein and placebo. High volume resistance training is effective for improving some indices of muscle mass and strength in postmenopausal women, but the strategic ingestion of whey protein during training sessions does not augment this response.


Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia.
The decision to re-induce patients with acute myeloid leukemia (AML) based on results of the day 14 bone marrow (BM) biopsy is variable and lacks evidence based data. The aim of our review was to evaluate the accuracy of a day 14 BM biopsy in determining the need for re-induction chemotherapy. Seventy-four patients with newly diagnosed de novo AML treated with induction chemotherapy were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on their day 14 BM biopsy. Response to therapy in this analysis was based on morphology alone. Of the 74 patients undergoing standard induction, 45 patients (61%) had no evidence of leukemia on their day 14 BM biopsy. Eighteen patients (24%) had definitive residual disease (RD), and 11 patient's (15%) were classified as indeterminate response (IR). Fifteen patients with RD and one with IR underwent re-induction chemotherapy. However, thirteen patients (3 RD and 10 IR) were observed until count recovery without any re-induction therapy. Eleven of these 13 patients who were observed eventually attained a morphologic complete remission (CR), including two patients with RD. A day 14 BM biopsy may have suboptimal sensitivity for the detection of residual leukemia. Some patients with an IR on day 14 may not require re-induction chemotherapy, but instead, may benefit from careful observation until count recovery to avoid the mortality and morbidity associated with re-induction chemotherapy.


The value of situational judgement tests for assessing non-academic attributes in dental selection.
Situational judgement tests (SJTs) have been shown to be reliable and valid tools for assessing non-academic attributes across numerous healthcare professions. However, within the context of selection into dental foundation training (DFT) in the UK the introduction of an SJT is relatively new. This expert opinion highlights four key considerations regarding the DFT SJT in order to inform further debate amongst researchers and stakeholders. We clarify that SJTs measure non-academic attributes important for success in dental training, and that their context and content must be updated regularly to ensure their relevance, realism and fairness to current applicants. We outline that SJTs are efficient and cost-effective for high volume selection in the long term, in comparison to face-to-face interviews. Finally we summarise the value of practice material being available for high-stakes SJTs, such as the DFT SJT. Implications for practice are discussed throughout.


Description of a Culture-Sensitive, Low-Threshold Psychoeducation Intervention for Asylum Seekers (Tea Garden).
Asylum seekers often suffer from high levels of mental distress. However, as a result of a lack of knowledge about mental health and health care, as well as cultural and language barriers, the utilization of mental health care in Western host countries is often difficult for these individuals. Reducing these barriers may thus be a crucial first step towards appropriate mental health care. Previous research showed that psychoeducation may be helpful in this regard. The current manuscript describes a short, low-threshold and transdiagnostic intervention named 'Tea Garden (TG)'. The TG aims to increase specific knowledge about mental health problems and available treatments, and may improve psychological resilience and self-care. In this manuscript, we specifically focus on culturally sensitive facets, following the framework proposed by Heim and colleagues (2021, https://doi.org/10.32872/cpe.6351), and lessons learned from three independent pilot evaluations (Ns = 31; 61; 20). The TG was found to be feasible and quantitative results showed that it was helpful for male and female asylum seekers from different countries of origin (e.g., Afghanistan, Syria, Pakistan, Iraq) and with different educational levels. Interestingly, even asylum seekers who had already been in Germany or Austria for three or more years benefited from the TG. The TG specifically aims to be culture-sensitive rather than culture-specific, to be transdiagnostic rather than focused on specific mental disorders, and to be suitable for asylum seekers who are still in the insecure process of applying for asylum. It may also be helpful for distressed asylum seekers who do not fulfill the criteria for a mental disorder, and for healthy asylum seekers who could use the knowledge gained in the TG to help others.


Relationship between Stroke Volume Variation and Blood Transfusion during Liver Transplantation.
Intraoperative blood transfusion increases the risk for perioperative mortality and morbidity in liver transplant recipients. A high stroke volume variation (SVV) method has been proposed to reduce blood loss during living donor hepatectomy. Herein, we investigated whether maintaining high SVV could reduce the need for blood transfusion and also evaluated the effect of the high SVV method on postoperative outcomes in liver transplant recipients. We retrospectively analyzed 332 patients who underwent liver transplantation, divided into control (maintaining <10% of SVV during surgery) and high SVV (maintaining 10-20% of SVV during surgery) groups. We evaluated the blood transfusion requirement and hemodynamic parameters, including SVV, as well as postoperative outcomes, such as incidences of acute kidney injury, durations of postoperative intensive care unit and hospital stay, and rates of 1-year mortality. Mean SVV values were 7.0% ± 1.3% in the control group (n = 288) and 11.2% ± 1.8% in the high SVV group (n = 44). The median numbers of transfused packed red blood cells and fresh frozen plasmas in the high SVV group were significantly lower than those in control group (0 vs. 2 units, P = 0.003; and 0 vs. 3 units, P = 0.033, respectively). No significant between-group differences were observed for postoperative outcomes. Maintaining high SVV can reduce the blood transfusion requirement during liver transplantation without worsening postoperative outcomes. These findings provide insights into improving perioperative management in liver transplant recipients.


[Chemical Constituents from Jasminum elongatum].
To investigate the chemical constituents of Jasminum elongatum. The chemical constituents were isolated and purified by various column chromatographic methods and preparative HPLC. Their structures were identified by physicochemical properties and spectral analysis. Nine compounds were isolated from the methanol extract of Jasminum elongatum and identified as protocatechuic acid( 1),caffeic acid( 2),salicylic acid( 3),isovanillic acid( 4),ferulic acid( 5),methyl caffeate( 6),caffein( 7),3,6-diisopropylpiperazin-2,5-dione( 8),scopoletin( 9). All the compounds are isolated from the this plants for the first time.


Follicular lymphoma with blastic conversion: a report of two cases with confirmation by immunoperoxidase studies on bone marrow sections.
Two cases of low-grade follicular lymphoma are presented in which evolution to a blastic phase with marrow and peripheral blood involvement occurred. One case was a follicular and diffuse mixed-cell lymphoma, while the second was a follicular and diffuse small cleaved-cell lymphoma. In both cases, at two and three years after initial presentation, a clinical picture resembling acute leukemia developed, with immature blastic-appearing infiltrates in the bone marrow and circulating blastic cells. Immunoperoxidase studies on fresh frozen sections of bone marrow in both cases confirmed the B-cell nature of the infiltrates and excluded the clinical impression of acute non-lymphocytic leukemia. The differential diagnosis of hematolymphoid infiltrates in the bone marrow in patients with follicular lymphoma is discussed.


Comparison of ROC umbrella volumes with an application to the assessment of lung cancer diagnostic markers.
Receiver operating characteristic (ROC) analysis is widely used to assess the ability of diagnostic markers to correctly classify into one of two disease classes. ROC surfaces and umbrella surfaces generalize the utility of ROC analysis when there are three disease classes. Identification of lung cancer diagnostic markers is an active area of research since prognosis for those diagnosed with lung cancer is so poor and there is not an accurate method for early detection of lung cancer. A study conducted for the assessment of DNA methylation markers motivated the comparison of ROC umbrella surfaces which is developed in this article using U-statistics and bootstrap methodology.


New therapeutic approach to the hirsute patient.
Spironolactone, an aldosterone antagonist currently used in the treatment of hypertension, has numerous antiandrogenic side effects. Decreased production rates of testosterone in intact (N = 10) and hirsute (N = 6) women, respectively, were noted after short (7 days) or long-term (6 months) administration of the drug, 25 mg twice daily. A 50% diminution in the urinary 17-ketosteroid excretion was also observed after 6 months of therapy. Assessment of the treatment was done by the patients: a reduction in hair growth rate was initially observed after 3 to 4 months, followed by the appearance of a more downy type of new growth and a decrease in diameter of the hair shaft. It is concluded that this beneficial effect is obtained by a decrease in the testosterone production rate and probably through competitive inhibition of spironolactone and/or canrenone with the androgen receptor in human hair follicles.


