Symptom complexes in patients with seropositive arthralgia and in patients newly diagnosed with rheumatoid arthritis: a qualitative exploration of symptom development.
The aim of this study was to explore symptoms and symptom development during the earliest phases of RA in patients with seropositive arthralgia and patients newly diagnosed with RA. Interviews were conducted with 15 seropositive patients (anti-CCP positive, and often with arthralgia) and 11 newly presenting RA patients [classified according to the 2010 ACR/European League Against Rheumatism (EULAR) criteria]. Feedback procedures shared the experiences of seropositive arthralgia patients with early RA patients and vice versa. Data were analysed using thematic analysis. Symptoms common to both groups included joint pain, psychological distress, muscle cramps, abnormal skin sensations, stiffness, loss of motor control, weakness, fatigue and sleeping difficulties. Also, patterns of symptom evolution and the order of symptom development were described. Seropositive arthralgia patients described pain as annoying, while RA patients described how the severity of pain intensified before diagnosis, to the point where symptoms were psychologically distressing. Patients with seropositive arthralgia described reddening of the skin and burning sensations that they felt were indicative of the onset of swelling. Intense pain appeared to precede the onset of swelling for those with RA, which was often palindromic and travelled between joints until it later became persistent. This study highlights the breadth of symptoms that constitute the earliest phases of RA. Further research is needed to develop measures of symptom patterns and clusters to allow the predictive utility of symptoms to be assessed and to allow the integration of aspects of the patient's history into evidence-based investigative and management algorithms for use in primary and secondary care.


Implications of low mechanical impedance in upper limb reaching motion.
The equilibrium point hypothesis (EPH), much discussed in recent years, is central in a class of theories that posits an important role for muscular mechanical and reflex properties in the control of voluntary movement. We review briefly the findings of our studies testing the idea of equifinality, a major tenet of the EPH, which predicts that terminal limb position will be achieved regardless of transient perturbations in initial position or during ongoing movement. Our observations do not support this prediction of equifinality. We also report our findings that joint viscosity and elastic stiffness estimated during ballistic motion are unexpectedly low, limiting their potential contributions to the regulation either of limb movement trajectory or of limb stability. Taken together, our results imply that neuromuscular mechanical properties are unlikely to be used for regulating voluntary motion, and that other control strategies, most notably the use of feedforward controllers in which muscles act as force generators acting primarily on inertial loads, are more consistent with our observations.


Personal experience in the treatment of seropositive rheumatoid arthritis with drugs used in combination.
Drug therapy for seropositive rheumatoid arthritis (RA) is entirely empiric. Single agents often fail to control synovial inflammation adequately. Combination therapy with relatively small doses of several agents shown to be effective in controlled trials when used alone often produce sustained and marked therapeutic control. Adverse effects are frequent but probably are no greater than those associated with the use of an effective dose of a single agent. As in the treatment of malignancy or tuberculosis, the use of potent drugs in combination may prevent or delay the clonal expansion of resistant cells. If this is indeed the case in the treatment of RA, then consideration should be given to the routine use of drug combinations. It is conceivable that we do patients a disservice by using potentially valuable drugs sequentially rather than in tandem. Whatever its merits, combination drug therapy for seropositive RA is clearly a stopgap measure whose usefulness will end as more specific means of controlling joint inflammation become available.


Imaging biomarkers are underutilised but highly predictive prognostic factors for the more fatal breast cancer subtypes.
The development and refinement of breast imaging modalities offer a wealth of diagnostic information such as imaging biomarkers, which are primarily the mammographic appearance of the various breast cancer subtypes. These are readily available preoperatively at the time of diagnosis and can enhance the prognostic value of currently used molecular biomarkers. In this study, we investigated the relative utility of the molecular and imaging biomarkers, both jointly and independently, when predicting long-term patient outcome according to the site of tumour origin. We evaluated the association of imaging biomarkers and conventional molecular biomarkers, (ER, PR, HER-2, Ki67), separately and combined, with long-term patient outcome in all breast cancer cases having complete data on both imaging and molecular biomarkers (n = 2236) diagnosed in our Institute during the period 2008-2019. Large format histopathology technique was used to document intra- and intertumoural heterogeneity and select the appropriate foci for evaluating molecular biomarkers. The breast cancer imaging biomarkers were strongly predictive of long-term patient outcome. The molecular biomarkers were predictive of outcome only for unifocal acinar adenocarcinoma of the breast (AAB), but less reliable in the multifocal AAB cases due to variability of molecular biomarkers in the individual tumour foci. In breast cancer of mesenchymal origin (BCMO), conventionally termed classic invasive lobular carcinoma, and in cancers originating from the major lactiferous ducts (ductal adenocarcinoma of the breast, DAB), the molecular biomarkers misleadingly indicated favourable prognosis, whereas the imaging biomarkers in BCMO and DAB reliably indicated the high risk of breast cancer death. Among the 2236 breast cancer cases, BCMO and DAB comprised 21% of the breast cancer cases, but accounted for 45% of the breast cancer deaths. Integration of imaging biomarkers into the diagnostic workup of breast cancer yields a more precise, comprehensive and prognostically accurate diagnostic report. This is particularly necessary in multifocal AAB cases having intertumoural heterogeneity, in diffuse carcinomas (DAB and BCMO), and in cases with combined DAB and AAB. In such cases, the imaging biomarkers should be prioritised over molecular biomarkers in planning treatment because the latter fail to predict the severity of the disease. In combination with the use of the large section histopathology technique, imaging biomarkers help alleviate some of the current problems in breast cancer management, such as over- and under-assessment of disease extent, which carry the risk of overtreatment and undertreatment.


Olivanic acids, a family of beta-lactam antibiotics with beta-lactamase inhibitory properties produced by Streptomyces species. II. Isolation and characterisation of the olivanic acids MM 4550, MM 13902 and MM 17880 from Streptomyces olivaceus.
The olivanic acids MM 4550, MM 13902 and MM 17880 are members of a new family of beta-lactam antibiotics. An isolation and purification process utilising ion-par extraction and ion-exchange chromatography is described and the metabolites are characterised by physico-chemical and biological properties.


The association between Patient Assessment of Chronic Illness Care Scores and quality of life in type 2 diabetes patients.
Chronic illness care is an important factor for health promotion in diabetes since it affects health outcomes such as quality of life. The aim of this study was to investigate the relationship between the Patient Assessment of Chronic Illness Care and the quality of life in type 2 diabetes patients. The study used a cross-sectional and correlational design. The sample included 317 patients with type 2 diabetes. A socio-demographic and disease-related questionnaire form, the Patient Assessment of Chronic Illness Care (PACIC) scale and the WHOQOL-BREF Quality of Life Scale were used to collect data. According to the regression analysis, the stronger predictor affecting all domains of quality of life was the overall PACIC. This study demonstrated the importance of satisfaction level of chronic illness care in the improvement of quality of life. Therefore, the factors affecting the satisfaction level with chronic care services should be determined to improve the quality of life of patients. In addition, healthcare based on the chronic-care model should be provided in the care of the patients. PACIC had an important effect on quality of life of the patients. This study demonstrated the importance of satisfaction level on chronic illness care in the improvement of quality of life.


Ecological inferences about marine mammals from passive acoustic data.
Monitoring on the basis of sound recordings, or passive acoustic monitoring, can complement or serve as an alternative to real-time visual or aural monitoring of marine mammals and other animals by human observers. Passive acoustic data can support the estimation of common, individual-level ecological metrics, such as presence, detection-weighted occupancy, abundance and density, population viability and structure, and behaviour. Passive acoustic data also can support estimation of some community-level metrics, such as species richness and composition. The feasibility of estimation and certainty of estimates is highly context dependent, and understanding the factors that affect the reliability of measurements is useful for those considering whether to use passive acoustic data. Here, we review basic concepts and methods of passive acoustic sampling in marine systems that often are applicable to marine mammal research and conservation. Our ultimate aim is to facilitate collaboration among ecologists, bioacousticians, and data analysts. Ecological applications of passive acoustics require one to make decisions about sampling design, which in turn requires consideration of sound propagation, sampling of signals, and data storage. One also must make decisions about signal detection and classification and evaluation of the performance of algorithms for these tasks. Investment in the research and development of systems that automate detection and classification, including machine learning, are increasing. Passive acoustic monitoring is more reliable for detection of species presence than for estimation of other species-level metrics. Use of passive acoustic monitoring to distinguish among individual animals remains difficult. However, information about detection probability, vocalisation or cue rate, and relations between vocalisations and the number and behaviour of animals increases the feasibility of estimating abundance or density. Most sensor deployments are fixed in space or are sporadic, making temporal turnover in species composition more tractable to estimate than spatial turnover. Collaborations between acousticians and ecologists are most likely to be successful and rewarding when all partners critically examine and share a fundamental understanding of the target variables, sampling process, and analytical methods.


Bilateral anterior minithoracotomy with video assistance for lung volume reduction surgery and pulmonary metastasectomy.
Incisional access to pulmonary pathology involving both lungs has often involved bilateral standard thoracotomies, median sternotomy, and, recently, sequential lateral video-assisted thoracic surgical approaches. Significant problems are inherent to each of these approaches. We introduce a hybrid technique of bilateral simultaneous minithoracotomy with video assistance as an alternative to these other surgical approaches.


Exporters' risk perceptions during covid times: a study with Colombian and Brazilian SMEs.
The present study aims to provide an initial highlight on risk perceptions of exporting SMEs from Latin America during the covid-19 pandemic. A sample of Colombian and Brazilian companies was analyzed using 24 scenarios based on 8 risk types: contamination risk, exchange rate risk, trade risks, logistics and operations risks, risk of policy and regulation changes, credit risk, supplier-related risks, buyer-related risks and employee-related risks. Results show significant differences between countries as well as a highly distinction between 2020 and 2021 perceptions of threat, impact, loss, and likelihood.


Primer: SNP-associated studies and what they can teach us.
Single-nucleotide polymorphisms (SNPs) are single base-pair alterations in the DNA sequence that represent a major source of genetic heterogeneity. Well-developed and sophisticated technologies exist to measure and analyze the presence of SNPs, and SNP genotyping is an important tool with which to investigate other genetic variants. SNP-based, large-scale, genome-wide association studies are detecting many polymorphisms that can be used to evaluate the risk of various common traits, including rheumatic diseases. This increased knowledge of genetic risk could potentially be used to refine medical care in rheumatology clinics in the near future.


