[Long term results of a series of cementless total hip prostheses on patients of less than 50 years old].
Since 1974, we have more than 20 years experience with cementless rehabitable total hip arthroplasty.The purpose of this work is a long term study of development of this type of fixation about a personal series of 83 hips which benefitted from this type of arthroplasty before 50 years old between 1974 and 1980. The implants used are among the oldest. On the acetabular side, we used the BG spiked acetabular component (Fig. 1), containing 4 teeth for primary fixation, 3 equatorial armatures and a surface treatment. This metal back in two sizes 50 and 54 mm, initially permitted the insertion of a polyethylen insert of an interior diameter of 32 mm with a peripheric thickness of 5.5 mm; since 1979, the insert had a 22.2 mm diameter, assuring 10 mm minimal thickness of. The femoral implant (Fig. 2) for 62 hips was the Huchet prothesis, then in 16 cases, the minimadreporic prothesis composed of a morse cone and a head of 22.2, the Huchet prothesis was one-piece femoral implant.The dominant etiology was coxarthrosis (56 cases) of which 50 % had major dysplasis. The average age at the time of the intervention was 41 years old (18-50 years), the follow-up of this series is 17 years, and 8 months (15-21 years). Resumption of former activities was the rule.Results of the rehabitable pro thesis up to 12.31.1995: Of the 83 cases, the outcome of 55 of them (66.3%) is known : 49 (59%) were examined for this study; the evolution has been documented; 28 (33.7%) were uncontactable, 6 patients (7.3%) were deceased between 8 and 9 years following the operation, without having had the hip revised.Among the 49 protheses which were evaluated, 22 (44.9%) have not been revised to date. Clinically, the function is normal and there are no radiological signs of attrition of the insert or mobilisation of implants. There are 10 Huchet Protheses and 12 minimadreporic protheses in this group. The average age at the time of the intervention was 42 years old (30-50 years old), the follow-up was 16 years and 7 months (15-19 years) (Fig. 3a-d).27 hips (51%) needed to be revised, but the causes of reoperationn include different reasons tied to the failure of biological fixation but particularly to errors in the initial concept of the Huchet prothesis.Reoperation linked to the failure of the biological fixation: Out of 7 acetabular implant reoperations, one was carried out systematically on a cup which was perfectly bone-integrated during the changing of a femoral component, 3 were necessary due to perforation (attrition of the insert). Only 3 acetabular implants (6.1%) required reoperation for symptomatic loosening.Four femoral implants (8.6%) have been taken out because of failure of biological fixation between 2 and 11 years follow-up. Finally, for one patient the persistance of the incapacitating crural pain which lasted for more than one year led to the removal of the femoral stem, nevertheless perfectly integrated.Reoperation linked to the concept of the Huchet prothesis: These were undertaken in two sets of circumstances.Changing only the polyethylene insert was only called for in the Huchet prosthesis and concerned 18 hips (36.7%); the delay to reoperation varied from 11 to 18 years with an average of 14 years delay. Changing of the insert had a simple short post-operative outcome and functional recuperation was between 6 and 8 weeks (Fig. 4a-c).Removal for perforative attrition of polyethylene insert causing metal-to-metal wear between head and metal back. Five Huchet prostheses are included in this group, with an average delay to reoperation of 16 years and 3 months (14-19 years). This retrospective study with a 66.3 % rate of re-examination permits three types of comments.The principal cause of revision (23 cases), is linked to polyethylene attrition and is only found in the group with Huchet prosthesis. More than the quality of the polyethylene used at this time, it is its thickness in contact with a 32 mm head which led to the complete removal of the prosthesis in 10.2% of the cases.The second comment argues for the modularisation of the femoral implant. The presence of a stem with a cone and a removable head would have avoided the removal of 5 perfectly bone-integrated femoral implants. Certainly, the literature demonstrates the risk of corrosion generated by the morse cone but it is up to the manufacturers to improve their procedures.Finally, the third comment concerns the current state of the long term of the biological fixation by rehabilitation with surface treatment. With 17 years 8 months follow-up (15-21 years), 81.6% of components are still fixed, the real failure of the bony ingrowth of 10.2% is comparable to the rate of failure in long term follow-up of totally cemented prothesis found in young subjects. With more than 20 years follow-up for the older cases, the concept of the biological fixation of an implant by bony ingrowth using surface treatment seems to be very reliable.The experience of this long term study argues for the thickness of polyethylene to be at least 10 mm for all metal back acetabular component and the future of this kind of implant seems to lie in modularisation made possible by the morse cone which would allow the replacement of the bearing surfaces.


Jordanian nurses perception of physicians' verbal abuse: findings from a questionnaire survey.
The purpose of this descriptive study was to describe the frequency, severity, emotional reactions, and coping behavior of Jordanian nurses working in hospitals in response to verbal abuse. A convenience sample of 138 nurses employed in five hospitals was surveyed using the verbal abuse questionnaire (VAQ), which was developed for this study and received limited testing for reliability (homogeneity) and validity. This instrument measured different aspects of verbal abuse against Jordanian nurses. Findings indicate that the most frequent and most severe forms of verbal abuse reported were judging and criticizing, accusing and blaming, and abusive anger; the most common emotional reactions were anger, followed by shame, humiliation and frustration and most nurses used engaging in negative activities to cope with verbal abuse. Findings of this study highlights the need for hospitals to develop protocols for reporting and dealing with verbal abuse from physicians toward nurses.