Beta-haemolytic streptococcal endocarditis: clinical presentation, management and outcomes.
Beta-haemolytic streptococcal (BHS) endocarditis is rare, but well-recognised for its high morbidity and mortality. This study sought to further characterise clinical features, management and outcomes of BHS endocarditis. Retrospective review of all adultpatients (≥ 18 years old) with BHS endocarditis treated at the Mayo Clinic from 1 January 2000 to 31 December 2014. Forty-nine cases of BHS endocarditis were identified with a mean (± SD) age of 64 (± 14.9) years and 65% were males. The infection was community acquired in 92% of the cases, with a median (IQR) time to diagnosis from symptom onset of 6 days (5-10). Associated conditions included the presence of a prosthetic valve (41%), malignancy (33%) and diabetes mellitus (DM) (31%). Median (IQR) vegetation size was 12 mm (9-17 mm). In a univariate analysis patients with DM had larger vegetations, median (IQR) = 17 mm (10.5-26 mm) compared to non-diabetic patients, median (IQR) = 11 mm (8-15 mm) (p = 0.01). Septic brain emboli occurred in 43% of cases. Eighteen patients (37%) underwent early (within 30 days) surgery. All-cause 1 month and 6 month mortality rates were 25% and 31%, respectively. BHS endocarditis has an acute onset and is complicated by relatively large vegetations with a high rate of systemic embolisation. DM was the second most common associated medical condition and patients with DM had larger vegetations. Despite medical and surgical advances, mortality due to BHS endocarditis remains high, particularly within 30 days of diagnosis.


Recidivism prevention for impaired driving: Longitudinal 5-year outcomes from Quebec's severity-based intervention assignment program.
Driving while impaired by alcohol (DWI) is a persistent problem. Tailoring intervention modality to client risk and needs (i.e., risk/needs) is posited to both reduce recidivism more efficiently than uniform approaches and circumvent overtreatment or undertreatment. DWI drivers in Quebec must participate in a severity-based intervention assignment program to be relicensed, but like most tailoring programs it has yet to undergo systematic scrutiny. The current longitudinal cohort study tests two main hypotheses underpinning this approach: 1) drivers classified at higher recidivism risk based on their arrest characteristics (DWIR) show poorer outcomes over up to 5-years postassessment compared to drivers classified at lower risk (DWIF); and 2) for both DWIR and DWIF groups, assignment of drivers with greater risk/needs to intensive intervention (II) will be advantageous for reducing recidivism risk compared to assignment into brief intervention (BI) for those with lower risk/needs. Drivers who entered the program from 2012 to 2016 were followed to the end of 2018 (N = 37,612). Survival analysis examined the predictive validity of the initial classification into DWIR or DWIF groups for documented recidivism over a follow-up of up to 5 years. Logistic regression discontinuity evaluated the relative outcomes of drivers who were assigned to either BI or II. The study explored interaction effects between classification and intervention assignment with age and sex. In line with the hypothesis, the average hazard of recidivism was 58 % greater in DWIR drivers compared to DWIF drivers. In both DWIF and DWIR drivers, assignment of drivers with greater risk/needs to II was associated with reduced recidivism compared to assignment of drivers with lower risk/needs to BI, with 57 % and 35 % decreased probability of recidivism, respectively. Younger age was more strongly associated with recidivism risk in DWIF drivers than in DWIR drivers. The current study found that Quebec's severity-based intervention assignment approach accurately identifies DWI drivers who: i) by their arrest characteristics pose a greater risk for recidivism, which may require expeditious exposure to preventative countermeasures; and ii) as a function of their greater risk/needs, benefit from assignment to more intensive intervention to mitigate their recidivism risk.


Professional quality of life of Japanese nurses/midwives providing abortion/childbirth care.
This study explored the relationship between professional quality of life and emotion work and the major stress factors related to abortion care in Japanese obstetric and gynecological nurses and midwives. Between October 2011 and January 2012, questionnaires that included questions concerning eight stress factors, the Professional Quality of Life Scale, and the Japanese version of the Frankfurt Emotional Work Scale, were answered by 255 nurses and midwives working in abortion and childbirth services. Professional Quality of Life scores (compassion fatigue, compassion satisfaction, burnout) were significantly associated with stress factors and emotion work. Multiple regression analysis revealed that of all the evaluated variables, the Japanese version of the Frankfurt Emotional Work Scale score for negative emotions display was the most significant positive predictor of compassion fatigue and burnout. The stress factors "thinking that the aborted fetus deserved to live" and "difficulty in controlling emotions during abortion care" were associated with compassion fatigue. These findings indicate that providing abortion services is a highly distressing experience for nurses and midwives.


The metabolic syndrome and cardiovascular risk: implications for clinical practice.
The clinical importance of the metabolic syndrome (MeS) is confused by the existence of at least three different definitions proposed by prominent organizations, and by a lack of information about the prognostic value of diagnosing a person as having the syndrome by any of the definitions. We used the US National Health and Nutrition Evaluation Survey (NHANES) to determine the prevalence in the United States of the variables used to define the MeS and cardiovascular disease (CVD), and to create a simulated population that matched the US population with respect to all the important characteristics, risk factors and treatments for CVD. We then used the Archimedes model to calculate the long-term CVD outcomes for each person in the simulated population. The definitions implied an increased risk of CVD of 1.5-1.6. The definitions varied considerably in their ability to identify people at risk of myocardial infarctions (MIs); the proportion of people destined to have a future MI captured by the different definitions varied from 57 to 77%. The definitions also varied widely in how well they ruled out future MIs; failure to have MeS by a definition still left a chance of a future MI ranging from 23 to 42%. The definitions differed importantly in which people they identified as having MeS; 34% of those who met the ATP definition did not meet the WHO definition, 30% of those who met the WHO definition did not meet the ATP definition and 28% of those who met the IDF definition did not meet the ATP definition. Of the components of the definitions, the most important single factor for identifying a person at risk of future CVD was high glucose, with hypertension, obesity, high triglycerides and low HDL following in that order. High glucose, by itself, was as good as any definition of the MeS in predicting risk of future MI. Whichever definition was used, individuals who met the definition varied widely in their risk of CVD. For assessing a particular person's risk of future CVD and for making treatment decisions a diagnosis of MeS by any of the definitions added little if anything to assessing each person's risk factors.


The cancer survivorship care plan: health care in the context of cancer.
A 6-year cancer survivor shares how participating in the development of his cancer survivorship care plan yielded physical and emotional benefits, and laments that such plans are not more readily available.


Solitary fibrous tumour of the tongue.
Solitary fibrous tumour (SFT) is a neoplasm most often localised in the pleura and peritoneum. The tumour is composed of spindled fibroblastic cells arranged in a haphazard way. Recently SFT has been described in many locations. Only one case of oral SFT has been described in the cheek: this is the second case of an oral SFT located in the tongue. The differential diagnosis must be made from many soft tissue tumours. SFTs stain strongly, in almost all cases, for CD34.


Aplasia of the thumbs and great toes as the outstanding feature of Yunis and Varon syndrome. A new entity. A new observation.
Aplasia of the thumbs and great toes, and aplasia of terminal and dysplasia of middle phalanges with absence of nails were noted in the child of related parents, who died at the age of 3 months from cardiorespiratory insufficiency. This is the 7th case of an (AR) genetic syndrome called after Yunis and Varon.