Contemporary and future strategies in polycythemia vera.
Polycythemia vera (PV) is characterized by clonal proliferation of a hematopoietic stem cell leading to erythrocytosis. Patients with PV have significantly higher morbidity and mortality compared to the general population due to increased risk of thrombosis, hemorrhage, and well-characterized microvascular and constitutional symptoms. There is also a propensity to transform to myelofibrosis and to an aggressive form of acute leukemia, further increasing morbidity and mortality. Current management is aimed at reducing the risk of thromboembolic events and improving symptom burden; however, none of the existing therapies have proven the ability to deplete the underlying malignant clone, or definitively reduce the risk of disease, progression leaving a large area of unmet need. In this review, we highlight the pathophysiology of PV, current management and limitations therein. We propose highly debated clinical practices that require further investigation. We conclude by discussing therapies in development and how these may fill unmet needs and be incorporated into the future PV treatment paradigm.


Macrophages and not granulocytes are involved in cervical ripening.
To clarify the role of leucocytes in human cervical ripening and dilatation, cervical biopsies were obtained from six non-pregnant women, eight women undergoing early termination of pregnancy, 18 pregnant women undergoing elective Caesarean section at term (both with and without a ripe cervix as determined by Bishop score) and 11 women after term vaginal delivery. Leucocytes were localised by immunohistochemistry labelling and quantified in subepithelial and deep stromal areas. CD45+ leucocytes were more numerous in the subepithelial area of the cervix than in the deep stroma in all groups (P<0.01). CD14+ macrophages and CD15+ granulocytes were increased in both the subepithelial and deep stromal areas only in the vaginal delivery group (P<0.01). The number of macrophages in the ripening cervix (Bishop score above 4) was higher than in the unripe cervix (Bishop score 4 or less; P<0.05) with no differences in other leucocyte populations. CD3+ CD8+ T cells in the subepithelial area were reduced in late pregnancy and after vaginal delivery (P<0.01), but showed no relationship to Bishop score. Macrophages and granulocytes may be involved in the process of cervical dilatation, but macrophage infiltration into the ripening cervix before labour suggests their role in the ripening process. Reduced numbers of CD3+ CD8+ T-lymphocytes in late pregnancy and after vaginal delivery suggests that local immunity is down-regulated in the late pregnancy period. Regional differences in leucocyte subpopulations in the cervix indicate that leucocyte infiltration is likely to be regulated by local factors.


Femoral neuropathy due to compression by retroperitoneal haemorrhage: a modern evaluation.
We report a case of femoral neuropathy due to retroperitoneal haemorrhage occurring during the administration of heaprin. The site of the hematoma is illustrated in the CT scan. It is emphasised that the modern assessment of peripheral neuropathies in the lower limbs associated with retroperitoneal haemorrhage by means of CT scan will promote our understanding of the natural history of this condition.


Nonspecific psychological distress, psychosocial stressors and delusional psychosis. A comparison with psychiatrically symptom free surgical controls.
The purpose of the study was to examine patients with delusional psychosis regarding characteristic personality traits as illustrated by nonspecific psychological distress, and psychosocial stress prior to onset of the psychosis. The design of the study was a comparison of first-admitted psychiatric patients with delusional psychosis and psychiatrically symptom free surgical controls. Patients with delusional psychosis reported significantly more psychosocial stress than controls during the 3 months prior to admission. They also reported significantly higher mean values than controls on the subscales named poor self-esteem, helplessness-hopelessness, dread, sadness, anxiety and approval of rule breaking on the schedule of nonspecific psychological distress. In discriminating patients with delusional psychosis and surgical controls, approval of rule breaking, helplessness-hopelessness, and severity of psychosocial stressors were the most informative variables. Patients with delusional psychosis will be followed up in order to analyze if nonspecific psychological distress and psychosocial stressors are of importance for the prediction of the course and the outcome.


The use of a peritoneal catheter for the irrigating system in arthroscopy: a better system for accurate diagnosis.
The use of a peritoneal catheter enhances diagnosis using arthroscopy by affording a clear visibility of the knee joint. The accuracy in diagnosis is significantly enhanced using this method of irrigation. No better method of irrigation is available for cases of acute knee joint injuries.


Recombinant retroviruses encoding human papillomavirus type 18 E6 and E7 genes stimulate proliferation and delay differentiation of human keratinocytes early after infection.
Human papillomavirus (HPV) DNAs are detected in most genital dysplasias and cancers, suggesting that these viruses perturb epithelial growth and differentiation. The E6 and E7 genes of HPV type 18 induce immortality in keratinocytes cultured from genital tract epithelia, and the immortal cell lines display aberrant squamous differentiation. To examine whether the E6 and E7 proteins directly alter keratinocyte growth and differentiation, high-titer recombinant retroviruses were constructed for efficient transfer and expression of HPV-18 genes E6, E6* and E7 in cultures of normal human keratinocytes. Infection with retroviruses encoding E6 and E7 stimulated cell proliferation, reduced the requirement for bovine pituitary extract and induced immortality. E6 and E7 also delayed but did not prevent the onset of terminal squamous differentiation. The magnitude of effects on growth and differentiation of cultured cells was directly related to levels of E7 protein expression. Thus, expression of the HPV-18 E6 and E7 genes stimulates cell proliferation and delays differentiation of keratinocytes in vitro.


Religion and bioethics: toward an expanded understanding.
Before asking what U.S. bioethics might learn from a more comprehensive and more nuanced understanding of Islamic religion, history, and culture, a prior question is, how should bioethics think about religion? Two sets of commonly held assumptions impede further progress and insight. The first involves what "religion" means and how one should study it. The second is a prominent philosophical view of the role of religion in a diverse, democratic society. To move beyond these assumptions, it helps to view religion as lived experience as well as a body of doctrine and to see that religious differences and controversies should be welcomed in the public square of a diverse democratic society rather than merely tolerated.


Using response models to study coding strategies in monkey visual cortex.
Usually the conditional probabilities needed to calculate transmitted information are estimated directly from empirically measured distributions. Here we show that an explicit model of the relation between response strength (here, spike count) and its variability allows accurate estimates of transmitted information. This method of estimating information is reliable for data sets with nine or more trials per stimulus. We assume that the model characterizes all response distributions, whether observed in a given experiment or not. All stimuli eliciting the same response are considered equivalent. This allows us to calculate the channel capacity, the maximum information that a neuron can transmit given the variability with which it sends signals. Channel capacity is uniquely defined, thus avoiding the difficulty of knowing whether the 'right' stimulus set has been chosen in a particular experiment. Channel capacity increases with increasing dynamic range and decreases as the variance of the signal (noise) increases. Neurons in V1 send more variable signals in a wide dynamic range of spike counts, while neurons in IT send less variable signals in a narrower dynamic range. Nonetheless, neurons in the two areas have similar channel capacities. This suggests that variance is being traded off against dynamic range in coding.


Does rectal washout during anterior resection prevent local tumor recurrence?
Colorectal cancer is one of the leading causes of cancer deaths in the industrialized nations. Left-sided tumors, especially rectal, rectosigmoid, and sigmoid, account for more than half of these tumors. Among many colorectal surgeons, the practice of rectal washout with cytocidal agents before anastomosis is common. It is widely believed that this practice prevents implantation of free malignant cells. It is unclear whether this translates into a reduction in the incidence of local recurrence. This study was designed to evaluate the effectiveness of cytocidal rectal washout in reducing the incidence of local recurrence. Case notes and histology reports of all patients who underwent curative anterior resection for adenocarcinoma of the rectum and rectosigmoid between 1992 and 1994 were reviewed. A total of 141 patients were deemed suitable for the study. Of these, 90 patients underwent rectal washout using cetrimide before anastomosis. Fifty-one patients did not have rectal washout before anastomosis. Local recurrences between the two groups were compared. The two study groups were identical in all respects. Overall, the local recurrence rate for all comers was 5 percent (n = 7). Among the washout group, the local recurrence rate was 4.4 percent (n = 4) compared with 5.9 percent (n = 3) among the no washout group. Because of the size of the study, we were unable to demonstrate the benefit or lack thereof of cytocidal agents in reducing local recurrence.


Conservative management of high-flow priapism.
High-flow priapism most frequently occurs as a result of penile trauma with subsequent unchecked arterial flow into the corpora cavernosa. An improved understanding of its underlying pathophysiology has allowed a more selective therapeutic approach, usually with preservation of potency. We report on 4 cases of traumatic high-flow priapism seen over a 5-year period. The patients were managed successfully with conservative treatment consisting of observation after arteriography or percutaneous duplex ultrasound-guided autologous clot embolization where tortuous vessels prevented selective embolization. No patient required surgical repair and hospitalization was brief (0 to 2 days). The use of color duplex ultrasonography provided a noninvasive modality for establishing the site of the injury and allowed serial follow-up evaluation. When conservative measures failed, the color duplex ultrasound study confirmed the presence of the ruptured cavernous artery and allowed percutaneous autologous clot embolization in 1 patient. Long-term follow-up (1 to 4 years) of these patients revealed a return to their preinjury state of erectile function.


Nonmelanoma skin cancer in women.
Men continue to develop nonmelanoma skin cancer (NMSC) at higher rates than women, but the epidemiologic pattern of NMSC development is evolving. We present a selective, narrative review of the literature showing that there is a trend toward a development of basal cell carcinomas in women at younger ages, and highlight potential causes of this trend. We review evidence that indoor tanning is associated with the development of NMSC and show that young women use indoor tanning more than any other age-sex group. We discuss societal factors that relate to the tanning behavior of young women. Finally, we argue that facial NMSCs may have more of a negative impact on quality of life in women than in men.


Carcinoembryonic antigen in fetal eccrine glands: an immunohistochemical study.
Developing fetal eccrine glands were examined for the presence of carcinoembryonic antigen (CEA) using an unlabeled antibody peroxidase-antiperoxidase technique and rabbit antibody to human CEA. The earliest sign of commitment to the formation of an eccrine gland was the presence of CEA within a single keratinocyte in fetal epidermis. As the eccrine unit evolved, we found CEA in both acrosyringeal cells and the ductal cells. Although the function of CEA in eccrine gland remains undefined, this substance may play an integral role in the earliest development of the gland as well as in its normal function in the adult.