An antifungal protein from flageolet beans.
A protein with antifungal and hemagglutinating activities was isolated from dried flageolet beans (Phaseolus vulgaris cv. 'Flageolet Bean'). The protein was unadsorbed on DEAE-cellulose but adsorbed on Affi-gel blue gel and CM-cellulose. The protein demonstrated antifungal activity against Mycophaerella arachidicola with an IC50 of 9.8 microM, but was inactive toward Fusarium oxysporum and Botrytis cinerea. Its hemagglutinating activity could not be inhibited by a variety of the sugars tested. The activity was stable up to 60 degrees C. At 70 degrees C, 75% of the hemagglutinating activity remained while no activity was discernible at and above 100 degrees C. The hemagglutinating activity was stable in the presence of a variety of monovalent, divalent and trivalent chlorides, and also when the ambient pH changed from 3 to 12. It did not exert any mitogenic activity on mouse splenocytes in vitro. Neither did it inhibit HIV-1 reverse transcriptase. It inhibited [3H-methyl]-thymidine incorporation into leukemia L1210 cells with an IC50 of about 4 microM.


PAS kinase: integrating nutrient sensing with nutrient partitioning.
Recent data suggests that PAS kinase acts as a signal integrator to adjust metabolic behavior in response to nutrient conditions. Specifically, PAS kinase controls the partitioning of nutrient resources between the myriad of possible fates. In this capacity, PAS kinase elicits a pro-growth program, which includes both signaling and metabolic control, both in yeast and in mammals. We propose that, like other kinases possessing these properties-AMPK and TOR, PAS kinase might be target for therapy of diabetes, obesity and cancer.


Marked decrease in the incidence and prevalence of hepatitis A in the Basque Country, Spain, 1986-2004.
The aim of this study was to determine changes in the epidemiology of hepatitis A virus (HAV) infection in the Basque Country, Spain, and to evaluate their implications for vaccination strategies. A total of 1356 persons were enrolled in a study of the prevalence of anti-HAV in 2004 and compared with two previous studies (1986-1987 and 1992). The selection method and the characteristics of the population were similar in the three studies. A marked decline in the seroprevalence in all age groups (P<0.001) and in the incidence of cases/100,000 inhabitants (from 38.0 in 1986-1988 to 2.9 in 2002-2004) were observed. The mean age of patients with hepatitis A increased from 17.7 years in 1986-1992 to 21.2 years in 1993-1998 and 25.3 years in 1999-2004 (P<0.001). Between 1997 and 2004, 20% of patients were hospitalized. The changes observed have occurred rapidly causing a change in the epidemiological pattern from middle-high endemicity (1986) to low endemicity (2004).


1H and 13C NMR study of the molecular interaction mechanism between chloramphenicol and human serum albumin.
Molecular mechanism of the interaction between human serum albumin and cloramphenicol was studied by 1H and 13C NMR-spectroscopy. It was found that the main role belongs to [formula: see text] groups of chloramphenicol. A schematic model of the complex-formation between serum albumin and chloramphenicol was proposed.


The efficacy of patient specific instrumentation (PSI) in total hip arthroplasty (THA): A systematic review and meta-analysis.
Patient-specific instrumentation (PSI) has been suggested to reduce improper component positioning, though the effectiveness of PSI in total hip arthroplasty (THA) remains inconclusive. The purpose of this study was to evaluate the radiographic parameters and clinical outcomes comparing PSI and standard instrumentation (SI). This systematic review and meta-analysis was conducted in accordance with the 2020 PRISMA statement and was registered on PROSPERO. PubMed, Embase, Scopus, Google Scholar, and ClinicalTrials.gov were searched for relevant studies pertaining to the use of PSI in THA. Inclusion criteria included PSI used in THA, PSI was directly compared to SI, and publication in English. Exclusion criteria included non-primary THA, review articles, abstracts, book chapters, and animal models. 2,458 studies were initially identified, with 13 studies (677 THAs: 338 controls, 339 PSI) meeting all criteria. PSI was favored for the deviation from the preoperative plan for acetabular cup position for anteversion (p = 0.04) and inclination (p = 0.0002); risk of acetabular cup positioning outside the Lewinnek safe zone for anteversion (p = 0.005) and inclination (p < 0.0001); and postoperative Harris Hip Score (p = 0.0002). No significant differences were found for the deviation from the preoperative plan for femoral stem position for anteversion (p = 0.74) or varus/valgus (p = 0.15); intraoperative time (p = 0.55); or intraoperative blood loss (p = 0.62). The use of PSI in THA is effective in improving acetabular component positioning and postoperative functional outcomes, without increasing intraoperative time or blood loss, compared to SI.


How informed are endocrine surgery patients about the risks of surgery after approving an informed consent?
The aim is to evaluate if patients reach the level of competence that enables them to make the best decision for themselves with oral and written informed consent process that is legally valid. This study included 62 patients who applied to Ege University Hospital Department of General Surgery Endocrine Surgery Clinics and in whom oral and written informed consent was obtained by a surgeon. Patients who were willing to participate in the study were asked to fill in a questionnaire containing questions regarding the concept of consent. Seventy-one percent of patients were female and 29% were male, with a mean age of 50.4±17.9 years. Six percent of patients were illiterate, 51.6% had primary education and 16.1% were college graduates. One in every two patients stated that they have never heard of informed consent concept before, 16% stated that they signed the consent without reading it. Among these patients, 88% reported that they trusted the physician and did not bother reading because they have already been verbally informed. Verbal briefing by the doctor was detected as 92%. Similarly, 91% of the patients reported that the time allocated to read and fill-in the form was enough. Informing is not composed simply of conveying information, but also to elevate patients to a proficiency level where they could decide with their best interest. It is thought that the results obtained in this study might guide studies to improve the quality of information in patients undergoing surgery.