Processing of sinusoidally frequency modulated signals in the nuclei of the lateral lemniscus of the big brown bat, Eptesicus fuscus.
Neurons in the nuclei of the lateral lemniscus (NLL) of the big brown bat, Eptesicus fuscus, show several distinctive patterns of response to unmodulated tones. Previous work suggests that sustained responders are specialized to transmit information about sound level and duration while onset responders transmit precise timing information. The biosonar signals of E. fuscus consist of multiple, downward frequency modulated sweeps that change in slope and repetition rate as the bat approaches a target. An obvious hypothesis would be that NLL neurons with sustained responses should discharge during the time when the frequency of a signal is within their response area, but that onset responders should discharge each time the frequency enters the excitatory portion of their response area. In this study we examined the responses of NLL neurons to sinusoidally frequency modulated (SFM) signals presented monaurally to awake, restrained bats. Extracellular recordings were obtained from single neurons in the multipolar and columnar divisions of the ventral nucleus (VNLLm and VNLLc), the intermediate nucleus (INLL) and the dorsal nucleus of the lateral lemniscus (DNLL). All NLL neurons responded synchronously to SFM signals under some conditions. The temporal precision of synchronization was quantified using a coefficient of synchronization (CS), where a value of I equals perfect synchrony. Maximum CS values ranged from 0.70 to >0.99, were generally highest at low modulation rates ( <200 Hz), and showed lowpass characteristics for modulation rate. The maximal modulation rates that elicited synchronous discharge ranged from 50 to 500 Hz. The highest maximal rates were found in the VNLLm and VNLLc, the lowest in DNLL. The ability of NLL neurons to synchronize their discharge to the pattern of an SFM signal is intermediate between that of neurons in the cochlear nucleus and in the inferior colliculus. For the majority of neurons in VNLLm, INLL and DNLL, the precision of synchronization was approximately equal for the downward and upward components of the SFM signal; in contrast, 69% of VNLLc neurons responded selectively to the downward component of the SFM signal. All VNLLc neurons and a subset of those in VNLLm, INLL, and DNLL responded synchronously to SFM signals only if the frequency excursions included a border of the excitatory frequency bandwidth, suggesting that the synchronous discharge was due primarily to the repeated passage of the stimulus frequency into and out of the excitatory portion of the response area. In the case of VNLLc neurons, only the high frequency border was effective; Other neurons, especially those in DNLL, responded synchronously to SFM signals with frequency excursions that were confined entirely within the excitatory response area.


Reconstruction of chronic scalp erosion after deep brain stimulation surgery.
To investigate the reconstructive effectiveness for chronic scalp erosion after deep brain stimulation (DBS). Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease. However, this surgery is not exempt from hard-ware related complications, especially scalp erosions on scalp. Scalp erosions usually accompanied with chronic infection and wound contamination. If not arrested, infections may spread through the entire equipment which would endanger the patient's life. Along with review of previous literatures, we summarized our experience in the management of scalp erosion and implemented a systemic treatment plan for reconstruction. We retrospectively analyzed the clinical data of patients with chronic scalp erosion after DBS in the past 40 months. The treatment plan was composed of three sequential major steps, including wound care and conservative methods, debridement and local flap, and revaluation of the wound. In each of the cases, wound debridement and local scalp flap repair were conducted, and assisted by negative pressure wound therapy (NPWT) device and double cannula irrigation. The local scalp flap survived in all 6 patients. The chronic scalp erosions all healed without refractory. The DBS devices still functioned properly after the treatments in all patients. The average follow-up period was 13.33 months (range: 4 to 23 months), and no infection recurrence or re-erosion of the scalp flap was reported. A combination of wound debridement, local scalp flap repair, the use of NPWT device and double cannula irrigation provides effective treatment method for chronic erosion post DBS surgery.


The serotonin transporter sustains human brown adipose tissue thermogenesis.
Activation of brown adipose tissue (BAT) in humans is a strategy to treat obesity and metabolic disease. Here we show that the serotonin transporter (SERT), encoded by SLC6A4, prevents serotonin-mediated suppression of human BAT function. RNA sequencing of human primary brown and white adipocytes shows that SLC6A4 is highly expressed in human, but not murine, brown adipocytes and BAT. Serotonin decreases uncoupled respiration and reduces uncoupling protein 1 via the 5-HT2B receptor. SERT inhibition by the selective serotonin reuptake inhibitor (SSRI) sertraline prevents uptake of extracellular serotonin, thereby potentiating serotonin's suppressive effect on brown adipocytes. Furthermore, we see that sertraline reduces BAT activation in healthy volunteers, and SSRI-treated patients demonstrate no 18F-fluorodeoxyglucose uptake by BAT at room temperature, unlike matched controls. Inhibition of BAT thermogenesis may contribute to SSRI-induced weight gain and metabolic dysfunction, and reducing peripheral serotonin action may be an approach to treat obesity and metabolic disease.


Pregnancy and sexual related problems among women living on the street in dire Dawa City, Eastern Ethiopia, 2021: qualitative study.
The problem of women and youths living on the street is a global phenomenon. It has created countless problems while they lived on the street; such as unwanted pregnancies, sexual exploitation and prostitution. It is a frequent observation to see women begging on the streets of major cities in Ethiopia having one or two babies by their sides. This study will give an in-depth understanding of the distressing and highly challenging problem among women on the street regarding pregnancy and related problems. To explore pregnancy and sexual-related problems among women living on the street in Dire Dawa city, Eastern Ethiopia 2021. A community-based phenomenological qualitative study was conducted at Dire Dawa city. Data was collected from homeless women and Key informants through focus group discussion and in-depth interviews using a semi-structured tool aided by a voice recorder. Data were analyzed thematically using computer-assisted qualitative data analysis software Atlas.ti7. The thematic analysis with inductive approach goes through 6 steps; Familiarization, Coding, Generating themes, Reviewing themes, Defining and naming themes and Writing up. Women living on the street are more likely to experience physical abuse, sexual harassment, Sexual transmitted infection, unprotected sex and unwanted pregnancy. As a result, the fate of this pregnancy is abortion leads to high risk of getting health complications as most abortions are made in illegal and unsafe ways. Teen pregnancy, STI, rape and unsafe abortion are the major concerns as it accompanied by their homelessness situation and abusive lifestyles. The regional health bureau needs to understand the extent of problem and plan to organize an awareness creation program on STI, risk of pregnancy and SRH services.


Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study.
Biliopancreatic diversion (BPD) is the most effective bariatric procedure in terms of weight loss and remission of diabetes type 2 (T2DM), but it is accompanied by nutrient deficiencies. Sleeve gastrectomy (SG) is a relatively new operation that has shown promising results concerning T2DM resolution and weight loss. The objective of this study was to evaluate and compare prospectively the effects of BPD long limb (BPD) and laparoscopic SG on fasting, and glucose-stimulated insulin, glucagon, ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) secretion and also on remission of T2DM, hypertension, and dyslipidemia in morbidly obese patients with T2DM. Twelve patients (body mass index [BMI] 57.6 ± 9.9 kg/m(2)) underwent BPD and 12 (BMI 43.7 ± 2.1 kg/m(2)) underwent SG. All patients had T2DM and underwent an oral glucose tolerance test (OGTT) before and 1, 3, and 12 months after surgery. BMI decreased more after BPD, but percent excess weight loss (%EWL) was similar in both groups (P = .8) and T2DM resolved in all patients at 12 months. Insulin sensitivity improved more after BPD than after SG (P = .003). Blood pressure, total and LDL cholesterol decreased only after BPD (P<.001). Triglycerides decreased after either operation, but HDL increased only after SG (P<.001). Fasting ghrelin did not change after BPD (P = .2), but decreased markedly after SG (P<.001). GLP-1 and PYY responses during OGTT were dramatically enhanced after either procedure (P = .001). SG was comparable to BPD in T2DM resolution but inferior in improving dyslipidemia and blood pressure. SG and BPD enhanced markedly PYY and GLP-1 responses but only SG suppressed ghrelin levels.


Hyperglycaemia and mortality from all causes and from cardiovascular disease in five populations of Asian origin.
The study was done to assess how well fasting and 2-h plasma glucose (FPG, 2-h PG) after a 75-g OGTT predict cardiovascular disease (CVD) and all-cause mortality in Asian subjects. People ( n=6817) of Japanese and Asian Indian origin from five prospective studies in five countries were monitored for 5 to 10 years. Hazard ratios for death from all causes and CVD were estimated using Cox proportional hazard models, adjusting for FPG, 2-h PG and established risk factors. Multivariate Cox regression analysis showed that an increase in FPG from 7.0 to 8.0 mmol/l (increase of 0.76 SD) increased relative risk (95% CI) by 1.14 (1.05-1.25) for all-cause and 1.24 (1.10-1.39) for CVD mortality. An increase in 2-h PG from 9.0 to 11.9 mmol/l (0.76 SD) increased relative risks by 1.29 (1.18-1.41) and 1.35 (1.19-1.54). Inclusion of 2-h PG in the FPG model improved the predictive value ( p<0.001), whereas FPG did not influence the predictive value of 2-h PG ( p>10). In a model containing FPG and 2-h PG, hazards ratios for 2-h PG in subjects with IGT or diabetes were 1.35 (1.03-1.77) or 3.03 (2.18-4.21) for all-cause and 1.27 (0.86-1.88) or 3.39 (2.14-5.37) for CVD mortality, compared with normal subjects. The respective hazards ratio for FPG in subjects with IFG or diabetes were 0.94 (0.68-1.31) or 0.88 (0.59-1.32) for all-cause and 1.05 (0.67-1.65) or 0.88 (0.51-1.51) for CVD mortality, compared with normal subjects. For prediction of premature death, 2-h PG was superior to FPG in several Asian populations.