Screening for ocular surface disease in the intensive care unit.
Ventilated patients in the intensive care unit (ICU) often develop exposure keratopathy. This predisposes to the development of bacterial keratitis, which in ICU is often bilateral, with a high risk of perforation. As regular examinations of all ventilated patients by ophthalmologists would be impractical, the purpose of this study was to assess whether ICU staff can screen reliably for keratopathy. A prospective study was performed in a general adult ICU. Twice each week, two junior ICU doctors examined the lid position and ocular surface of all patients who had been continuously sedated for more than 24 h, using fluorescein and a pen torch with a blue filter. An ophthalmologist performed similar examinations using a portable slit lamp. A total of 48 ocular examinations were performed in 18 patients. Exposure keratopathy was found by the ophthalmologist in 37.5% of examinations and by ICU doctors in 31.3% of examinations. ICU doctors had a sensitivity of 77.8% and a specificity of 96.7% in detecting keratopathy, when compared with the findings of the ophthalmologist. All cases missed by ICU doctors had punctate erosions of less than 5% of the corneal surface. Keratopathy was significantly commoner in patients with incomplete lid closure than in patients with closed lids (70.0 vs 28.9%; two-tailed Fisher's exact test P=0.027). ICU staff can perform screening examinations for exposure keratopathy with reasonable sensitivity and specificity. Regular screening by ICU staff would facilitate appropriate treatment of exposure keratopathy and promote earlier identification of cases of keratitis.


Depression in epilepsy: why aren't we treating?
Depression is a common and largely untreated comorbidity in patients with epilepsy. Our aim was to examine physician attitudes that may contribute to this treatment gap. We surveyed primary care physicians, neurologists, and psychiatrists chosen from the Ohio State Medical Board registry on the topics of depression in epilepsy, seizures with antidepressant use, and comfort in treating depression in epilepsy. Our data identified fear of increased seizure frequency with antidepressant use as a significant barrier to treatment. There was a clear inverse relationship between the estimated risk of antidepressant-induced seizures and comfort treating depression in epilepsy (P = 0.02), with 52% of primary care physicians identifying this as a reason for not treating depression in this population. Further education of community physicians and neurologists regarding the importance of treating depression in patients with epilepsy and research into the use of antidepressants in this population are indicated.


Group vs Individual Prenatal Care and Gestational Diabetes Outcomes: A Secondary Analysis of a Randomized Clinical Trial.
The impact of group-based prenatal care (GPNC) model in the US on the risk of gestational diabetes (GD) and related adverse obstetric outcomes is unknown. To determine the effects of the GPNC model on risk of GD, its progression, and related adverse obstetric outcomes. This is a single-site, parallel-group, randomized clinical trial conducted between February 2016 and March 2020 at a large health care system in Greenville, South Carolina. Participants were individuals aged 14 to 45 years with pregnancies earlier than 21 weeks' gestational age; follow-up continued to 8 weeks post partum. This study used an intention-to-treat analysis, and data were analyzed from March 2021 to July 2022. Eligible participants were randomized to receive either CenteringPregnancy, a widely used GPNC model, with 10 group-based sessions or traditional individual prenatal care (IPNC). The primary outcome was the incidence of GD diagnosed between 24 and 30 weeks of gestation. The secondary outcomes included progression to A2 GD (ie, GD treated with medications) and GD-related adverse obstetric outcomes (ie, preeclampsia, cesarean delivery, and large for gestational age). Log binomial models were performed to estimate risk differences (RDs), 95% CIs, and P values between GPNC and IPNC groups, adjusting for all baseline covariates. Of all 2348 participants (mean [SD] age, 25.1 [5.4] years; 952 Black participants [40.5%]; 502 Hispanic participants [21.4%]; 863 White participants [36.8%]), 1176 participants were randomized to the GPNC group and 1174 were randomized to the IPNC group. Among all participants, 2144 (91.3%) completed a GD screening (1072 participants [91.3%] in GPNC vs 1071 [91.2%] in IPNC). Overall, 157 participants (6.7%) developed GD, and there was no difference in GD incidence between the GPNC (83 participants [7.1%]) and IPNC (74 participants [6.3%]) groups, with an adjusted RD of 0.7% (95% CI, -1.2% to 2.7%). Among participants with GD, GPNC did not reduce the risk of progression to A2 GD (adjusted RD, -6.1%; 95% CI, -21.3% to 9.1%), preeclampsia (adjusted RD, -7.9%; 95% CI, -17.8% to 1.9%), cesarean delivery (adjusted RD, -8.2%; 95% CI, -12.2% to 13.9%), and large for gestational age (adjusted RD, -1.2%; 95% CI, -6.1% to 3.8%) compared with IPNC. In this secondary analysis of a randomized clinical trial among medically low-risk pregnant individuals, the risk of GD was similar between participants who received GPNC intervention and traditional IPNC, indicating that GPNC may be a feasible treatment option for some patients. ClinicalTrials.gov Identifier: NCT02640638.


[Autoreactive urticaria and autoimmune urticaria].
Symptoms in patients with autoreactive urticaria (ArU), a sub-form of chronic urticaria (CU), are caused by circulating histamine-releasing signals. ArU patients are readily identified by the autologous serum skin test, in which they exhibit inflammatory reactions to their serum after intracutaneous injection. CU patients who also exhibit functional autoantibodies against IgE and/or its high affinity receptor Fc(epsilon)RI are thought to suffer from autoimmune urticaria (Aiu). ArU and AiU are pathogenetically and clinically different from other sub-forms of CU.


Exploring the role of renal pharmacists in outpatient dialysis centres: a qualitative study.
Pharmacists' involvement in outpatient dialysis centres in Australia is currently limited, despite the positive contribution of pharmacists to renal patients' medication management and health outcomes outlined in the literature. An expanded role for pharmacists in this setting may be required as a consequence of the increasing burden of renal disease in the population. To explore renal-specialised hospital pharmacists' intentions to implement pharmacy services in outpatient dialysis centres. Australian renal-specialised hospital pharmacists. Semi-structured interviews were conducted with a purposeful sample of renal pharmacists recruited through the Society of Hospital Pharmacists of Australia Renal Special Interest Group. The interview guide was developed based on the theory of planned behaviour. To identify behavioural intention, the three components of the theory-attitudes, subjective norm, and perceived behavioural control-were explored. The interviews were recorded, transcribed verbatim, and thematically content analysed following a qualitative approach. Pharmacists' views on their potential involvement and perceived ease or difficulty in implementing pharmacy services in outpatient dialysis centres. Thirteen renal pharmacists were interviewed until data saturation achievement. The following services for this setting were suggested: medication reconciliation, medication review, patient education, promotion of compliance, involvement in protocol development with subsequent anaemia/phosphate management. Pharmacists demonstrated positive attitudes towards the implementation of the services. Outcomes expected included benefits to patients, the renal team, and the pharmacy profession, as well as economic savings due to dose optimisation and improvement of patients' adherence. Subjective norm was favourable meaning that nephrologists, nurses and patients were expected to be receptive towards future pharmacy services. Barriers pointed out for the implementation comprised: funding, hospital administrators' approval, time and staff shortage, academic training, relationship with physicians, and attitudes of pharmacists, renal team, and patients. Facilitators mentioned by respondents included: having an interview room with access to information sources, consent from the team, access to patients' profiles, and a full-time pharmacist with a clearly defined role. Pharmacists showed positive attitudes, favourable subjective norm and strong perceived behavioural control, which originated a clear behavioural intention to develop pharmacy services in outpatient dialysis centres. The potential barriers and enablers outlined should be taken into account, as well as the holistic approach for the successful implementation of cognitive pharmacy services.


[Assessment of fetal fibronectin concentration in identifying patients at risk for preterm delivery].
Identifying patients at risk for preterm delivery continues to be difficult. This study aimed at evaluating fetal fibronectin concentrations in cervical secretions measured by an enzyme-linked immunosorbent assay, as a tool for of premature delivery screening in patients with preterm uterine contractions. Symptomatic 115 women, admitted to Department of Perinatology (RIPMMH) between 24 weeks 0 days and 34 weeks 6 days, with intact amniotic membranes, single pregnancy, cervical dilatation <3 cm and with no cerclage were included. Samples of the cervical secretion were taken every week until the delivery or to hospital discharge. The enzyme-linked immunosorbent assays revealed sensitivity of 73.7% and specificity of 90.9%. This test was found to be a good tool for the prediction of premature delivery.


Addition of MnO2 in synthesis of nano-rod erdite promoted tetracycline adsorption.
Erdite is a rare sulphide mineral found in mafic and alkaline rocks. Only weakly crystallised fibrous erdite has been artificially synthesised via evaporation or the hydrothermal method, and the process generally requires 1-3 days and large amounts of energy to complete. In this study, well-crystallised erdite nanorods were produced within 3 h by using MnO2 as an auxiliary reagent in a one-step hydrothermal method. Results showed that erdite could synthesised in nanorod form with a diameter of approximately 200 nm and lengths of 0.5-3 μm by adding MnO2; moreover, the crystals grew with increasing MnO2 addition. Without MnO2, erdite particles were generated in irregular form. The capacity of the erdite nanorods for tetracycline (TC) adsorption was 2613.3 mg/g, which is higher than those of irregular erdite and other reported adsorbents. The major adsorption mechanism of the crystals involves a coordinating reaction between the -NH2 group of TC and the hydroxyl group of Fe oxyhydroxide produced from erdite hydrolysis. To the best of our knowledge, this study is the first to synthesise erdite nanorods and use them in TC adsorption. Erdite nanorods may be developed as a new material in the treatment of TC-containing wastewater.