Phytochelatin induction, cadmium accumulation, and algal sensitivity to free cadmium ion in Scenedesmus vacuolatus.
Phytochelatins are small, intracellular, metal-binding polypeptides produced by algae on exposure to increased metal concentration in their environment. The aim of the present study was to examine the relationship between phytochelatin concentration, bioaccumulated metal, and sensitivity of algal growth on cadmium exposure. For that purpose, intracellular cadmium concentration and thiol (glutathione, gamma-glutamylcysteine [gammaGluCys], and phytochelatins [PCn]) content were determined in the freshwater green alga Scenedesmus vacuolatus exposed to growth-inhibitory and noninhibitory concentrations of free Cd2+ in the range from 10(-14) to 10(-7) M. The algal growth rate was optimal up to a free Cd2+ concentration of 10(-9) M and then decreased by 40% at higher concentrations. The intracellular cadmium content increased sharply from 0.22 to 746 amol/cell over this free Cd2+ range. At the lowest Cd2+ concentration (control), glutathione was the only detectable thiol (127 amol/cell). With increasing Cd2+, formation of gammaGluCys and phytochelatins from PC2 to PC6 were observed. The predominant oligomer was PC3, with 42 amol/cell at the highest Cd2+ concentration (10(-7) M). The ratio of the concentration of total thiol groups to intracellular cadmium was important for maintaining optimal growth. In contrast, thiol groups from phytochelatins were never measured in excess to intracellular cadmium content.


Synthesis, Biological Evaluation, and In Silico Studies of Novel Coumarin-Based 4H,5H-pyrano[3,2-c]chromenes as Potent β-Glucuronidase and Carbonic Anhydrase Inhibitors.
The search for novel heterocyclic compounds with a natural product skeleton as potent enzyme inhibitors against clinical hits is our prime concern in this study. Here, a simple and facile two-step strategy has been designed to synthesize a series of novel coumarin-based dihydropyranochromenes (12a-12m) in a basic moiety. The synthesized compounds were thus characterized through spectroscopic techniques and screened for inhibition potency against the cytosolic hCA II isoform and β-glucuronidase. Few of these compounds were potent inhibitors of hCA II and β-glucuronidase with varying IC50 values ranging from 4.55 ± 0.22 to 21.77 ± 3.32 μM and 440.1 ± 1.17 to 971.3 ± 0.05 μM, respectively. Among the stream of synthesized compounds, 12e and 12i were the most potent inhibitors of β-glucuronidase, while 12h, 12i, and 12j showed greater potency against hCA II. In silico docking studies illustrated the significance of substituted groups on the pyranochromene skeleton and binding pattern of these highly potent compounds inside enzyme pockets.


An examination of the incremental contribution of emotion regulation difficulties to health anxiety beyond specific emotion regulation strategies.
Given the potential transdiagnostic importance of emotion dysregulation, as well as a lack of research examining emotion dysregulation in relation to health anxiety, the present study sought to examine associations among specific emotion regulation strategies (cognitive reappraisal and expressive suppression), emotion regulation difficulties, and health anxiety in a physically healthy sample of adults (N=482). As hypothesized, results of a series of hierarchical multiple regression analyses showed that emotion regulation difficulties provided a significant incremental contribution, beyond the specific emotion regulation strategies, in predicting each of the three health anxiety variables. Among the six dimensions of emotion regulation difficulties, the dimension representing perceived access to effective emotion regulation strategies was the only emotion regulation difficulty dimension that predicted all three health anxiety variables beyond the effects of the specific emotion regulation strategies. Results indicate that emotion regulation difficulties, and particularly one's subjective appraisal of his/her ability to effectively regulate emotions, may be of importance to health anxiety. Clinical implications are discussed.


A refined method for digitally modeling small and complex plant structures in 3D: An example from the grasses (Poaceae).
A refined procedure is described for modeling small, intricate plant structures using computer-aided design software. The procedure facilitates the study of wind pollination in the family Poaceae and provides virtual biological illustrations for public outreach. Spikelets were fixed in gFAA, dehydrated using ethanol and xylene, embedded in paraffin wax, and then sectioned with a rotary microtome. Images of serial sections were used as a reference for modeling the shape of bracts with splines in a computer-aided design program. Virtual models produced by this method have many potential uses; examples include geometric morphometric analyses and simulations of computational fluid dynamics. This protocol is a synthesis of modern biological illustration and engineering technology. Virtual models facilitate quantitative experiments that may address questions about reproductive biology, conditions shaping the form of anatomical support, or the morphological evolution of structures of biomechanical interest.