Does the number of hypopnoeas influence therapy in patients with obstructive sleep apnoea?
The definition of hypopnoea varies widely between sleep laboratories. This study sought to evaluate the impact upon therapeutic decision of the most commonly used one, which defines hypopnoea as a reduction in airflow of 50% (or more) accompanied by a decreased blood oxygen saturation of 4% (or more) (Agency for Health Care Policy and Research). We studied 109 consecutive patients (99 male) with an apnoea-hypopnoea index (AHI) greater than 5. The same investigator evaluated each patient twice. First, the hypopnoea index (HI) was unavailable to him by study design, and judgment was based upon the number of apnoeas and the clinical situation of the patient. Thereafter, he evaluated all patients again, in random order, this time taking into account the AHI and the clinical condition of the patient. Therapeutic decision was compared at the end of the study. Mean age was 54 +/- 11 years (+/- SD) and body mass index 33 +/- 6 kg m-2. Most patients had normal spirometry and day-time arterial blood gases. Mean apnoea index (AI) was 35 +/- 24 h-1. Therapeutic decision based on the AI lead to conservative treatment (diet and sleep hygiene) in 32 cases and to active treatment in 77 patients [76 continuous positive airway pressure (CPAP) and one surgery]. The AHI was 40 +/- 24 h-1. The consideration of the number of hypopnoeas lead to a therapeutic change only in four patients (3.7%) (chi 2 = 0.36, P > 0.3). These four patients had an AI of 15, 7, 3, and 9 h-1 and an AHI of 22, 10, 46, and 17 h-1, respectively. Combined with their clinical data, this increase was considered a requirement for active treatment (CPAP). The most commonly used definition of hypopnoea has a small impact upon therapeutic decision in patients with obstructive sleep apnoea syndrome (OSAS). We suggest the need to develop new definitions of hypopnoea that incorporate other variables (neurophysiological, cardiovascular) of potential clinical relevance. Our results also show that the outcome of any new definition has to be assessed rigorously in terms of its clinical impact.


Functional limitations in children and adolescents suffering from chronic pain: validation and psychometric properties of the German Functional Disability Inventory (FDI-G).
Our objective was to translate the Functional Disability Inventory (FDI) into German, to evaluate its validity and to assess functional limitation in a large cohort of children and adolescents with juvenile fibromyalgia syndrome (jFMS). We administered several questions (e.g., sociodemographics, school-related issues) and questionnaires to 329 patients and one parent. The questionnaires included, among others, a German version of the FDI, the CHAQ (parent report), KIDSCREEN, tender point score (TPS), Depression Inventory for Children and Adolescents (DIKJ) and others. Patients were asked about the severity of pain today (NRS = numerical rating scale) and other symptoms. Internal consistency was evaluated with Cronbach's alpha. Construct validity of the FDI was evaluated by correlating the FDI with the questionnaires as well as with the pain and other variables, e.g., days missed school. An exploratory factor analysis (EFA) was also performed. Mean age was 13.9 years (SD ±2.48). Means were for pain today 5.37 (±2.39) and for the TPS 39.71 (±21.56). Internal consistency was α = .90. Low-to-moderate correlations were obtained between the FDI and the CHAQ (ρ = .51**), KIDSCREEN (e.g., physical well-being ρ = -.62**; peers and social support ρ = -.28**) as well as the pain variables (NRS ρ = .24**; TPS ρ = .38**). Psychological variables were also correlated with the FDI (e.g., DIJK ρ = .28**). An EFA suggested a two-factor solution. The FDI is a valid instrument for measuring functional limitations in German children and adolescents with jFMS.


[Dengue as haemorrhagic fever].
Dengue virus is distributed in tropical and subtropical regions and transmitted by mosquitoes of the genus Aedes. In September 2010 two cases of indigenous dengue fever were diagnosed in metropolitan France for the first time and next DENV infection was diagnosed in a German traveler returning from a trip to Croatia. The Aedes albopictus mosquitoes were found in several European countries (for example in greenhouses in Netherlands). The indigenous DENV infections in Europe are rare diseases, probably acquired after bites of infected mosquitoes imported by airplanes from endemic areas. Nonspecific symptoms including: fever (up to 39 degrees C), chills, arthralagia, headache, myalgia and abnormalities in laboratory tests such as: thrombocytopaenia, leukopaenia and liver tests cause problems with differential diagnosis ofhematologic and hepatologic syndromes. The most serious complications are associated with dengue shock syndrome with mortality rate of 50%.


Phase 2 Study of Trabectedin in Patients With Hormone Receptor-Positive, HER-2-Negative, Advanced Breast Carcinoma According to Expression of Xeroderma Pigmentosum G Gene.
Preclinical and clinical data suggest that xeroderma pigmentosum G gene (XPG) status might predict trabectedin efficacy. This phase 2 study evaluated the efficacy of trabectedin at a dose of 1.3 mg/m2 as a 3-hour intravenous infusion every 3 weeks in hormone receptor-positive, HER-2 (human epidermal growth factor receptor 2)-negative, advanced breast cancer patients according to the tumor level of XPG mRNA expression. Patients were stratified into high-XPG (>3) or low-XPG (≤ 3) groups. The primary efficacy end point was progression-free survival (PFS) rate at 16 weeks (PFS4); secondary efficacy end points were overall response rate (ORR), duration of response, PFS, overall survival, and safety of trabectedin in this patient population. Forty-four patients were treated, 21 with high XPG and 23 with low XPG. Four high-XPG and 6 low-XPG patients experienced PFS4; the criterion for further recruitment (> 6 patients experienced PFS4) was thus not met, and recruitment was stopped. One high-XPG patient had a partial response (ORR, 5%). One low-XPG patient had a complete response, and 2 low-XPG patients had partial responses (ORR, 13%). Comparison of efficacy parameters between high-XPG and low-XPG patients showed no statistically significant differences. ORR in the efficacy population was 9.3%, median PFS was 1.9 months, and overall survival was 11.8 months. The safety of trabectedin in breast carcinoma was similar to that shown in other indications. Trabectedin as single agent had limited activity in hormone-positive, HER-2-negative advanced breast cancer. XPG mRNA expression was not predictive of trabectedin efficacy.


Nigral influence on focal epilepsy.
The substantia nigra (SN) has been proposed as a structure involved in epileptiform phenomena. Previous investigations demonstrated that SN is able to elicit hippocampal rhythmic slow activity (RSA) as well as to inhibit hippocampal interictal spikes induced by parenteral administration of penicillin. The present series of experiments was carried out in order to characterize the action of SN on a focal model of hippocampal epilepsy. Experiments were performed on encéphale isolé cats in which steady epileptiform activity was induced by locally applied penicillin. Electrical stimulation of SN pars reticulata (pr) caused a statistically significant decrease of hippocampal spike frequency and amplitude in 30% of the total number of stimulation sessions. Stimulation of SN pars compacta (pc) was even more effective. It induced inhibitory effects on hippocampal spikes in 91% of the cases. In 30% of the cats, RSA was noted on hippocampal recordings in correspondence to nigral activation. Experimental data support the hypothesis that the SNpc influences hippocampal excitability: a differential role may be played by SNpc and SNpr in the control of seizure processes.