Determinants of hyperemesis gravidarum among pregnant women attending antenatal care at public and private hospitals in Bahir Dar City, North-West Ethiopia, 2022: a multicenter unmatched case control study.
Hyperemesis gravidarum is a severe form of nausea and vomiting during pregnancy characterized by more than 5% weight loss and ketonuria. Although there are cases in Ethiopia, there is still insufficient information regarding the determinant factors of hyperemesis gravidarum.This finding helps to decrease maternal as well as fetal complications of hyperemesis gravidarum by early identification of pregnant mothers who are at high risk. This study aimed to assess determinants of hyperemesis gravidarum among pregnant women attending antenatal care at public and private hospitals in Bahir Dar, North-West Ethiopia, 2022. A multicenter, facility-based, unmatched case-control study was conducted on 444 pregnant women (148 cases and 296 controls) from January 1 to May 30. Women with a documented diagnosis of hyperemesis gravidarum on the patient chart were considered as cases, and women who attended antenatal care service without hyperemesis gravidarum were assigned as controls. Cases were selected using a consecutive sampling technique, whereas controls were selected using systematic random sampling technique. Data were collected using an interviewer-administered structured questionnaire. The data were entered into EPI-Data version 3 and exported into SPSS version 23 for analysis. Multivariable logistic regression was performed to identify determinants of hyperemesis gravidarum at a p-value of less than 0.05. An adjusted odds ratio with a 95% confidence interval was used to determine the direction of association. Living in urban (AOR = 2.717, 95% CI : 1.693,4.502), primigravida (AOR = 6.185, 95% CI: 3.135, 12.202), first& second trimester of pregnancy (AOR = 9.301, 95% CI: 2.877,30.067) & (AOR = 4.785, 95% CI: 1.449,15.805) respectively, family history of hyperemesis gravidarum (AOR = 2.929, 95% CI: 1.268,6.765), helicobacter pylori (AOR = 4.881, 95% CI: 2.053, 11.606) & Depression (AOR = 2.195, 95% CI: 1.004,4.797) were found to be determinants of hyperemesis gravidarum. Living in an urban area, primigravida woman, being in the first and second trimester, having family history of hyperemesis gravidarum, Helicobacter pylori infection, and having depression were the determinants of hyperemesis gravidarum. Primigravid women, those living in urban areas, and women who have a family history of hyperemesis gravidarum should have psychological support and early treatment initiation if they develop nausea and vomiting during pregnancy. Routing screening for Helicobacter pylori infection and mental health care for a mother with depression at the time of preconception care may decreases hyperemesis gravidarum significantly during pregnancy.


Cost-effectiveness and cost-utility of add-on, low-dose prednisolone in patients with rheumatoid arthritis aged 65+: The pragmatic, multicenter, placebo-controlled GLORIA trial.
The GLORIA placebo-controlled trial found a favorable balance of benefit and harm for two years of prednisolone (5 mg/day) as add-on treatment for rheumatoid arthritis (RA) patients aged 65+. This study evaluated the cost-effectiveness of low-dose prednisolone in the treatment of RA. The economic evaluation had a societal perspective with a time horizon of two years. Cost data were collected with questionnaires and from recorded events, and valued with standard Dutch unit prices of 2017. The primary effectiveness outcome was the disease activity score in 28 joints (DAS28). For cost-utility, quality-adjusted life years (QALYs) were estimated from the EuroQol-5 Dimension (EQ-5D) questionnaire. Bootstrapping assessed the uncertainty around the average differences in costs and health outcomes. In total, 444 of 451 randomized patients were included in the modified intention-to-treat analysis. Patients had median four active comorbidities at baseline. Mean total costs over two years were k€10.8 in the prednisolone group, k€0.5 (95% CI -4.0; 1.8) lower than in the placebo group. Total direct medical costs were k€0.5 (95% CI -4.0; 1.5) lower in the prednisolone group. The mean number of QALYs was similar in both groups (difference 0.02 [-0.03; 0.06] in favor of prednisolone). The DAS28 was 0.38 lower in the prednisolone group than in the placebo group (0.19; 0.56). With greater effectiveness (DAS28) at non-significantly lower costs, low-dose, add-on prednisolone is cost-effective for RA compared to placebo over two years. QALYs were equal in both groups, most likely due to the impact of multiple comorbidities.


Proteolytic activity and immunoreactivity of chemically modified papain.
The effect of different chemical modifications of papain on the proteolytic activity and immunoreactivity has been studied. Modification with Dextran T 2000 caused increasing decline in proteolytic activity both with increasing degree of dextran oxidation and amount of bound dextran, whilst the immunoreactivity determined by nephelometry remained unchanged. Modification of papain with glutaraldehyde and formaldehyde causes rapid drops in both activities, even at very low concentrations of agents. Acetylation of papain showed expressive maxima of both proteolytic and immunochemical activities at the same degree of enzyme acetylation. Modification with diazobenzenesulfonic acid caused a high increase in immunoreactivity and a small increase in proteolytic activity.


Grafts of pacinian corpuscles reinnervated by dorsal root axons.
In adult rats, a piece of the crural interosseous nerve with several Pacinian corpuscles attached was removed from the crural region, autotransplanted onto the surface of the lumbar spinal cord and connected with the peripheral stump of a transected dorsal root. From 10 days up to 6 months after the operation, the grafts were investigated by light and electron microscopy. The regenerating dorsal root axons grew along the grafted nerves into the attached Pacinian corpuscles. By 1-2 months after the operation, the nerves and their branches became almost completely reinnervated by myelinated and unmyelinated dorsal root axons. In a sample of corpuscles examined 2-6 months after grafting, 75% of corpuscles were found reinnervated; each of them was supplied by 1-5 large myelinated axons that formed multiple axon terminals in the inner core. The maximal number of axonal profiles found in a transverse section through different levels of the inner core varied, in individual corpuscles, from 3 to 17 axons and terminals. The dorsal root terminals formed in the grafted corpuscles were mainly filled with mitochondria and resembled peripheral sensory endings. In some instances, the newly formed endings developed lateral processes and membrane specializations characteristic for peripheral Pacinian terminals. Thus regenerating dorsal root axons recognize a grafted peripheral mechanoreceptor as their target and reinnervate it with axon terminals, most of them structurally transformed into peripheral sensory endings.


Effect of nitrogen and phosphorus on growth of toxic and nontoxic Microcystis strains and on intracellular microcystin concentrations.
The growth and intracellular microcystin concentration of two hepatotoxic and two nontoxic axenic Microcystis strains were measured in batch cultures with variable nitrogen (0.84-84 mg L(-1)) and phosphorus (0.05-5.5 mg L(-1)) concentrations. Growth was estimated by measuring dry weight, optical density, chlorophyll a, and cellular protein concentration. Microcystin concentrations in cells and in culture medium were measured by HPLC analysis. Both nontoxic strains needed less nutrients for their growth at low nutrient concentrations. With high nutrient concentrations the toxic strains grew better than the nontoxic strains. Growth and intracellular microcystin concentration did not correlate in the hepatotoxic strains. Multivariate regression analysis together with mathematical modeling revealed a significant interactive effect of nitrogen and phosphorus, which partly explains the controversial results obtained in previous studies. In this study we have shown that variation of nitrogen and phosphorus concentrations influence the growth and the microcystin production of Microcystis strains and that the strains differ in their response to nutrients. High levels of nitrogen and phosphorus in freshwaters may favor the growth of toxic Microcystis strains over nontoxic ones.


Visceral adipose tissue and markers of the insulin resistance syndrome in obese black and white teenagers.
To determine the relationships between visceral and general adiposity, cardiovascular fitness, and markers of the insulin resistance syndrome in obese black and white teenagers. Cross-sectional survey of 81 obese 13- to 16-year-old youths. Visceral adipose tissue was measured with magnetic resonance imaging, and percentage body fat was measured with dual-energy X-ray absorptiometry. Cardiovascular fitness was assessed with a submaximal treadmill test. Fasting blood samples were analyzed for lipids/lipoproteins and insulin. Resting blood pressure was obtained using an automated cuff. Visceral adipose tissue was significantly correlated with unfavorable levels of: triacylglycerol (r = 0.27, p < 0.05), total cholesterol (r = 0.27, p < 0.05), high-density lipoprotein cholesterol (r = -0.26, p < 0.05), the ratio of total cholesterol/high-density lipoprotein cholesterol (r = 0.42, p < 0.01), low-density lipoprotein cholesterol (r = 0.27, p < 0.05), apolipoprotein B (r = 0.38, p < 0.01), and systolic blood pressure (r = 0.30, p < 0.01). Multiple regression analyses revealed that visceral adipose tissue was more powerful than percentage body fat for explaining variance in lipoproteins (e.g., for the ratio of total cholesterol/high-density lipoprotein cholesterol, r2 = 0.13, p < 0.01, and for systolic blood pressure, r2 = 0.07, p < 0.05). Ethnicity was the most powerful of the demographic predictors for blood lipids (r2 = 0.15 for triacylglycerol with lower levels in blacks; r2 = 0.10 for high-density lipoprotein cholesterol with higher levels in blacks; r2 = 0.06 for the ratio of total cholesterol/high-density lipoprotein cholesterol with lower levels in blacks). Cardiovascular fitness was not retained as a significant predictor of markers of the insulin resistance syndrome. Some of the deleterious relationships between visceral adiposity and markers for the insulin resistance syndrome seen in adults were already present in these obese young people.


Maintenance of pig brain function under extracorporeal pulsatile circulatory control (EPCC).
Selective vascular access to the brain is desirable in metabolic tracer, pharmacological and other studies aimed to characterize neural properties in isolation from somatic influences from chest, abdomen or limbs. However, current methods for artificial control of cerebral circulation can abolish pulsatility-dependent vascular signaling or neural network phenomena such as the electrocorticogram even while preserving individual neuronal activity. Thus, we set out to mechanically render cerebral hemodynamics fully regulable to replicate or modify native pig brain perfusion. To this end, blood flow to the head was surgically separated from the systemic circulation and full extracorporeal pulsatile circulatory control (EPCC) was delivered via a modified aorta or brachiocephalic artery. This control relied on a computerized algorithm that maintained, for several hours, blood pressure, flow and pulsatility at near-native values individually measured before EPCC. Continuous electrocorticography and brain depth electrode recordings were used to evaluate brain activity relative to the standard offered by awake human electrocorticography. Under EPCC, this activity remained unaltered or minimally perturbed compared to the native circulation state, as did cerebral oxygenation, pressure, temperature and microscopic structure. Thus, our approach enables the study of neural activity and its circulatory manipulation in independence of most of the rest of the organism.