Sentinel lymph node biopsy in breast cancer patients: the medical oncology perspective.
Recent data indicates that the sentinel lymph node biopsy (SLNB) is a possible alternative to axillary lymph node dissection (ALND) in early breast cancer patients, with minimal risk of complications. From the medical oncologist's point of view, the impact of SLNB on the management of patients should consider if SLNB is useful to choose adjuvant treatment, if it is adequate to provide local control, and what is the significance of lymph node micrometastases on treatment and staging. Lymph node involvement has always been recognised as the most important prognostic factor in early-stage breast cancer, even if many other parameters have been evaluated in recent years. However, the lack of knowledge of nodal status in patients with false-negative SLNB seems to result in an undertreatment in a very low percentage of patients. Adjuvant chemotherapy and hormonal therapy with tamoxifen are associated with an absolute reduction of the risk of recurrence and death both in node-positive and in node-negative patients, then if patients are treated with modern adjuvant systemic therapy, any effect associated with false negative SLN should be minimised. The impact of axillary treatment on survival is still controversial, but in recent times axillary lymph node positivity is considered as an indicator for high risk of systemic diffusion of the disease rather than a possible origin of systemic metastases. The significance of occult sentinel lymph node metastases detected by immunohistochemistry (IHC) or molecular biology on prognosis is still uncertain. The new version of the staging system of breast cancer has recognised the need for a standard diagnostic approach and of a nomenclature system which also takes SLNB into account.


Untangling the web of glioblastoma treatment resistance using a multi-omic and multidisciplinary approach.
Glioblastoma (GBM), the most common human brain tumor, has been notoriously resistant to treatment. As a result, the dismal overall survival of GBM patients has not changed over the past three decades. GBM has been stubbornly resistant to checkpoint inhibitor immunotherapies, which have been remarkably effective in the treatment of other tumors. It is clear that GBM resistance to therapy is multifactorial. Although therapeutic transport into brain tumors is inhibited by the blood brain barrier, there is evolving evidence that overcoming this barrier is not the predominant factor. GBMs generally have a low mutation burden, exist in an immunosuppressed environment and they are inherently resistant to immune stimulation, all of which contribute to treatment resistance. In this review, we evaluate the contribution of multi-omic approaches (genomic and metabolomic) along with analyzing immune cell populations and tumor biophysical characteristics to better understand and overcome GBM multifactorial resistance to treatment.


Altered host response and special infections in the elderly.
Infection remains one of the most common causes for Emergency Department evaluation and hospital admission in the elderly. Unfortunately, aged individuals may not manifest the typical symptoms and signs as their younger counterparts. The emergency physician must recognize that the elderly individual may exhibit a less vigorous physiologic response to infectious states, which can delay or make diagnosis difficult. This article attempts to explain the apparent dysfunctions in the elderly that places this important population at greater risk for certain infections.


Predictors of prolonged survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma.
A total of 149 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem cell transplantation (allo-HCT) with myeloablative (MAC; n = 38) or reduced-intensity conditioning (RIC; n = 110) regimens at MD Anderson Cancer Center were evaluated. Of the total, 120 (81%) patients had relapsed or had refractory disease. Median age of MM patients was 50 (28-70) years with a followup time of 28.5 (3-164) months. The 100-day and 5-year treatment related mortality (TRM) rates were 17% and 47%, respectively. TRM was significantly lower with RIC regimens (13%) vs. 29% for MAC at 100 days (P = 0.012). The cumulative incidence of Grade II-IV acute graft-versus-host disease (GVHD) was 35% and chronic GVHD was 46%. PFS and OS at 5 years were 15% and 21%, respectively. In multivariate analysis, allo-HCT for primary remission consolidation was associated with longer PFS (HR 0.35; 95% CI, 0.18-0.67) and OS (HR 0.29; 95% CI 0.15-0.55), while absence of high-risk cytogenetics was associated with longer PFS only (HR 0.59; 95% CI 0.37-0.95). We observe that TRM has decreased with the use of RIC regimens, and long-term disease control can be expected in a subset of MM patients undergoing allo-HCT. Further studies should be conducted in carefully designed clinical trials in this patient population.


Macrophage-secreted MMP9 induces mesenchymal transition in pancreatic cancer cells via PAR1 activation.
Targeting tumor-infiltrating macrophages limits progression and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC). Protease-activated receptor (PAR)1 drives monocyte/macrophage recruitment, and stromal ablation of PAR1 limits cancer growth and enhances gemcitabine sensitivity in experimental PDAC. However, the functional interplay between PAR1, macrophages and tumor cells remains unexplored. Here we address the PAR1-macrophage-tumor cell crosstalk and assess its contributions to tumor progression. PAR1 expression and macrophage infiltration were correlated in primary PDAC biopsies using gene expression datasets and tissue microarrays. Medium transfer experiments were used to evaluate the functional consequences of macrophage-tumor cell crosstalk and to assess the contribution of PAR1 to the observed responses. PAR1 cleavage assays were used to identify a macrophage-secreted PAR1 agonist, and the effects of candidate proteases were assessed in medium transfer experiments with specific inhibitors and/or recombinant agonist. PAR1 expression correlates with macrophage infiltration in primary PDACs, and macrophages induce mesenchymal transition of PDAC cells through PAR1 activation. Protease profiling identified macrophage-secreted matrix metalloprotease 9 (MMP9) as the relevant PAR1 agonist in PDAC. PAR1 and/or MMP9 inhibition limited macrophage-driven mesenchymal transition. Likewise, preventing mesenchymal transition by silencing ZEB1 or by pharmacological inhibition of the MMP9/PAR1 axis significantly reduced the ability of tumor cells to survive the anti-tumor activities of macrophages. Macrophages secrete MMP9, which acts upon PDAC cell PAR1 to induce mesenchymal transition. This macrophage-induced mesenchymal transition supports the tumor-promoting role of macrophage influx, explaining the dichotomous contributions of these immune cells to tumor growth.