Therapy with anti-TNFα antibody enhances number and function of Foxp3(+) regulatory T cells in inflammatory bowel diseases.
Inflammatory bowel diseases (IBDs) are associated with up-regulation of TNFα, hyperactivation of proinflammatory effector T cells (Teffs) and inefficient control by regulatory CD4(+) CD25(+) Foxp3(+) T cells (Tregs). The aim of this prospective study was to investigate the short-term impact of treatment of IBD patients with anti-TNFα antibodies (infliximab or adalimumab) on the frequency, phenotype, and suppressive function of Tregs. Active IBD patients including 16 with Crohn's disease and 9 with ulcerative colitis were treated with anti-TNFα mAb. PBMCs were harvested immediately before and 2 weeks after the first injection. The frequency and phenotype of circulating CD4(+) CD25(+) Foxp3(+) Tregs were analyzed by flow cytometry, and their suppressive function was assessed by the ability of purified CD4(+) CD25(+) CD127(-) Tregs to inhibit the proliferation of allogenic CD4(+) CD25(-) Teffs. CD4(+) CD25(+) Foxp3(+) Treg frequency was significantly lower in active IBD patients than in controls (2.8% ± 0.4% vs. 4.6% ± 0.6%, respectively; P = 0.01). On day 14 following the first anti-TNFα infusion, the frequency of circulating Tregs was significantly enhanced in IBD patients (4.0% ± 0.5% vs. 2.8% ± 0.4%, before treatment; P = 0.001), with a 2- to 3-fold increase in the intensity of Foxp3 expression. In addition, infliximab treatment enhanced the suppressive function of circulating Tregs, as shown by inhibition of Teff proliferation at a 1:8 Treg/Teff ratio (28% ± 5% vs. 66% ± 10%, after treatment; P = 0.04). These data demonstrate that anti-TNFα treatment of active IBD rapidly enhances the frequency of functional Foxp3(+) Tregs in blood and potentiates their suppressive function. This indicates that Treg potentiation may represent an unanticipated outcome of anti-TNFα biotherapy in IBD.


Geotropism of hornet comb construction under persistent acceleration.
Social wasps (Vespinae) are insects which build in a precise geotactical orientation. The effect of persistent acceleration on comb construction by Oriental hornet (Vespa orientalis) workers was assessed experimentally within breeding boxes of various size and shape. Groups of hornets at the building phase were subjected to a centrifugal and gravitational force with a resultant ranging between 26 degrees and 45 degrees. The comb construction within such boxes was compared to that within control boxes under ordinary gravitational pull. It was found that: a) juvenile hornets (1-2 days of age) placed in quasi-rectangular boxes built in the direction of the resultant force; b) juvenile and adult hornets (3-7 days of age) placed in spherical shaped containers also built in the direction of the resultant force; c) adult hornets who had spent their first days of life in a stationary rectangular box, apparently learned the direction of the gravitational force and "tried" to build in this direction when exposed to a centrifugal force; d) adult hornets made to spin in quasi-rectangular boxes tilted in the direction of the calculated resultant force built in the direction of the resultant. These results suggest that hornets learn the direction of the gravitational force during the first days of life and that geometrical cues within the breeding box enable them to build in the direction of the force to which they have become habituated. From the standpoint of geometric cues, only the roof of the breeding box is of critical importance.


The Microscopic Mechanism and Rheological Properties of SBS-Modified Asphalt with Warm Mixing Fast-Melting.
To overcome the shortcomings of traditional wet styrene-butadiene-styrene (SBS) modification technology, such as its high energy consumption and thermal decomposition, a warm mix and fast-melting SBS modifier was developed. Based on the theory of rheology, a dynamic shear rheometer (DSR) was applied to investigate the viscoelastic properties of the warm mix and fast-melting SBS-modified asphalt using a frequency scanning test. Atomic force microscopy (AFM) was used to reveal the modification mechanism of the SBS-modified asphalt. An investigation of the thermal stability of the asphalt binder was conducted using a thermogravimetric test (TG). The results exhibited that the SBS-modified asphalt had good viscoelastic properties, as well as thermal stability. The "bee structure" of the SBS-modified asphalt was finer and more stable. In addition, the adhesion and the Derjaguin-Muller-Toporov (DMT) modulus of the SBS-modified asphalt at a warm mixing speed was higher than that of regular SBS-modified asphalt.


Chemoselective Reduction: Xanthates as Traceless Precursors of Polyfunctionalized α,α-Dichloroketones.
The use of BEt3·H2O has allowed the chemoselective reductive dexanthylation in the presence of the very fragile α,α-dichloroketone motif. This has solved a major hurdle in our approach to this important, but hitherto grossly understudied, family of compounds and opened access to a number of very useful synthetic transformations.


Do recurrences after paraesophageal hernia repair matter? : Ten-year follow-up after laparoscopic repair.
The recurrence rate for paraesophageal hernias (PEH) can be as high as 30% following laparoscopic repair. The aim of this study was to determine the severity of symptoms in patients with recurrences and the need for reoperation 10 years after surgery. Consecutive laparoscopic paraesophageal cases performed at a single institution between 1993 and 1996 were identified from the institution's foregut database. Patients were asked about the presence and severity of symptoms (heartburn, chest pain, regurgitation, and dysphagia). Patients were also asked whether they had (1) been diagnosed with hernia recurrence or (2) undergone repeat surgical intervention. Complete follow-up was obtainable in 31 of the total of 52 patients (60%). The proportion of patients reporting moderate/severe symptoms was less at 10 years than preoperatively: heartburn 12% versus 54% (p < 0.001), chest pain 9% versus 36% (p = 0.01), regurgitation 6% versus 50% (p < 0.001), and dysphagia 3% versus 30% (p = 0.001). Two patients underwent repeat surgical intervention for symptomatic recurrences within the first postoperative year. Eight more patients have been diagnosed with hernia recurrences on either contrast esophagram or upper endoscopy but had not required reoperation. At ten years, more patients with hernia recurrence had heartburn than those who did not have recurrences (60% versus 14%; p < 0.05). Despite a hiatal hernia recurrence rate of 32% 10 years after surgery, laparoscopic PEH was a successful procedure in the majority of patients; most remained symptomatically improved and required no further intervention 10 years after surgery.


A preliminary investigation into the control of trichostrongylosis in calves in Kenya.
A series of 3 grazing experiments was carried out to collect data relevant for designing techniques to prevent trichostrongylosis in dairy calves in Kenya. In the first experiment 1 week in/5 weeks out rotation was compared with set stocking. The results indicated that rotation is not an effective control measure. In the second experiment the effects of daily removal of faeces from the field were investigated. This practice also had a limited effect in controlling nematode infection in calves. The third experiment concentrated on the influence of nutrition level. It was shown that feeding level does affect the growth rate but its effect on the course of the egg output was not clear-cut. The results also indicated that the dry season greatly reduces herbage infestation.


Increase of serum angiopoietin-2 during pregnancy is suppressed in women with preeclampsia.
Numerous recent reports demonstrated that changes in serum levels of angiogenesis-related factors were associated with preeclampsia. Here, we determined the serum concentration of angiopoietin-2 (Ang-2), a natural antagonist of angiopoietin-1 (Ang-1) involved in promoting angiogenesis in the presence of angiogenic stimuli such as vascular endothelial growth factor (VEGF), in women with preeclampsia. The levels of serum Ang-2 and Tie-2, a receptor for Ang-1 expressed on endothelial cells, were determined by enzyme-linked immunosorbent assay. The concentrations of serum Ang-2 were significantly elevated in healthy pregnant women (18.9 ng/mL) as compared to nonpregnant women or women in postpartum period. Increase in the levels of serum Ang-2 was significantly suppressed in preeclamptic women (4.5 ng/mL). The serum Ang-2 concentrations inversely correlated with gestational age in healthy pregnant women, but not in preeclamptic women. The serum Ang-2 concentrations positively correlated with placental weight or mean blood pressure (BP) in healthy pregnant women, but not in preeclamptic women. The serum Ang-2 concentrations inversely correlated with proteinuria in preeclamptic women. The serum concentrations of Tie-2 were not significantly different between preeclamptic and nonpreeclamptic women. These results suggest the potential requirement of circulating Ang-2 in proper formation of placental vasculatures during pregnancy. Although we cannot exclude the possibility that suppression in the increase of serum Ang-2 levels during pregnancy in preeclampsia as a consequence rather than a cause, measurement of serum Ang-2 concentration in pregnant women may serve as a useful marker in the diagnosis and potentially in predicting subsequent development of preeclampsia.