Application of spherical harmonics for DEER data analysis in systems with a conformational distribution.
Double electron-electron resonance (DEER) and other pulse electron paramagnetic resonance (EPR) techniques are valuable tools for determining distances between paramagnetic centres. DEER theory is well developed for a scenario where relative orientations of paramagnetic centres do not affect the DEER data. In particular, such theory enables a number of approaches for extracting distance distributions. However, in a more general case, when orientation selection effects become substantial, the analytical theory of DEER is less well developed, therefore quite commonly researchers rely on a comparison of some model-based simulations with experimental data. This work elaborates the theory of DEER with orientation selection effects, focusing on a scenario of a moderate conformational disorder, leading to an orientation distribution in a pair of paramagnetic centres. The analytical treatment based on expansions into spherical harmonics, provides important insights into the structure of DEER data. As follows from this treatment, DEER spectra with orientation selection can be represented as a linear combination of modified Pake pattern (MPP) components. The conformational disorder has a filtering effect on the weights of MPP components, specifically by significantly suppressing MPP components of higher degrees. The developed theory provides a pathway for model-based simulations of DEER data where orientation distribution is defined by analytical functions with parameters. The theory based on spherical harmonics expansions was also applied to develop an iterative processing algorithm based on Tikhonov regularization, which disentangles the distance and orientation information in a model-free manner. As an input, this procedure takes several DEER datasets measured at various positions of an EPR line, and outputs a distance distribution and orientation distribution information encoded in a set of coefficients related to the weights of MPP components. The model-based and model-free approaches based on the developed theory were validated for a nitroxide biradical and a spin-labelled protein.


Intrahepatic biliary cysts after hepatic portoenterostomy in four children with biliary atresia.
We report our experience with 4 cases of cystic dilatation of intrahepatic bile ducts following hepatic portoenterostomy for biliary atresia. Two of the cases did not achieve satisfactory bile excretion and all four cases developed recurrent cholangitis after hepatic portoenterostomy. The attacks of cholangitis seemed to be associated with the presence of intrahepatic cysts. Although one case resulted in death from hepatic failure, three other cases are now outpatients. Patients who develop recurrent cholangitis following hepatic portoenterostomy, should be examined to exclude the presence of intrahepatic biliary cysts. Ultrasonography, computed tomography and percutaneous transhepatic cholangiography were all effective in detecting cysts and provided valuable information for planning treatment. Percutaneous transhepatic or surgical drainage of the bile ducts was effective in reducing jaundice, and recurrent cholangitis.


Atypical vocal quality in women with the FMR1 premutation: an indicator of impaired sensorimotor control.
Women with the FMR1 premutation are susceptible to motor involvement related to atypical cerebellar function, including risk for developing fragile X tremor ataxia syndrome. Vocal quality analyses are sensitive to subtle differences in motor skills but have not yet been applied to the FMR1 premutation. This study examined whether women with the FMR1 premutation demonstrate differences in vocal quality, and whether such differences relate to FMR1 genetic, executive, motor, or health features of the FMR1 premutation. Participants included 35 women with the FMR1 premutation and 45 age-matched women without the FMR1 premutation who served as a comparison group. Three sustained /a/ vowels were analyzed for pitch (mean F0), variability of pitch (standard deviation of F0), and overall vocal quality (jitter, shimmer, and harmonics-to-noise ratio). Executive, motor, and health indices were obtained from direct and self-report measures and genetic samples were analyzed for FMR1 CGG repeat length and activation ratio. Women with the FMR1 premutation had a lower pitch, larger pitch variability, and poorer vocal quality than the comparison group. Working memory was related to harmonics-to-noise ratio and shimmer in women with the FMR1 premutation. Vocal quality abnormalities differentiated women with the FMR1 premutation from the comparison group and were evident even in the absence of other clinically evident motor deficits. This study supports vocal quality analyses as a tool that may prove useful in the detection of early signs of motor involvement in this population.


Physiological roles of NOX/NADPH oxidase, the superoxide-generating enzyme.
NADPH oxidase is a superoxide (O(2) (•-))-generating enzyme first identified in phagocytes, essential for their bactericidal activities. Later, in non-phagocytes, production of O(2) (•-) was also demonstrated in an NADPH-dependent manner. In the last decade, several non-phagocyte-type NADPH oxidases have been identified. The catalytic subunit of these oxidases, NOX, constitutes the NOX family. There are five homologs in the family, NOX1 to NOX5, and two related enzymes, DUOX1 and DUOX2. Transgenic or gene-disrupted mice of the NOX family have also been established. NOX/DUOX proteins possess distinct features in the dependency on other components for their enzymatic activities, tissue distributions, and physiological functions. This review summarized the characteristics of the NOX family proteins, especially focused on their functions clarified through studies using gene-modified mice.


[Risk factors for early recurrence after radical resection of proximal gastric cancer].
To explore the risk factors for early recurrence (recurrence within 2 years) of proximal gastric cancer after radical resection. The clinical data of 367 proximal gastric cancer patients who underwent radical resection in the Cancer Institute and Hospital of Tianjin Medical University between January 2000 and May 2006 were reviewed. Among them, there are 71 patients (19.3%) with early recurrence. Univariate analysis and multivariate analysis were applied to investigate risk factors for early recurrence. Univariate analysis showed that Borrmann type (P<0.01), histology type (P<0.01), depth of invasion (P<0.05), negative lymph nodes count (P<0.05) were risk factors for early recurrence of proximal gastric. On multivariate analysis, histology type (P<0.05), depth of invasion (P<0.05), negative lymph nodes counts (P<0.05) were independent risk factors for early recurrence of proximal gastric cancer. Negative lymph nodes in early recurrence patients were 8.4 ± 7.2, which were significantly less as compared to patients without early recurrence (10.7 ± 8.7) (P<0.05). For T3 proximal gastric adenosquamous cancer, extended resection and lymphadenectomy should be considered. Intraoperative or postoperative adjuvant treatment should be administered as routine.


Food partitioning and community organization in a mountain lizard guild of Northern Mexico.
Food niche relationships among four sympatric Sceloporus species were studied in the Sierra Madre Occidental, N.E. Mexico. Although some very high food-niche overlap values were observed, this does not prove that interspecific competition is currently important in organizing this lizard assemblage. Moreover, explaining habitat segregation among the coexisting species as an ecological result of interspecific competitive pressure is unlikely: the overall ecology and behaviour of these species is too much dependent on their microhabitat or substrate specialization to allow such an exclusive interpretation. Thus, this community is probably not mainly organized by species interactions but rather through the specific ecological needs of each species.


Traveling for care: inter-regional mobility for aortic valve substitution in Italy.
Patient flows across the regions of the Italian National Health Service can shed light on patient mobility, including cross-border flows within the European Union. We used 2009 data on 11,531 NHS admissions for aortic valve replacement operations to measure the extent of inter-regional patient mobility and to determine whether resident and non-resident patients differ. We also investigated whether public and private hospitals behave differently in terms of attracting patients. For this major cardio-surgical intervention, patient mobility in Italy is substantial (13.6% of total admissions). Such mobility mainly involves patients moving from southern to northern regions, which often requires several hundred kilometers of travel and a transfer of financial resources from poorer to richer regions. Patients admitted in the regions where they reside are older than those admitted outside their regions (69.2 versus 65.6, p<0.0001), and stay in hospital approximately 0.7 days longer (14.7 versus 14.0, p=0.017). Compared to public hospitals, private hospitals are more likely to admit non-resident patients (OR between 2.1 and 4.4). The extent and direction of patients' mobility raise equity concerns, as receiving care in locations that are distant from home requires substantial financial and relational resources.


Isatin-3-acylhydrazones with Enhanced Lipophilicity: Synthesis, Antimicrobial Activity Evaluation and the Influence on Hemostasis System.
Water-soluble trialkylammonium isatin-3-hydrazone derivatives bearing phenolic substituent were easily synthesized with high yields. XRD studies confirmed the presence of these compounds as trans-(Z)-isomers in a crystal. It was shown that an increase in the lipophilicity of the cationic center leads to an increase in activity against Gram-positive bacteria Staphylococcus aureus and Bacillus cereus, including methicillin-resistant Staphylococcus aureus (MRSA) strains. The MIC values of all compounds turned out to be 2-100 times higher than the MIC of norfloxacin against the MRSA strains in the absence of hemo- and cytotoxicity. Antiaggregation and anticoagulation properties were in vitro better than for acetylsalicylic acid and sodium heparin drugs. It has been shown by UV spectroscopy and fluorescence microscopy that the mechanism of antimicrobial action of new acylhydrazones is associated with their ability to destroy the bacterial cell membrane.


Quantitation of human chorionic gonadotrophin (hCG) by radioreceptor assay.
A sensitive radioreceptor assay was developed for pharmaceutical preparations of human chorionic gonadotrophin with the use of rat testicular membranes as receptor preparation and human 125I-chorionic gonadotrophin as tracer. The addition of unlabelled human chorionic gonadotrophin or luteinizing hormone inhibited the binding of 125I-chorionic gonadotrophin to the receptors in a concentration dependent way. Concentrations of human chorionic gonadotrophin between 30-300 mIU ml(-1) were normally used for a three-dose assay fulfilling pharmacopoeial statistical requirements for assay validity. The relative standard deviation for five assays was 7%. Estimates of potency of commercial preparations of human chorionic gonadotrophin obtained with the radioreceptor assay correlated well with corresponding estimates from in vivo assays. The proposed radioreceptor assay, however, provides a considerable saving in the number of animals required, requires less technical support, and is more precise than the in vivo method.


Studies on the pathophysiology of the low urine pH in patients with uric acid stones.
A very low urine pH is the major risk factor for uric acid stone formation. A subgroup of patients with a history of uric acid stones and a persistently low urine pH (<5.5 for at least 12 h/day) were selected for detailed study. Based on their relative ammonium (NH(+)(4)) and sulfate (SO(2-)(4)) excretions, patients were divided into two groups. The first group (N = 2) excreted 173 and 139% more NH(+)(4) than SO(2-)(4). Their daily urinary unmeasured anion excretion was higher than their calculated net diet alkali input (38 and 61 vs. 24 and 49 mEq, respectively). In the second group (N = 12), NH(+)(4) excretion was 69 +/- 5% that of SO(2-)(4). In 2 of 12, decreased renal ammoniagenesis was suspected due to a plasma potassium of 5.3 mmol/L and/or a lower GFR (65 and 59 L/day); these patients had an extremely low citrate excretion (3 and 1 mEq/day). In contrast, citrate excretion was not low in the remaining 10 patients (10.4 +/- 1.3 mEq/day). Patients in group 1 needed a higher NH(+)(4) excretion possibly because of a H+ load from excessive renal excretion of organic anions. We speculate that an alkaline proximal tubular cell pH could be the basis for the low NH(+)(4) and high citrate excretions in 10 of 12 patients in group 2. Dietary factors and/or a molecular lesion may contribute to their pathophysiology.


Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery.
To investigate the effect of parenteral administration of vitamin C on neutrophil apoptosis by determining Fas receptor expression and caspase-3, poly (ADP-ribose) polymerase (PARP), and Bcl-2 levels in neutrophils from septic abdominal surgery patients. Twenty septic abdominal surgery patients were studied in a prospective, randomized, double-blinded clinical trial. A group of healthy volunteers (n = 10) constituted a reference group for baseline parameter values. The patients were randomly assigned to a vitamin C-treated (n = 10) or placebo-treated (n = 10) group. For a 6-d period from 12 h post-surgery, the vitamin C group received 450 mg/d of the vitamin in 3 doses and the placebo group an identical administration of 5% dextrose. Early-morning peripheral blood samples were obtained daily from 24 h after vitamin C administration until d 6 post-surgery (T1d-T6d). Vitamin C group showed a nonsignificant reduction in Fas (CD95) expression on CD15-positive peripheral blood neutrophils, significantly decreased caspase-3, and PARP levels (caspase-3: T4d: P < 0.05, T5d: P < 0.05, T6d P < 0.01; and PARP: T3d: P < 0.05, T4d: P < 0.05, T6d: P < 0.05), and significantly increased Bcl-2 levels (T3d: P = 0.001) versus placebo group. Postoperative vitamin C treatment of septic abdominal surgery patients exerts an antiapoptotic effect on peripheral blood neutrophils, reducing caspase-3 and PARP levels, and increasing Bcl-2 levels. However, these antiapoptotic effects are not maintained at all time points.


A new validated method for the simultaneous determination of benzocaine, propylparaben and benzyl alcohol in a bioadhesive gel by HPLC.
A new HPLC-RP method has been developed and validated for the simultaneous determination of benzocaine, two preservatives (propylparaben (nipasol) and benzyl alcohol) and degradation products of benzocaine in a semisolid pharmaceutical dosage form (benzocaine gel). The method uses a Nucleosil 120 C18 column and gradient elution. The mobile phase consisted of a mixture of methanol and glacial acetic acid (10%, v/v) at different proportion according to a time-schedule programme, pumped at a flow rate of 2.0 ml min(-1). The DAD detector was set at 258 nm. The validation study was carried out fulfilling the ICH guidelines in order to prove that the new analytical method, meets the reliability characteristics, and these characteristics showed the capacity of analytical method to keep, throughout the time, the fundamental criteria for validation: selectivity, linearity, precision, accuracy and sensitivity. The method was applied during the quality control of benzocaine gel in order to quantify the drug (benzocaine), preservatives and degraded products and proved to be suitable for rapid and reliable quality control method.


Biodegradation rates in adapted surface water can be assessed following a preadaptation period with semi-continuous operation.
The paper presents a semi-continuous preexposure procedure (SCEP) for use with surface water batch simulation biodegradability tests at low test substance concentrations (0.1-100 microg/l). Simple one step batch tests are normally used first of all for determining "initial rates" characteristic of the water as sampled, as by contrast to "adapted" rates obtained as a result of exposure of the microbial community to the test compound. The aim of the SCEP is to facilitate this adaptation and to become able to estimate reproducible "adapted rates" representing a steady state situation. This is accomplished by maintaining the microbial diversity and a supply of test substance and natural substrates. Conducting a SCEP involves regular renewal of part (e.g. one third) of the test suspension (e.g. every two weeks) adding freshly collected natural water with test compound of the initial concentration. An example study was performed with aniline, 4-nitrophenol, 2,4-dichlorophenoxyacetic acid, 4-chloroaniline, and water from the urban river Mølleå. Following preadaptation lag phases were considerably reduced and much more reproducible than obtained with simple batch tests. In tests at 100 microg/l lag phases for aniline decreased from 5.2 to <1 day, 4-nitrophenol from 10 to <1 day, 2,4-dichlorophenoxyacetic acid from 24 to <1 day, and 4-chloroaniline from 88 to 9 days, respectively. Adapted rates obtained with the SCECP were roughly the same as final rates in simple batch tests with successful adaptation. The adapted rate constant is perceived as an inherent characteristic of the test compound at a specific concentration and under environmental influence (temperature, natural substrates, etc.) but with no simple links back to the original microbial population. By contrast, the initial rates in one step batch tests are determined also by the microbial population initially present in the water sampled.


Expression of specific white adipose tissue genes in denervation-induced skeletal muscle fatty degeneration.
Denervation of skeletal muscle results in rapid atrophy with loss of contractile mass and/or progressive degeneration of muscle fibers which are replaced to a greater or lesser degree by connective and fatty tissues. In this study, we show that denervated rabbit muscles are transformed into a white adipose tissue, depending on their fiber types. This tissue does express LPL, G3PDH and particularly the ob gene, a white adipose tissue-specific marker, and does not express the brown adipose tissue molecular marker UCP1 mRNA.


Quantitative evaluation of digital-image enhancement during heads-up surgery.
Image-processing is an advantage of heads-up surgery and expected to facilitate ophthalmic surgeries. To evaluate image-processing quantitatively, we analyzed the surgical images of twenty eyes that underwent vitrectomy with internal limiting membrane (ILM) peeling assisted by Brilliant Blue G (BBG). Still images of the peeling procedure were obtained from the surgical video, and the color difference was calculated between two adjacent spots inside and outside the ILM-peeling contour, i.e., without and with BBG staining, respectively. The color differences were compared between the two settings with and without image-processing, delivered by an algorithm to enhance the color and contrast. Color differences were calculated using two methods: the Euclidean distance based on RGB values (RGB distance) and the Delta-E00 formula provided by the International Commission on Illumination. In five cases, minimum light intensities required to recognize the contour of ILM-peeling were compared during surgeries between the two settings with and without enhancement. Image-processing increased the mean color difference significantly (P < 0.001) from 15.47 and 4.49 to 34.03 and 8.00, respectively, for the RGB distance and Delta-E00. The minimum light intensity was reduced from 15 to 5 on average by image-enhancement. These results showed image-processing enhances color differences and reduces light intensities during vitrectomy.


Quantitative biodistribution of biotherapeutics at whole body, organ and cellular levels by autoradiography.
Tools for mapping and quantifying monoclonal antibody (mAb) and peptide biotherapeutics distribumtion were evaluated by comparing data from three independent methods conducted at the whole body, organ or tissue, and cellular levels. [3H]-mAb1 and [3H]-peptide A were administered intravenously to rats followed by quantitative whole-body autoradiography, kidney macro-autoradiography and micro-autoradiography. [3H]-mAb1 and [3H]-peptide A concentrations were measured in anatomical regions ranging from whole body to whole organ to sub-organ level, such as the kidney glomerulus, with increasing resolution. The tissue/blood [3H]-mAb1 concentrations in selected kidney microenvironments were comparable among the three quantitative methods. Quantitative whole-body autoradiography, tissue macro-autoradiography and micro-autoradiography all provide useful tools for quantifying the concentrations of biotherapeutics at different anatomical levels in tissues, facilitating better predictions of efficacy and toxicity.


Percutaneous transcatheter treatment of an intracavitary aspergilloma.
We describe a case of massive hemoptysis, secondary to an intracavitary aspergilloma, successfully treated by computed tomography (CT)-guided placement of a Cope-loop catheter with daily transcatheter instillation of amphotericin B and cavitary irrigation. Over a 15-day period, this regimen resulted in cessation of hemoptysis and radiographic resolution of the aspergilloma. No complications were encountered. A follow-up CT of the thorax showed no recurrence of the aspergilloma at 3 months.


Acute and chronic illness after tick-bite Borrelia burgdorferi-infections: results of treatment.
We report on clinical and laboratory findings of 28 patients with tick-bite Borrelia burgdorferi-infection. In 5 cases chronic tertiary metaluetic manifestations were recognized. All were treated either with high-dose penicillin intravenously or tetracycline. Results of treatment and recommendations are given.


Facile bio-fabrication of ZnO@AC nanoparticles from chitosan: Characterization, hydrogen generation, and photocatalytic properties.
In this work, activated carbon-supported zinc oxide nanoparticles (ZnO@AC NPs) were studied using the thermal synthesis method. The activated carbon-supported zinc oxide catalyst was characterized by UV-Vis spectrometry techniques, Fourier Transform Infrared Spectrophotometer (FTIR), Transmissive electron microscopy (TEM), and X-ray diffraction (XRD) methods. XRD characterization measurements showed that the average size of the crystal NPs was 6.89 nm. According to the TEM analysis results, the nanoparticles' average size was 11.411 nm, and the particles had a spherical structure. The catalytic properties of the synthesized material were determined using the sodium borohydride methanolysis reaction. A kinetic study was performed regarding the effects of temperature, catalyst, and substrate concentration on the methanolysis reaction. Reusability experiments showed that the catalyst had excellent catalytic activity (85%), stability, and selectivity. As a result of the kinetic study, activation energy, enthalpy (ΔH), entropy (ΔS), and hydrogen production rate activation parameters were found to be 42.52 kJ/mol, 39.98 kJ/mol, -181.42 J/mol.K, 1257.69 mL/min. g, respectively. Also, the photocatalytic activity of ZnO@AC NPs was analyzed against Rhodamine B (RhB) dye, and the maximum degradation percentage was observed to be 76% at 120 min. This study aimed to develop the ZnO@AC NPs into an efficient photocatalyst to prevent industrial wastewater pollution and as a catalyst for hydrogen synthesis as an alternative energy source.


Properties of proteinaceous toxins in the salivary gland of the marine gastropod (Monoplex echo).
Three proteinaceous toxins (named echotoxins 1, 2, and 3) with both lethal and hemolytic activities were purified from the salivary gland of the marine gastropod (Monoplex echo) by gel filtration on Sephadex G-75 and cation-exchange FPLC on Mono S, although marked reduction in toxicity was observed in the latter chromatography. When subjected to reverse-phase HPLC on TSKgel Phenyl-5PW RP, echotoxin 2 afforded a single peak, while both echotoxins 1 and 3 were further separated into two components, respectively. All echotoxins are monomeric simple proteins with a molecular mass of about 25kDa and their N-termini are blocked. Amino acid compositions of echotoxins 1a, 1b, and 2 are closely similar to one another, being characterized by the abundance of Gly and Ala and the absence of half-Cys, Met, and Trp. Of the sugars, lipids and glycolipids tested, gangliosides potently inhibited the hemolytic activity of echotoxins. Furthermore, ganglioside G(T1b) inhibited both in vivo hemolysis and lethality in mice displayed by echotoxins. It is thus concluded that echotoxins injected into mice induce rapid hemolysis by binding to receptors (possibly gangliosides) gangliosides in the erythrocyte membrane, eventually leading to death of mice.