Microstructure and biopharmaceutical performances of curcumin-loaded low-energy nanoemulsions containing eucalyptol and pinene: Terpenes' role overcome penetration enhancement effect?
The objective of this work was to develop low-energy nanoemulsions for enhanced dermal delivery of curcumin, using monoterpene compounds eucalyptol (EUC) and pinene (PIN) as chemical penetration enhancers. Spontaneous emulsification was the preparation method. All formulations contained 10% of the oil phase (medium-chain triglycerides (MCT), or their mixture with EUC or PIN). Formulations were stabilized by the combination of polysorbate 80 and soybean lecithin (surfactant-to-oil-ratio=1). Concentration of curcumin was set to 3 mg/ml. Average droplet diameter of all tested formulations ranged from 102 nm to 132 nm, but the ones containing monoterpenes had significantly smaller size compared to the MCT formulation. Such finding was profoundly studied through electron paramagnetic resonance spectroscopy, which proved that the presence of monoterpenes modified the nanoemulsions' interfacial environment, resulting in droplet size reduction. The release study of curcumin (using Franz cells) demonstrated that the cumulative amount released after 6 h of the experiment was 10.1 ± 0.2% for the MCT nanoemulsions, 13.9 ± 0.1% and 14.0 ± 0.2% for PIN and EUC formulations, respectively. In vivo tape stripping revealed their performances in delivering curcumin into the skin, indicating the following order: EUC>MCT>PIN. The formulation with EUC was clearly the most successful, giving the highest cumulative amount of curcumin that penetrated per surface unit: 34.24±5.68 µg/cm2. The MCT formulation followed (30.62±2.61 µg/cm2) and, finally, the one with PIN (21.61±0.11 µg/cm2). These results corelated with curcumin's solubility in the chosen oils: 4.18±0.02 mg/ml for EUC, 1.67±0.04 mg/ml for MCT and 0.21±0.01 mg/ml for PIN. Probably, higher solubility in the oil phase of the nanoemulsion promoted curcumin's solubility in the superficial skin layers, providing enhanced penetration.


Phonological short-term store impairment after cerebellar lesion: a single case study.
The cerebellum is a recent addition to the growing list of cerebral areas involved in the multifaceted structural system that sustains verbal working memory (vWM), but its contribution is still a matter of debate. Here, we present a patient with a selective deficit of vWM resulting from a bilateral cerebellar ischemic lesion. After this acute event, the patient had impaired immediate and delayed word-serial recall and auditory-verbal delayed recognition. The digit span, however, was completely preserved. To investigate the cerebellar contribution to vWM, four experiments addressing the function of different vWM phonological loop components were performed 18 months after the lesion, and results were compared with normative data or, when needed, with a small group of matched controls. In Experiment 1, digit span was assessed with different presentation and response modalities using lists of digits of varying lengths. In Experiment 2, the articulatory rehearsal system was analyzed by measurement of word length and articulatory suppression effects. Experiment 3 was devoted to analyzing the phonological short-term store (ph-STS) by the recency effect, the phonological similarity effect, short-term forgetting, and unattended speech. Data suggested a possible key role of the semantic component of the processed material, which was tested in Experiment 4, in which word and nonword-serial recall with or without interpolating activity were analyzed. The patient showed noticeably reduced scores in the tasks that primarily or exclusively engaged activity of the ph-STS, namely those of Experiment 3, and good performance in the tests that investigated the recirculation of verbal information. This pattern of results implicates the ph-STS as the cognitive locus of the patient's deficit. This report demonstrates a cerebellar role in encoding and/or strengthening the phonological traces in vWM.


Glucosyl transferase activity and diabetic microangiopathy.
Thickening of the basement membrane and deposition of collagen-like substances in vascular lesions are well-known findings in diabetes mellitus, suggesting altered metabolism of glycoproteins. Glomerular glucosyltransferase activity were measured in normal and diabetic rats. Enzymic activity in diabetic animals did not differ from control. Another mechanism must be involved in the thickening of the B.M., such as increased production of hydroxylysine-rich peptides or decreased breakdown of B.M. materials.


Uptake of genetic counselling and predictive DNA testing in hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy is a common autosomal dominant disease, associated with heart failure and arrhythmias predisposing to sudden cardiac death. After the detection of the causal mutation in the proband predictive DNA testing of relatives is possible (cascade screening). Prevention of sudden cardiac death in patients with a high risk by means of an implantable cardioverter defibrillator is effective. In 97 hypertrophic cardiomyopathy families with a sarcomere gene mutation we retrospectively determined uptake of genetic counselling and predictive DNA testing in relatives within 1 year after the detection of the causal mutation in the proband. Uptake of genetic counselling was 39% and did not differ significantly by proband's or relative's gender, nor by young age of the relative (< 18 years) or a family history positive for sudden cardiac death. In second-degree relatives, eligible for predictive DNA testing when the first-degree relative had died, uptake was 27.5% (P = 0.047). Uptake of predictive genetic testing was 39%; conditional uptake of predictive genetic testing was 99%. Uptake of genetic counselling in hypertrophic cardiomyopathy is comparable to uptake in oncogenetics. Conditional uptake of predictive DNA testing, however, is much higher. Because sudden cardiac death can be prevented uptake of genetic counselling in hypertrophic cardiomyopathy should be as high as possible. To achieve this research into the determinants of uptake is needed.