PKA-mediated phosphorylation of Dexras1 suppresses iron trafficking by inhibiting S-nitrosylation.
Dexras1 is a small GTPase and plays a central role in neuronal iron trafficking. We have shown that stimulation of glutamate receptors activates neuronal nitric oxide synthase, leading to S-nitrosylation of Dexras1 and a physiological increase in iron uptake. Here we report that Dexras1 is phosphorylated by protein kinase A (PKA) on serine 253, leading to a suppression of iron influx. These effects were directly associated with the levels of S-nitrosylated Dexras1, whereby PKA activation reduced Dexras1 S-nitrosylation in a dose dependent manner. Moreover, we found that adiponectin modulates Dexras1 via PKA. Hence these findings suggest the involvement of the PKA pathway in modulating glutamate-mediated ROS in neurons, and hint to a functional crosstalk between S-nitrosylation and phosphorylation.


Expression of the calpain system is associated with poor clinical outcome in gastro-oesophageal adenocarcinomas.
Surgery is critical in the management of gastro-oesophageal cancer, and the addition of neo-adjuvant chemotherapy has proved to be of benefit. The calpain system has been implicated in tumour progression and response to various anti-cancer therapies, and therefore expression of the system was determined in this tumour type. Two cohorts of gastro-oesophageal adenocarcinomas were investigated for calpain-1, calpain-2, calpain-9 and calpastatin expression using conventional immunohistochemistry. 88 patients who received neo-adjuvant chemotherapy and 140 patients who received surgery alone were investigated using a tissue microarray approach. Calpain-1, calpain-2 and calpastatin expression was associated with adverse cancer-specific survival in the neo-adjuvant cohort (P = 0.004, P = 0.001 and P = 0.012 respectively); which remained significant in multivariate analysis (Hazard ratio (HR) = 0.337; 95% confidence interval (CI) = 0.140-0.81; P = 0.015, HR = 0.375; 95% CI = 0.165-0.858; P = 0.020 and HR = 0.481; 95% CI = 0.257-0.900; P = 0.022 respectively). Calpain-1 and calpastatin expression was also associated with adverse cancer specific survival in the primary surgery cohort (P = 0.001 and P = 0.013 respectively); which remained significant in multivariate analysis (HR = 0.309; 95% CI = 0.159-0.601; P = 0.001 and HR = 0.418; 95% CI = 0.205-0.850; P = 0.016 respectively). Calpain-9 expression was not associated with cancer-specific survival in the neo-adjuvant and primary surgery cohorts. Determining the expression levels of calpain-1, calpain-2 and calpastatin may provide clinically relevant prognostic information for gastro-oesophageal adenocarcinomas; these findings warrant further studies in larger cohorts of patients.


Impact of occurrence of cardiac arrest in the donor on long-term outcomes of pediatric heart transplantation.
The impact of cardiac arrest in the donor on long-term outcomes of pediatric heart transplantation has not been studied. The UNOS database was queried for primary pediatric heart transplantation (1999-2020). The cohort was divided into recipients who received a cardiac allograft from a donor who had a cardiac arrest (CA) versus a donor who did not (NCA). Univariable and multivariable analysis was done to compare recipient outcomes, followed by survival analysis using the Kaplan-Meier method. A total of 7300 patients underwent heart transplantation, of which 579 (7.9%) patients belonged to the CA group. The CA group was younger (median 3 vs. 5 years, p < .001), male (51% vs. 47%, p = .03), and smaller in weight (13 vs. 17 kg, p < .001) and height (101 vs. 109 cm, p < .001) than the NCA group. The groups were similar in recipient heart failure diagnosis and blood type. The CA donors were younger (3 vs. 6 years, p < .001) versus nonwhite (48% vs. 45%, p = .003) and died from drowning and asphyxiation compared to blunt injury and intracranial hemorrhage in the NCA group. The left-ventricular ejection fraction was similar between the groups. There was no difference in VAD and ECMO use before the transplant. The listing status, waitlist days, and allograft ischemic times were similar. Posttransplant morbidity such as stroke, dialysis, pacemaker implantation, and treated rejection were similar. Donor cardiac arrest (hazard ratio = 0.93, p = .5) was not an independent predictor of mortality on multivariable analysis. There was no survival difference even beyond 20 years of follow-up between the groups (p = .88). The occurrence of donor cardiac arrest has no impact on long-term survival in pediatric heart transplant recipients.


Single amino acid mutations block a late step in the folding of beta-lactamase from Staphylococcus aureus.
Two single amino acid mutant proteins of beta-lactamase PC1 from Staphylococcus aureus, P2 Thr40----Ile and P54 Asp146----Asn, have been investigated using urea-gradient polyacrylamide gel electrophoresis, circular dichroism and sedimentation velocity. Investigation of the folded states of the mutants has shown that compared to wild-type PC1 they are slightly more expanded, and have reduced aromatic circular dichroism, but the same content of secondary structure as PC1. The mutants exhibit fast refolding kinetics to the folded state, in contrast to PC1, which refolds only slowly. We conclude from these results that the folded mutants are in a state close to but distinct from the native state of PC1 and have certain properties in common with the compact intermediate in the folding of beta-lactamase. Therefore, these single amino acid substitutions result in a folding pathway blocked at a point located after collapse of the already folded structural units into a globular shape, and close to the final reshuffling step that leads to the native state of the wild-type enzyme.


Systematic review and meta-analysis of human Toll-like receptors genetic polymorphisms for susceptibility to tuberculosis infection.
Epidemiological data from the world health organization (WHO) show that Globally an estimated 10 million (range, 8.9-11.0 million) people around the world were infected with TB in 2019. M.tuberculosis (M.tb) is the major cause of tuberculosis. Infection with M.tb has varied host immune responses because of the host genetic factor and its response to the infection. Genetic polymorphism in TLRs imparts susceptibility or resistance to the host against several diseases. In the present study, a systematic review and meta-analysis were performed to describe the relationship among various TLRs and SNPs involved in M.tb infection and their association with susceptibility to pulmonary tuberculosis in various populations of the world. PubMed and Scihub databases from 2008 to 2019 were searched and 58 articles were shortlisted for the present study to explore the association between TLRs gene polymorphisms and susceptibility to tuberculosis infection. The combined analysis showed that the polymorphisms TLR1 (rs5743618), TLR1 (rs4833095), TLR2 (-196 to -174) del, TLR2 (rs3804099), TLR4 (rs4986790), TLR4 (rs4986791), TLR4 (rs7873784), TLR6 (rs5743810), TLR8 (rs3764880), TLR9 (rs5743836), TLR9 (rs352139) were significantly associated with TB disease in certain ethnic population. In our meta-analysis study, we have also found variations between studies in some polymorphism, for example. The TLR1 (rs 5743618), TLR2 (rs5743708), TLR4 Asp299Gly, TLR4 Thr399Ile, TLR4 (rs7873784), TLR6 (rs5743810), TLR9 (rs5743836) was associated with the protection against TB. Meta-analysis was performed between polymorphisms and pulmonary tuberculosis to define increase or decrease in susceptibility to tuberculosis in various populations, which indicated that a relationship exists between SNPs/host genetic factors and susceptibility or resistance in patients suffering from pulmonary tuberculosis our finding concludes that this gene polymorphism may be associated with susceptibility to TB. The present study adds value to the various researches and studies going on various populations of the world in better understanding the role of TLR polymorphism in TB.