Avoidance of Pitfalls and Complications During Surgery for Temporal Lobe Epilepsy.
Anterior temporal lobectomy with amygdalohippocampectomy is the most common epilepsy surgery, which, in cases of mesial temporal lobe epilepsy caused by mesial temporal sclerosis, usually leads to improvements in seizure control, cognitive function, and quality of life. Nevertheless, while the primary goal of intervention is achieved in a large majority of patients, a small number of them, unfortunately, encounter complications. Some morbidity is nonspecific and may be noted after any craniotomy (e.g., surgical site infections, meningitis, bone flap osteomyelitis, and operative site or craniotomy-related hematomas). On the other hand, certain complications are specifically associated with surgery for temporal lobe epilepsy and can be discussed from the etiological standpoint: mechanical injuries of the brain; injury of eloquent neuronal structures; arterial and venous injuries; cerebral venous thrombosis; remote cerebellar hemorrhage; and postoperative hydrocephalus, seizures, and psychiatric disorders. In many cases, these complications are manifested in the early postoperative period by alterations of consciousness and a focal neurological deficit, and it may require immediate decisions on their appropriate management.


Survival in familial and non-familial breast cancer by age and stage at diagnosis.
We aimed to compare the survival in familial and sporadic breast cancer (BC) patients who were diagnosed at an identical age and TNM stage. The Nationwide Swedish Family-Cancer Database including all Swedes born after 1931 and their biological parents, totalling >14.7 million individuals, was used. Hazard ratios (HRs) were calculated for women with BC in a first-degree relative (FDR) versus BC patients without positive family history. There was no difference in survival of familial BC patients who were diagnosed at higher TNM status or older age (>40) compared to sporadic BC cases diagnosed at the same late TNM stage. Young BC patients (age <40) in early stages had the worst survival when their FDR was diagnosed with single (HR: 2.0-3.7) or multiple (HR: 2.4-7.1) BC at any age. We concluded that there is no difference in survival of familial and non-familial BC patients who are diagnosed at higher TNM status or older ages (>40). Young familial BC patients (age <40), diagnosed at early stage, have the poorer survival compared to sporadic cases. Our results urge the need for identifying the underling genetic component for such a difference in survival of familial BC.


Quantitative characterization of enzyme adsorption and hydrolytic performance for ultrafine grinding pretreated corn stover.
Quantitative analysis of enzyme adsorption and hydrolysis were performed for sieve-based grinding corn stover (SGCS) and ultrafine grinding corn stover (UGCS)1 with different enzyme consumptions. The UGCS presented significantly higher enzyme adsorption quantity (5.15mg/g for UGCS, 1.33mg/g for SGCS), higher glucose yield (49.75% for UGCS, 28.75% for SGCS) under 20FPU/g and higher binding enzyme proportion (41.32% for UGCS, 10.64% for SGCS under 5FPU/g) which can be attributed to the more accessible microstructure properties. The relationship between enzyme adsorption and hydrolytic production was directly proportional for SGCS (GY1=21.04×AQ1+1.86 (R2=0.95)) while was exponential for UGCS (GY2=49.42×(1-e-0.57×AQ2) (R2=0.99)),2 indicating that overmuch enzyme consumption was not advisable for UGCS at economical aspect.


Psychophysical tuning curves in subjects with tinnitus suggest outer hair cell lesions.
A study by Penner (J Speech Hear Res 1980;23:779-86) found evidence for impaired lateral suppression in subjects with tinnitus and sensorineural hearing loss. If lateral suppression is related to tuning curve sharpness and lateral suppression is impaired, the shape of the tuning curve should be affected. The purpose of this study was to determine whether subjects with tinnitus have psychophysical tuning curves that are different from those of subjects without tinnitus. Psychophysical tuning curves and hearing thresholds were obtained from 18 subjects, 7 with tinnitus and 11 without tinnitus. Only subjects with normal audiograms (through 8 kHz) were selected for this study. In subjects with tinnitus psychophysical tuning curves were obtained in the region pitch-matched to their tinnitus. In nontinnitus subjects psychophysical tuning curves were determined at the same frequencies as for the tinnitus subjects in a yoked-control design. The slopes of the tails and tips and the Q10 and other measures were calculated for each tuning curve. The psychophysical tuning curves in subjects with tinnitus were significantly different (0.01 level) from those of control subjects and often had hypersensitive tails and some elevated tips. These shapes of tuning curves are consistent with cochlear lesions involving the loss of outer hair cells without damage to the inner hair cells or nerve fibers.


Focal laser photophacoablation of normal and cataractous lenses in rabbits: preliminary report.
We evaluated the effect of focal laser photophacoablation on (1) a normal lens and (2) previously induced traumatic anterior cortical and posterior subcapsular cataracts in New Zealand albino rabbits. A Q-switched neodymium:YAG (Nd:YAG) laser was used to deliver 6 to 97 50 microns laser spots of 2.0 mJ to 8.3 mJ of energy/pulse to the normal lens. A neodymium:YLF (Nd:YLF) laser was used to deliver 60 microJ to 140 microJ of energy/pulse with a 0.3 mm to 0.6 mm cube at 1053 nm to ablate selective parts of the normal and cataractous lens. The Nd:YAG laser photoablation of the normal lens produced persistent circular opacities lasting up to one year. The Nd:YLF laser photoablation of the normal lens produced an empty space in the area of treatment (visualized as increased translucency), followed by a return to normal lens architecture at two days. The area remained translucent by slitlamp biomicroscopy for up to six months. Partial photoablation of the induced cataracts with an Nd:YLF laser produced partial clearing of the opacity without any evidence of surrounding lenticular damage. Focal Nd:YLF laser photoablation of lenticular opacities appears to be a relatively safe and noninvasive procedure that can be used for focal lens ablation without lens capsule disruption. The potential use of this treatment for selective removal of focal lens opacities requires further study.


Oncogenic mutations cause dramatic, qualitative changes in the transcriptional activity of c-Myb.
The v-Myb oncoprotein encoded by Avian Myeloblastosis Virus is highly oncogenic, induces leukemias in chickens and mice and transforms immature hematopoietic cells in vitro. The v-Myb protein is a mutated and truncated version of c-Myb, a DNA-binding transcription factor expressed in many cell types that is essential for normal hematopoiesis. Previous studies suggested that two types of differences, DNA binding domain mutations and the deletion of a C-terminal negative regulatory domain were important for increasing the transforming activity of v-Myb. Here, we combined structure-function studies of the v-Myb and c-Myb proteins with unbiased microarray-based transcription assays to compare the transcriptional specificities of the two proteins. In human cells, the v-Myb and c-Myb proteins displayed strikingly different activities and regulated overlapping, but largely distinct sets of target genes. Each type of mutation that distinguished v-Myb from c-Myb, including the N- and C-terminal deletions, DNA binding domain changes and mutations in the transcriptional activation domain, affected different sets of target genes and contributed to the different activities of c-Myb and v-Myb. The results suggest that v-Myb is not just a de-repressed version of c-Myb. Instead, it is a distinct transcriptional regulator with a unique set of activities.


Macular neovascularization in inherited retinal diseases: A review.
Inherited retinal diseases (IRDs) are the most common cause of blindness in working-age adults. Macular neovascularization (MNV) may be a presenting feature or occurs as a late-stage complication in several IRDs. We performed an extensive literature review on MNV associated with IRDs. MNV is a well-known complication of Sorsby fundus dystrophy and pseudoxanthoma elasticum. Those with late-onset Stargardt disease may masquerade as exudative age-related macular degeneration (AMD) when MNV is the presenting feature. Peripherinopathies may develop MNV that responds well to a short course of anti-vascular endothelial growth factor (anti-VEGF) therapy, while bestrophinopathies tend to develop MNV in the early stages of the disease without vision loss. Enhanced S-cone syndrome manifests type 3 MNV that typically regresses into a subfoveal fibrotic nodule. MNV is only a rare complication in choroideraemia and rod-cone dystrophies. Most IRD-related MNVs exhibit a favorable visual prognosis requiring less intensive regimens of anti-vascular endothelial growth factor therapy compared to age-related macular degeneration. We discuss the role of key imaging modalities in the diagnosis of MNV across a wide spectrum of IRDs and highlight the gaps in our knowledge with respect to the natural history and prognosis to pave the way for future directions of research.


Upper Lumbar Bone Stress Injuries in Elite Cricketers.
Describe the proportion of upper lumbar bone stress injuries (LBSI; T12-L3) relative to all LBSI, and the clinical presentation and diagnosis of upper LBSI in elite cricketers. Case series. Professional domestic and international cricket teams over a 9-year period. Elite Australian cricketers. Symptomatic upper LBSI diagnosed based on clinical findings and medical imaging. Prevalence, injury history, and clinical management. Twenty-four pace bowlers (22 male and 2 female) sustained 39 cases of upper LBSI (T12:2, L1:3, L2:20, L3:14). Upper lumbar vertebrae were involved in 41% (95% CI 31-51) of all LBSI in this cohort. Twenty-seven (69%, 54-81) cases had an injury that occurred only on the side contralateral to the bowling arm. Ipsilateral injuries tended to occur secondary to a contralateral nonunited defect. In all 7 cases with known radiology follow-up that had a contralateral then ipsilateral LBSI, the contralateral injury did not achieve bony union before the onset of the ipsilateral LBSI. For stress fractures with imaging follow-up, those who achieved bony union took longer to return to bowling training [median 152 days (IQR 117-188)], compared to those who achieved partial or no union [median 68 days (IQR 46-115)]. Upper LBSI in elite cricketers occurs in approximately 2 out of 5 cases of LBSI. Clinicians should allow sufficient time for upper LBSI to resolve and unite (if a fracture) because cases that returned to bowling training earlier were less likely to achieve bony union, and those that failed to unite commonly went on to have a recurrent LBSI. Therapy/prognosis/diagnosis level 2b.