Quantitative evaluation of anterior tibial translation during isokinetic motion in knees with anterior cruciate ligament reconstruction using either patellar or hamstring tendon grafts.
We studied 79 patients with unilateral injury to the anterior cruciate ligament (ACL). The patients were randomly allocated to reconstruction with autologous patellar bone-tendon-bone (BTB) grafts (49 knees) or hamstring tendon (ST) grafts (30 knees). We measured anterior tibial translation (ATT) during isokinetic concentric contraction exercise 18-20 months after surgery using a computerized electrogoniometer. In both groups the highest ATT during exercise was observed at a knee flexion of about 20 degrees and was 13.5+/-3.0 mm in the BTB group and 13.9+/-3.4 mm in the ST group. There was no difference in the ATT between the reconstructed and healthy knees. For a range of knee flexion between 30 and 50 degrees the ATT in the ST group was significantly higher on the reconstructed side than on the healthy side. In the BTB group, the mean ATT in the reconstructed group was similar to that on the healthy side at a knee flexion angle between 0 and 90 degrees .


Major basic protein binding to thrombomodulin potentially contributes to the thrombosis in patients with eosinophilia.
The contribution of an eosinophil granule protein, major basic protein (MBP), to the pathogenesis of thrombosis seen in patients with eosinophilia was investigated. The sera from eosinophilic patients containing elevated levels of MBP inhibited thrombomodulin (TM) function as a cofactor for the thrombin-catalysed activation of protein C more significantly than those from normal individuals (means 48.5% v 17.4%, respectively). It was suggested that the binding of mature MBP in the sera to TM was electrostatic, because mature MBP (pI 10.9) bound to TM, whereas pro-MBP (pI 6.2) did not. The inhibition of TM cofactor activity by eosinophil granule proteins was mainly attributed to the mature MBP, because MBP-depleted eosinophil granule proteins did not inhibit TM cofactor activity significantly. This inhibition seemed to be due to the specific thrombin-binding to TM being blocked. We concluded that eosinophil granule proteins, particularly MBP, potentially contribute to the hypercoagulation seen in some conditions of eosinophilia, at least because of the inhibition of TM function as a cofactor of the anticoagulation system.


Combined Preparation of Human Olfactory Ensheathing Cells in the Therapy of Post-Traumatic Cysts of the Spinal Cord.
In experiments on rats, co-transplantation of olfactory ensheathing cells of the human olfactory mucosa and neural stem/progenitor cells from the same source into post-traumatic cysts of the spinal cord led to improvement of the motor activity of the hind limbs and reduced the size of the cysts in some animals by 4-12%. The transplantation of a combination of the olfactory mucosa cells is effective and can be used in preclinical trials for the treatment of spinal cord injuries.


Family history of postpartum hemorrhage is a risk factor for postpartum hemorrhage after vaginal delivery: results from the French prospective multicenter Haemorrhages and Thromboembolic Venous Disease of the Postpartum cohort study.
Postpartum hemorrhage is a major component of perinatal morbidity and mortality that affects young women worldwide and is still often unpredictable. Reducing the incidence of postpartum hemorrhage is a major health issue and identifying women at risk for postpartum hemorrhage is a key element in preventing this complication. This study aimed to estimate postpartum hemorrhage prevalence after vaginal delivery and to identify postpartum hemorrhage risk factors. Unselected pregnant women ≥16 years of age admitted to 1 of 6 maternity wards in Brittany (France) for vaginal birth after 15 weeks of gestation were recruited in this prospective, multicenter cohort study between June 1, 2015, and January 31, 2019. Postpartum hemorrhage was defined as blood loss ≥500 mL in the 24 hours following delivery. Independent risk factors for postpartum hemorrhage were determined using logistic regression. Missing data were imputed using the Multivariate Imputation by Chained Equations method. Among 16,382 included women, the postpartum hemorrhage prevalence was 5.37%. A first-degree family history of postpartum hemorrhage (adjusted odds ratio, 1.63; 95% confidence interval, 1.24-2.14) and a personal transfusion history (adjusted odds ratio, 1.90; 95% confidence interval, 1.23-2.92) were significantly associated with postpartum hemorrhage. The use of oxytocin during labor was also a risk factor for postpartum hemorrhage (adjusted odds ratio, 1.24; 95% confidence interval, 1.06-1.44). Inversely, smoking during pregnancy and intrauterine growth restriction were associated with a reduced risk for postpartum hemorrhage (adjusted odds ratio, 0.76; 95% confidence interval, 0.63-0.91, and 0.34; 95% confidence interval, 0.13-0.87, respectively). In addition to classical risk factors, this study identified a family history of postpartum hemorrhage and personal transfusion history as new characteristics associated with postpartum hemorrhage after vaginal delivery. The association of postpartum hemorrhage with a family history of postpartum hemorrhage suggests a hereditary hemorrhagic phenotype and calls for genetic studies. Identifying women at risk for postpartum hemorrhage is a key element of being prepared for this complication.


Built environment influences on urban climate resilience: Evidence from extreme heat events in Macau.
Systematic understanding of climate resilience in the urban context is essential to improve the adaptive capacity in response to extreme weather events. Although the urban built environment affects climate resilience, empirical evidence on the associations between the built environment and urban climate resilience is rare in the literature. In this study, urban heat resilience (HR) is measured as the land surface temperature (LST) difference in a given urban area between normal and extreme heat event, and it further explores the impact of two-dimensional (2D) and three-dimensional (3D) urban built environment features on HR. Using spatial regression, we find that solar insolation and water density are the dominant factors in determining land surface temperature. However, they do not appear to influence HR significantly. Results indicate that vegetation and urban porosity are crucial both in reducing LST and improving HR during extreme heat events. This study highlights the importance of 2D and 3D urban built environment features in improving HR to extreme heat events.