Screening of integrins localized on the surface of human epidermal melanocytes.
In vivo, melanocytes occupy three-dimensional (3D) space. Nevertheless, most experiments involving melanocytes are performed in a two-dimensional microenvironment, resulting in difficulty obtaining accurate results. Therefore, it is necessary to construct an artificial in vivo-like 3D microenvironment. Here, as a step towards engineering a precisely defined acellular 3D microenvironment supporting the maintenance of human epidermal melanocytes (HEMs), we examined the types of integrin heterodimers that are expressed transcriptionally, translationally, and functionally in HEMs. Real-time PCR and fluorescent immunoassay analyses were used to elucidate the expression of integrin α and β subunit genes at the transcriptional and translational levels, respectively. The functionality of the presumed integrin heterodimers was confirmed using attachment and antibody-inhibition assays. Among the genes encoding 12 integrin subunits (α1, α2, α3, α4, α5, α6, α7, αV, β1, β3, β5, and β8) showing significantly higher transcription levels, proteins translated from the integrin α2, α4, α5, β1, β3, and β5 subunit genes were detected on the surface of HEMs. These HEMs showed significantly increased adhesion to collagen I, fibronectin, laminin, and vitronectin, and functional blockade of the integrin α2 subunits significantly inhibited adhesion to collagen I, fibronectin, and laminin. In addition, there was no significant inhibition of the adhesion to fibronectin or vitronectin in HEMs with functional blockade of the integrin α4, α5, or αV subunits. These results indicate that the active integrin α2β1 heterodimer and the inactive integrin α4, α5, αV, β3, and β5 subunits are all localized on the surface of HEMs.


Incidence of Femoroacetabular Impingement and Surgical Management Trends Over Time.
Femoroacetabular impingement (FAI) is a well-known cause of hip pain in adolescents and young adults. However, the incidence in the general population has not been clearly defined. To (1) define the population-based incidence of diagnosis of FAI in patients with hip pain, (2) report the trends in diagnosis of FAI over time, and (3) determine the changes in the rate and type of surgical management over time. Cohort study; Level of evidence, 3. A geographic database was used to identify patients who were 14 to 50 years old with hip pain between the years 2000 and 2016. Chart and radiographic review was performed to determine which patients had FAI. To be included, patients had to have a triad of clinical symptoms, physical examination signs, and imaging findings consistent with FAI. Medical records were reviewed to obtain demographic information, clinical history, physical examination findings, imaging details, and treatment details. Statistical analysis determined the overall age- and sex-adjusted annual incidence of FAI diagnosis and trends over time. There were 1893 patients evaluated with hip pain, and 716 (38%; 813 hips) had diagnosed FAI. The mean ± SD age was 27.2 ± 8.4 years, and 67% were female. The incidence of FAI diagnosis was 54.4 per 100,000 person-years. Female patients had a higher incidence than male patients (73.2 vs 36.1 per 100,000 person-years; P < .01). Incidence of FAI diagnosis were higher from 2010 to 2016 (72.6 per 100,000 person-years; P < .01) as compared with 2005 to 2009 (45.3) and 2000 to 2004 (40.3). Hip arthroscopy, surgical hip dislocation, and periacetabular osteotomy utilization increased from the 2000-2004 to 2010-2016 periods, respectively: 1 (1%) to 160 (20%; P = .04), 2 (1%) to 37 (5%; P = .01), and 1 (1%) to 22 (3%; P = .58). The overall incidence of FAI diagnosis was 54.4 per 100,000 person-years, and it consistently increased between 2000 and 2016. Female patients had a higher incidence than male patients. The utilization of joint preservation operations, including hip arthroscopy, surgical hip dislocation, and anteverting periacetabular osteotomy, increased over time.


Acute Kidney Injury in the Inpatient and Outpatient Setting.
The incidence and prevalence of inpatient acute kidney injury is continuing to increase. Acute kidney injury (AKI) is an all-encompassing topic in renal care as well as critical care. The definition and criteria for diagnosis of AKI have evolved over time. There are many causes of AKI and identifying the cause is key in reversing and controlling the progression of disease. Metabolic acidosis, fluid overload, and sepsis require detailed evaluation to best provide the most appropriate plan and execution. Critical care nurses are vitally important when identifying and managing acute kidney injury. Renal replacement therapy is a remarkable tool that requires expertise from the critical nurse. Once it is mastered, the most vulnerable patient in the ICU can become the recipient of good and positive outcomes.


Acting on voices: Omnipotence, sources of threat, and safety-seeking behaviours.
Previous research indicates that beliefs about voice power and omnipotence are associated with distress, depression, and compliance. The present study investigates whether acting on voices to mitigate perceived threat, in a broader sense than compliance, is driven by delusional beliefs, as the Chadwick, Birchwood, and Trower cognitive-behavioural model of voices would suggest. The role of safety behaviours in maintaining beliefs about voice omnipotence and distress is also examined. A cross-sectional investigation of 30 individuals with current experience of auditory verbal hallucinations was conducted. Participants were assessed on self-report measures of voice topography, voice-related threat and distress, safety behaviour use, beliefs about voices, and depression and anxiety. Three sources of threat were identified: physical harm, shame, and loss of control. Twenty-six individuals had recently used safety behaviours, believing them to be effective in threat reduction. The degree of safety behaviour use and voice-related distress were associated with voice omnipotence beliefs; mood or voice characteristics did not account for this relationship. The association of safety behaviours with increased distress was mediated by beliefs about voice omnipotence. Acting on voices can be conceptualized as a form of safety seeking, associated with maintaining beliefs about voice omnipotence and distress.


Space, time and nature: exploring the public reception of biotechnology in New Zealand.
Nature is widely acknowledged to be a fluid, contested, material-semiotic construction, historically and spatially grounded. This is certainly the case for New Zealand, where a number of constructions of nature have been mobilized as a means to make judgements over the viability of particular biotechnologies that have entered into public debate. In this paper, we utilize Mikhail Bakhtin's space-time matrix, the chronotope, to explore a series of complementary nature-narratives that have been mobilized as a moral basis for making judgments over the acceptability of a series of exemplars of novel biotechnologies that were presented to participants in eleven national focus groups. We argue that it is the specific space-time manipulations that characterize these sometimes overlapping narrative constructions that are used to justify reactions to novel biotechnologies.


High-sensitivity imaging and quantification of intratumoral distributions of gold nanoparticles using a benchtop x-ray fluorescence imaging system.
A high-sensitivity benchtop x-ray fluorescence (XRF) imaging system, based on a high-power x-ray source and silicon drift detector, has been developed. This system allows gold L-shell XRF-based quantitative imaging of gold nanoparticles (GNPs) at concentrations as low as 0.007 mg/cm3 (7 ppm) in biological tissues/water. Its capability for biomedical applications was demonstrated by imaging the GNP distribution within a small (∼12×11×2 mm3) ex vivo sample (extracted from a murine tumor after intravenous GNP administration). The results suggest direct translatability for routine preclinical ex vivo imaging tasks involving GNPs, as well as the possibility for in vivo imaging of small/superficial animal tumors.


Phase II study of figitumumab in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: clinical activity and molecular response (GORTEC 2008-02).
Preclinical studies suggest that insulin-like growth factor-1 receptor (IGF-1R) blockage could be a promising therapeutic target in squamous cell carcinoma of the head and neck (SCCHN). Therefore, we investigated the efficacy and toxicity of figitumumab, an anti-IGF-1R monoclonal antibody, in palliative SCCHN. Patients with palliative SCCHN progressing after platinum-based therapy were treated with figitumumab i.v. 20 mg/kg, every 3 weeks. The primary end point was the disease control rate at 6-8 weeks after treatment initiation. Tumor biopsies and plasma samples were collected before and after figitumumab administration to monitor the molecular response. Seventeen patients were included. Only two patients achieved stable disease at 6-8 weeks. Median overall survival and progression-free survival were 63 and 52 days, respectively. The main grade 3-4 adverse event was hyperglycemia (41%). Translational research showed that figitumumab downregulated IGF-1R at the surface of tumor cells with activation of the epidermal growth factor receptor (EGFR) pathway, as shown by the upregulation of p-EGFR in tumor cells (P=0.016), and an increase in the plasma level of tumor growth factor-alpha (P=0.006). Figitumumab monotherapy has no clinically significant activity in unselected palliative SCCHN.