Out-of-body-like experiences are more probable in people with elevated complex partial epileptic-like signs during periods of enhanced geomagnetic activity: a nonlinear effect.
The ratings of subjective experiences of the self "leaving" or of being detached from the body were obtained (over a 3-yr. period) for a total of 128 men and women who had been exposed only once to an experimental setting which enhances the awareness of cognitive processes. As hypothesized, the individuals who exhibited the greatest proportion of complex partial epileptic-like signs also reported the most intense experiences of detachment from the body; however, these occurred primarily when the geomagnetic activity on the day of the experiment exceeded about 15 nT but was less than about 45 nT. Geomagnetic activity for the day after or the three days before the experiment was not associated with these experiences. The effect was equivalent to a correlation coefficient (eta) of .38.


Modulation of adenylate cyclase activity by sulfated glycosaminoglycans. I. Inhibition by heparin of gonadotrophin-stimulated ovarian adenylate cyclase.
Heparin inhibits (I50 = 2 microgram/ml) the activity of luteinizing hormone and human chorionic gonadotropin-stimulated adenylate cyclase in purified rat ovarian plasma membranes. Unstimulated enzyme activity and activity stimulated by NaF, GTP or guanosine 5'-(beta,gamma-imido)triphosphate were inhibited to a lesser extent. Human chorionic gonadotropin binding to this membrane preparation was inhibited by heparin (I50 = 6 microgram/ml). The inhibition with respect to hormone concentration was of a mixed type for hormone binding and adenylate cyclase stimulation. Inhibition by heparin was not eliminated at saturating hormone concentration. The degree of inhibition was unaffected by the order in which enzyme, hormone and heparin were introduced into the assay system. Heparin (3 microgram/ml) did not affect the pH activity relationship of basal and hormone-stimulated adenylate cyclase activity and did not change the dependence of enzyme activity on magnesium ion concentration. The inhibitory action of heparin cannot be solely attributed to interference with either catalysis or hormone binding. The possibility is considered that the highly charged heparin molecule interferes with enzyme receptor coupling, by restricting the mobility of these components or by effecting their conformation.


Associations of body mass index with cancer incidence among populations, genders, and menopausal status: A systematic review and meta-analysis.
In order to further reveal the differences of association between body mass index (BMI) and cancer incidence across populations, genders, and menopausal status, we performed comprehensive meta-analysis with eligible citations. The risk ratio (RR) of incidence at 10 different cancer sites (per 5kg/m(2) increase in BMI) were quantified separately by employing generalized least-squares to estimate trends, and combined by meta-analyses. We observed significantly stronger association between increased BMI and breast cancer incidence in the Asia-Pacific group (RR 1.18:1.11-1.26) than in European-Australian (1.05:1.00-1.09) and North-American group (1.06:1.03-1.08) (meta-regression p<0.05). No association between increased BMI and pancreatic cancer incidence (0.94:0.71-1.24) was shown in the Asia-Pacific group (meta-regression p<0.05), whereas positive associations were found in other two groups. A significantly higher RR in men was found for colorectal cancer in comparison with women (meta-regression p<0.05). Compared with postmenopausal women, premenopausal women displayed significantly higher RR for ovarian cancer (pre- vs. post-=1.10 vs. 1.01, meta-regression p<0.05), but lower RR for breast cancer (pre- vs. post-=0.99 vs. 1.11, meta-regression p<0.0001). Our results indicate that overweight or obesity is a strong risk factor of cancer incidence at several cancer sites. Genders, populations, and menopausal status are important factors effecting the association between obesity and cancer incidence for certain cancer types.


Integrating cytotoxic, targeted and immune therapies for cholangiocarcinoma.
Management of biliary tract cancers (BTCs) is rapidly evolving. The majority of patients are diagnosed with advanced disease. In this setting, chemotherapy with cisplatin and gemcitabine (with durvalumab) followed by second-line FOLFOX is the cornerstone of treatment. Targeted therapies for tumours harbouring FGFR2 fusions, IDH1 mutations, BRAF V600E mutations, NTRK fusions and/or HER2 (ERBB2) amplifications, among others, have brought precision medicine to the forefront of management of advanced BTC. This holds especially true for patients with intrahepatic cholangiocarcinoma. Recently, immunotherapy, especially combined with chemoterapy, has also shown promising activity. The field is now moving forward - management is no longer limited to chemotherapy or targeted therapies alone, with increasing research focused on how combination strategies could enhance therapeutic responses. We are therefore facing a change of paradigm, where immunotherapy, cytotoxic chemotherapy and targeted therapies will be administered concomitantly with the aim of harnessing potential synergies. This review will focus on the rationale behind these combinations and summarise current clinical trial data.


Mandibular sarcoma as a second neoplasm following radiotherapy for a nasopharyngeal carcinoma in childhood (case report).
We report an unusual case of mandibular sarcoma which developed in the field of irradiation of a patient treated successfully 10 years previously for nasopharyngeal carcinoma (NC). Although second malignant neoplasms are not rare among survivors of childhood cancer, this event is not included among the type of failures and complications of treatment of NC occurring either in children.


Post-transcriptional gene silencing of the chalcone synthase gene CHS causes corolla lobe-specific whiting of Japanese gentian.
Post-transcriptional gene silencing of the chalcone synthase gene CHS specifically suppresses anthocyanin biosynthesis in corolla lobes and is responsible for the formation of a stripe type bicolor in Japanese gentian. The flower of Japanese gentian is a bell-shaped corolla composed of lobes and plicae, which is painted uniformly blue. However, the gentian cultivar 'Hakuju' shows bicolor phenotype (blue-white stripe corolla), in which anthocyanin accumulation is suppressed only in corolla lobes. Expression analysis indicated that steady-state levels of chalcone synthase (CHS) transcripts were remarkably reduced in corolla lobes compared with plicae during petal pigmentation initiation. However, no significant difference in expression levels of other flavonoid biosynthetic structural and regulatory genes was detected in its lobes and plicae. On feeding naringenin in white lobes, anthocyanin accumulation was recovered. Northern blotting probed with CHS confirmed the abundant accumulation of small RNAs in corolla lobes. Likewise, small RNA-seq analysis indicated that short reads from its lobes were predominantly mapped onto the 2nd exon region of the CHS gene, whereas those from the plicae were scarcely mapped. Subsequent infection with the gentian ovary ringspot virus (GORV), which had an RNA-silencing activity, showed the recovery of partial pigmentation in lobes. Hence, these results strongly suggested that suppressing anthocyanin accumulation in the lobes of bicolored 'Hakuju' was attributed to the specific degradation of CHS mRNA in corolla lobes, which was through post-transcriptional gene silencing (PTGS). Herein, we revealed the molecular mechanism of strip bicolor formation in Japanese gentian, and showed that PTGS of CHS was also responsible for flower color pattern in a floricultural plant other than petunia and dahlia.


Synthesis, properties and biological activity of organotitanium substituted heteropolytungstates.
Six new compounds [(CpTi)X, Cp=upsilon(nabla)-c(nabla)H(nabla), X=Ge, Ga, B) have been prepared and their Keggin structures determined by elementary analysis, IR, UV, (infinity)H NMR and (infinity for all)WNMR spectrometry. The results show that the complexes retain Keggin structure. The complexes exhibit antitumoral activity in vitro as shown by MTT experiment.


Direct Production of Difructose Anhydride IV from Sucrose by Co-fermentation of Recombinant Yeasts.
A functional sweetener, difructose anhydride IV (DFA IV), is enzymatically produced from sucrose via levan by levansucrase (LSRase) followed by levan fructotransferase (LFTase). Here, we have demonstrated a consolidated production system for the direct conversion of DFA IV from sucrose using the co-culture of two recombinant yeast strains secreting LSRase from Bacillus subtilis and LFTase from Arthrobacter ureafaciens, respectively. To ensure secretory production of the enzymes, target protein-specific translational fusion partners (TFP) were employed, and the selected strains produced 3.8 U/mL of LSRase and 16.0 U/mL LFTase activity into the fermentation broth. To optimise the direct production, sucrose concentration and cell ratios were investigated. In the optimised conditions, 64.3 g/L crude DFA IV was directly produced from 244.7 g/L sucrose using co-fermentation of recombinant yeasts. These results promise an efficient production titre, yield, and DFA IV productivity in an industrially applicable method.


Chemistry and functional role of the invariant chain.
The invariant chain has two critical properties that regulate the function of the class II glycoproteins with which it associates. It prevents class II molecules from binding antigenic peptides during the early stages of their assembly and transport, and it contains a signal that drives the assembled class II-invariant chain complex to an endocytic compartment. Dissociation of the invariant chain in this compartment is believed to generate class II molecules capable of binding antigenic peptides.


Recovery of the medial gastrocnemius muscle after calcaneus fracture differs between contractile and elastic components.
Calcaneal fractures result in severe functional impairments and walking restrictions. Postoperative evaluation mainly focusses on the restoration of calcaneal anatomy while ankle plantar flexor insufficiency remains largely neglected. This study aims to investigate biomechanical and morphologic adaptions of elastic and contractile components of the gastrocnemius medialis after unilateral calcaneal fracture. 20 Patients (BMI: 27.6 ± 3.1 kgm-2, Age: 50 ± 12 years) were measured using gait analysis and portable ultrasound over a follow-up of three, six and twelve months after surgery. Data comparison was performed using 20 matched healthy controls (BMI: 26.2 ± 2.9 kgm-2, Age: 48 ± 11 years). Static and dynamic behavior of the gastrocnemius muscle tendon unit, muscle fascicle and the serial-elastic element as well ankle joint kinematics and kinetics were analyzed. Within patients, a significant (p < 0.05) increase in fascicle length (by 67%) during single support and a decrease of serial elastic element shortening (by 20%) during push off was found between three and twelve months follow-up comparisons. Patients showed differences for fascicle lengthening and pennation angle increase during single support after three and six months compared to healthy controls. A smaller shortening of the serial-elastic element (by 29%) and muscle-tendon unit (by 16%) persisted even for the twelve month comparisons. Patients with calcaneal fracture showed an incomplete restoration of the medial gastrocnemius dynamic morphological behavior. While muscle fascicle contraction almost recovered, the serial elastic component still showed restrictions regarding its shortening behavior. Limited foot mobility and plantarflexor strength as well as lowered responsiveness of elastic tissues to mechanical loading are regarded as key mechanisms.