Comparative analysis of cytotoxic T lymphocytes in lymph nodes and peripheral blood of simian immunodeficiency virus-infected rhesus monkeys.
Most studies of human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocytes (CTL) have been confined to the evaluation of these effector cells in the peripheral blood. What has not been clear is the extent to which CTL activity in the blood actually reflects this effector cell function in the lymph nodes, the major sites of HIV-1 replication. To determine the concordance between CTL activity in lymph nodes and peripheral blood lymphocytes (PBL), CTL specific for simian immunodeficiency virus of macaques (SIVmac) have been characterized in lymph nodes of infected, genetically selected rhesus monkeys by using both Gag peptide-specific functional CTL assays and tetrameric peptide-major histocompatibility complex (MHC) class I molecule complex staining techniques. In studies of six chronically SIVmac-infected rhesus monkeys, Gag epitope-specific functional lytic activity and specific tetrameric peptide-MHC class I staining were readily demonstrated in lymph node T lymphocytes. Although the numbers of tetramer-binding cells in some animals differed from those documented in their PBL, the numbers of tetramer-binding cells from these two different compartments were not statistically different. Phenotypic characterization of the tetramer-binding CD8(+) lymph node T lymphocytes of the infected monkeys demonstrated a high level of expression of the activation-associated adhesion molecules CD11a and CD49d, the Fas molecule CD95, and MHC class II-DR. These studies documented a low expression of the naive T-cell marker CD45RA and the adhesion molecule CD62L. This phenotypic profile of the tetramer-binding lymph node CD8(+) T cells was similar to that of tetramer-binding CD8(+) T cells from PBL. These observations suggest that characterization of AIDS virus-specific CTL activity by sampling of cells in the peripheral blood should provide a reasonable estimation of CTL in an individual's secondary lymphoid tissue.


Novel features in the evolution of adenylosuccinate lyase deficiency.
Adenylosuccinate lyase (ADSL) deficiency is an autosomal recessive disorder of the purine synthesis which results in accumulation of succinylpurines (succinyladenosine (S-Ado) and succinylamino-imidazole carboxamide riboside (SAICAr)) in body fluids. Patients present developmental delay, often accompanied by epilepsy and autistic spectrum disorders. To describe atypical neurological features in the evolution of three novel unrelated cases of ADSL deficiency. A 9-year-old boy with severe cognitive impairment and autistic behaviour received d-ribose therapy for one year. Drug withdrawal was associated with acute neurological deterioration, severe brain atrophy and demyelination on MRI. The second patient is a 5.5-year-old girl with mild developmental delay who presented a benign course with moderate cognitive impairment as the only feature in her evolution. The final patient is a 14-year-old boy with severe cognitive impairment who developed drug-resistant epilepsy and bathing reflex seizures, progressive spasticity in the lower limbs and thoracic deformity. SAICAr and S-Ado in urine were analysed by HPLC with diode array detection. Diagnosis was confirmed by molecular analysis of the ADSL gene. An elevation of S-Ado and SAICAr excretion in urine was detected in all three patients. The patients were homozygous for the missence change p.I369L and for the novel change p.M389V. Drug-resistant epilepsy and specific therapeutic interventions may modify the neurological outcome in ADSL deficiency. d-ribose must be considered with caution as, in our experience, it returns no clinical benefit and drug withdrawal can precipitate status epilepticus and acute neurological deterioration.


Deposition and mobilization of viruses in unsaturated porous media: Roles of different interfaces and straining.
The vadose zone is the first natural layer preventing groundwater pollution. Understanding virus transport and retention in the vadose zone is necessary. The effects of different interfaces and mechanisms on virus transport and retention were investigated by studying Escherichia coli phage migration in laboratory-scale columns under unsaturated conditions. The E. coli phage was used as a model virus. Colloid filtration theory, extended Derjagin-Landau-Verwey-Overbeek theory and two-site kinetic deposition model were used to calculate fitted parameters and interaction energies to assess virus retention at different interfaces. The collector diameters and the size of E. coli phages in the influent and effluent were compared to assess the effect of straining. The results indicated that the roles of solid-water interfaces (SWIs) and air-water interfaces (AWIs) in retaining E. coli phages are strongly controlled by the moisture content and hydrochemical conditions. Decreasing the moisture content and increasing the ionic strength (IS) of the suspension increased E. coli phage retention. At suspension ISs of 0.01 or 0.03 M and various moisture contents, E. coli phages were mainly retained at the SWIs rather than AWIs. When the IS was increased to 0.06 M, the viruses were strongly retained by becoming attached to both SWIs and AWIs. The role of straining in virus retention could not be ignored. Viruses were retained more at the SWIs and less straining occurred under acidic conditions than under neutral or alkaline conditions. This was mainly because of the effects of the pH and IS on surface charges and the model virus particle size. This study has important implications for modeling and predicting virus transport in soil affected by rainfall, snowmelt, and human activities (e.g., irrigation and artificial groundwater recharging).