Hormonal regulation of fatty acid synthetase, acetyl-CoA carboxylase and fatty acid synthesis in mammalian adipose tissue and liver.
The major objectives of this study were to define the roles of adrenal glucocorticoids and glucagon in the long-term regulation of fatty acid synthetase and acetyl-CoA carboxylase of mammalian adipose tissue and liver. Particular emphasis was given to elucidation of the mechanisms whereby these hormones produce their regulatory effects on enzymatic activity. To dissociate mental manipulation, nutritional conditions were ridgidly controlled in the experiments described. Administration of glucocorticoids to adult rats led to a marked reductionin activities of fatty acid synthetase and carboxylase in adipose in adipose tissue but no change occurred in liver. Adrenalectomy produced an increase in activities of these lipogenic enzymes in adipose tissure, but, again, no change was noted in liver. The decrease in enzymatic activities in adipose tissue with glucocorticoid administration correlated well with a decrease in fatty acid synthesis, determined in vivo by the 3-H2O method. The mechanisms whereby glucocorticoids led to a decrease in fatty acid synthetase activity were elucidated by the use of immunochemical techniques. Thus, the decrease in fatty acid synthetase activity observed in adipose tissue was shown to reflect a decrease in content of enzyme, and not a change in catalytic efficiency. The mechanism underlying the decrease in enzyme content is a decrease in synthesis of the enzyme. The relation of the effects of glucocorticoids to the effects of certain other hormones involved in regulation of lipogenesis was investigated in hypophysectomized and in diabetic animals. Thus, the observation that the glucocorticoid effect on synthetase and carboxylase occurred in adipose tissue of hypophysectomized rats indicated that alterations in levels of other pituitary-regulated hormones were not necessary for the effect. That glucocorticoids play some role in regulation of synthetase and carboxylase in liver, at lease in the diabetic state, was shown by the observation that the low activities of these enzymes in diabetic animals could be restored to normal by adrenalectomy. An even more pronounced restorative effect was apparent in adipose tissue of adrenalectomized, diabetic animals. Administration of glucagon during the refeeding of starved rats resulted in a marked reduction in the induction of fatty acid synthetase, acetyl-CoA carboxylase and in the rate of incorporation of 3-H from 3-H2O into fatty acids in liver, but no change in these parameters occurred in adipose tissue. Administration of theophylline resulted in intermediate reduction in liver. The mechanisms whereby glucagon led tto a decrease in fatty acid synthetase activity were elucidated by the use of immunochemical techniques. Thus, the changes in fatty acid synthetase activity were shown to reflect reductions in content of enzyme. The mechanism underlying these reductions in content is reduced synthesis of enzyme.


Reproductive and behavioural risk factors of low birth weight among newborns in Al Thawra Hospital, Sana'a, Yemen.
Low birth weight can lead to infant death, especially during the first year of life. To assess risk factors related to low birth weight babies in Sana'a, Yemen. We conducted an unmatched case-control study of 252 women who came for delivery at Al Thawra Hospital, Sana'a, Yemen, between August and October 2016. Significant risk factors for low birth weight were: birth interval < 2 years; history of pre-eclampsia during current pregnancy; preterm gestational age < 37 weeks; and khat chewing or smoking during pregnancy. After controlling for all the confounders, only birth interval < 2 years was significantly associated with low birth weight. Shorter birth interval is an important risk factor for low birth weight; therefore, improving maternal awareness of this should be emphasized during postnatal follow-up.


Rapid component I(Kr) of the guinea-pig cardiac delayed rectifier K(+) current is inhibited by beta(1)-adrenoreceptor activation, via cAMP/protein kinase A-dependent pathways.
The antiarrhythmic potential of betablockers contributes to their beneficial effects in the treatment of cardiac diseases, although the molecular basis of their class II antiarrhythmic action has not been clarified yet. To investigate a putative functional link between beta-adrenoreceptors and the fast component of cardiac delayed rectifier K(+) channels (I(Kr)), whole-cell patch-clamp experiments were performed with isolated guinea-pig ventricular myocytes. Tail currents of I(Kr) were measured at -40 mV after short (200 ms) test pulses to +40 mV. After application of the unspecific beta-receptor agonist isoproterenol (10 microM) for 12 min, the I(Kr) tail current was decreased by 72%, with an IC(50) of 1.4 microM. The specific beta(1)-blocker CGP207120A (10 microM) significantly attenuated the isoproterenol effect (net 24% decrease). The specific beta(1)-agonist xamoterol (10 microM), could mimic the isoproterenol effect (58% decrease). Modulators of beta(2)- or beta(3)-adrenoreceptors were far less effective. When isoproterenol or xamoterol were combined with KT5720 (2.5 microM), a specific inhibitor of protein kinase A (PKA), their effects were drastically reduced, indicating that PKA presumably mediates the beta(1)-adrenergic inhibition of I(Kr). Tail current reductions by cAMP, forskolin, PKA catalytic subunit and a combination of PKA holoenzyme and cAMP support an involvement of PKA in the regulation of I(Kr). The functional link between I(Kr) and the beta(1)-adrenergic receptor involving PKA may play an important role in arrhythmogenesis and contribute to the antiarrhythmic action of clinically used beta(1)-blockers.


The role of imidazole and benzimidazole heterocycles in Chagas disease: A review.
The haemoflagellate protozoan Trypanosoma cruzi (T. cruzi) is the causative agent of Chagas disease (CD), a potentially life-threatening disease. Little by little, remarkable progress has been achieved against CD, although it is still not enough. In the absence of effective chemotherapy, many research groups, organizations and pharmaceutical companies have focused their efforts on the search for compounds that could become viable drugs against CD. Within the wide variety of reported derivatives, this review summarizes and provides a global vision of the situation of those compounds that include broadly studied heterocycles in their structures due to their applications in medicinal chemistry: imidazole and benzimidazole rings. Therefore, the intention of this work is to present a compilation, as much as possible, of all the reported information, regarding these imidazole and benzimidazole derivatives against T. cruzi, as a starting point for future researchers in this field.


Adoptive immunotherapy for posttransplantation viral infections.
Viral diseases are a major cause of morbidity and mortality after hemopoietic stem cell transplantation. Because viral complications in these patients are clearly associated with the lack of recovery of virus-specific cellular immune responses, reconstitution of the host with in vitro expanded cytotoxic T lymphocytes is a potential approach to prevent and treat these diseases. Initial clinical studies of cytomegalovirus and Epstein-Barr virus in human stem cell transplant patients have shown that adoptively transferred donor-derived virus-specific T cells may restore protective immunity and control established infections. Preclinical studies are evaluating this approach for other viruses while strategies for generating T cells specific for multiple viruses to provide broader protection are being evaluated in clinical trials. The use of genetically modified T cells or the use of newer suicide genes may result in improved safety and efficacy.


Using spatial tracking with magnetic resonance imaging/ultrasound-guided biopsy to identify unilateral prostate cancer.
To create reliable predictive metrics of unilateral disease using spatial tracking from a fusion device, thereby improving patient selection for hemi-gland ablation of prostate cancer. We identified patients who received magnetic resonance imaging (MRI)/ultrasound-guided biopsy and radical prostatectomy at a single institution between 2011 and 2018. In addition to standard clinical features, we extracted quantitative features related to biopsy core and MRI target locations predictive of tumour unilaterality. Classification and Regression Tree (CART) analysis was used to create a decision tree (DT) for identifying cancer laterality. We evaluated concordance of model-determined laterality with final surgical pathology. A total of 173 patients were identified with biopsy coordinates and surgical pathology available. Based on CART analysis, in addition to biopsy- and MRI-confirmed disease unilaterality, patients should be further screened for cancer detected within 7 mm of midline in a 40 mL prostate, which equates to the central third of any-sized prostate by radius. The area under the curve for this DT was 0.82. Standard diagnostics and the DT correctly identified disease laterality in 73% and 80% of patients, respectively (P = 0.13). Of the patients identified as unilateral by standard diagnostics, 47% had undetected contralateral disease or were otherwise incorrectly identified. This error rate was reduced to 17% (P = 0.01) with the DT. Using spatial tracking from fusion devices, a DT was more reliable for identifying laterality of prostate cancer compared to standard diagnostics. Patients with cancer detected within the central third of the prostate by radius are poor hemi-gland ablation candidates due to the risk of midline extension of tumour.