Conception rate and pregnancy loss in fixed-time cattle embryo transfer programs are related to the luteal blood perfusion but not to the corpus luteum size.
This study aimed to evaluate the effect of luteal blood perfusion and corpus luteum (CL) area on the conception rate and occurrence of pregnancy loss of recipients in a large-scale fixed-time embryo transfer (FTET) program. Multiparous Brangus cows (n = 1700) at 45 days postpartum and body condition scores (BCS) between 2.5 and 4.0 (3.0 ± 0.3) were used in this study. On a random day of the estrous cycle (day -10), the females received progesterone and estradiol based on the FTET protocol. On day 7, 1465 recipients had at least one CL and were evaluated using B-mode ultrasound for the CL area (cm2) and color Doppler for the luteal blood perfusion score (I/low-vascularization area <40% of the CL; II/medium-vascularization >45% to < 50%; and III/high-vascularization >50%). Immediately after CL evaluation, each recipient received a single fresh embryo (blastocyst stage) ipsilateral to the CL, in vitro produced from a commercial laboratory. Pregnancy diagnosis was performed at 30 days and repeated 60 days later to evaluate pregnancy loss (30-90 days). Ultrasound evaluation and embryo transfer were performed by a single technician. For data analysis, in addition to luteal blood perfusion groups, recipients were retrospectively ranked according to CL area into small (<3 cm2; 2.63 ± 0.01), medium (>3 to < 4 cm2; 3.44 ± 0.01), and large (>4 cm2; 4.77 ± 0.03). Data were analyzed using a logistic regression model (P < 0.05). The overall conception rate was 44.2% (648/1465), influenced by the luteal blood perfusion score [P = 0.03; high 48.4%a (134/277), medium 44.6%a (427/958), and low 37.8%b (87/230)] but not by CL area ranking [P = 0.37; large 41.8% (225/538), medium 45.2% (276/610), and small 46.4% (147/317)]. There was no interaction between the luteal blood perfusion score and CL area ranking (P = 0.81), and the BCS did not affect the results of this study (P = 0.51). In terms of pregnancy loss up to 90 days, there was no effect on the CL area ranking (P = 0.77), but the flow score showed an effect [P = 0.03; high 3.6%b (5/139), medium 9.3%a (44/471), and low 10.3%a (10/97)]. The conception rate and occurrence of pregnancy loss in the FTET program in beef cattle are related to luteal blood perfusion but not CL size.


Significant correlation between expression of heat shock proteins 27, 70 and lymphocyte infiltration in esophageal squamous cell carcinoma.
The objective of this study was to clarify the clinicopathologic and prognostic significance of heat shock proteins (HSP) 27 and 70 expression in esophageal squamous cell carcinoma (SCC). Immunohistochemical staining for HSPs 27 and 70 was performed on surgical specimens obtained from 62 patients with esophageal SCC. The expression of both HSPs 27 and 70 correlated inversely with depth of invasion (P<0.05) and pathologic stage (P<0.05), and correlated positively with lymphocyte infiltration (P<0.05). Reduction of HSP 70 expression was significantly correlated with poor prognosis (P<0.05). Patients with HSP 27-negative tumors tended to have a poor prognosis compared with patients with HSP 27-positive tumors. The present findings suggest that HSPs 27 and 70 are significant prognostic factors for esophageal SCC.


Opposite effects of two resveratrol (trans-3,5,4'-trihydroxystilbene) tetramers, vitisin A and hopeaphenol, on apoptosis of myocytes isolated from adult rat heart.
It has been reported that resveratrol (trans-3,5,4'-trihydroxystilbene) from Vitis plants has various cardioprotective effects. Vitis plants also include various resveratrol tetramers. The aim of our study is to clarify the pharmacological properties of resveratrol tetramers. We isolated two resveratrol tetramers as major products of Vitis plants. One is vitisin A, a complex of two resveratrol dimers, (+)-epsilon-viniferin and ampelopsin B, and the other is hopeaphenol, composed of 2 mol ampelopsin B. Vitisin A (30-300 nM) unexpectedly dose-dependently facilitated swelling and depolarization of mitochondria and cytochrome c release from mitochondria, which are indices of cardiomyocyte apoptosis. Furthermore, vitisin A induced apoptosis in the primary culture of adult rat ventricular myocytes. On the other hand, hopeaphenol (1-10 microM) dose-dependently inhibited Ca(2+) (30 microM)-induced mitochondrial depolarization and cytochrome c release from mitochondria but had not affected mitochondrial swelling. Moreover, hopeaphenol inhibited vitisin A-induced apoptosis. In structural and functional studies, we further confirmed that vitisin B, one of the resveratrol tetramers having (+)-epsilon-viniferin unit, induces mitochondrial swelling and cytochrome c release from mitochondria like vitisin A and that vitisifuran A, one of the resveratrol tetramers having the ampelopsin B unit, inhibits Ca(2+)-induced cytochrome c release from mitochondria like hopeaphenol. These results show that resveratrol tetramers have at least two opposite effects on cardiomyocytes; the one having the (+)-epsilon-viniferin unit induces cardiomyocyte apoptosis, and the other having ampelopsin B but not (+)-epsilon-viniferin unit inhibits it.


Diagnostic performance of high-definition coronary computed tomography angiography performed with multiple radiation dose reduction strategies.
Numerous radiation dose reduction measures have been proposed for coronary computed tomographic angiography (CCTA). Although these techniques allow for imaging with reduced radiation, it is unknown whether diagnostic performance is maintained. A new high-definition CCTA (HD-CCTA) allows higher spatial resolution, reduced image noise, and lower radiation doses. The aim of this study was to determine the diagnostic performance of HD-CCTA, in combination with multiple radiation dose reduction strategies, for the detection of obstructive coronary artery disease. Consecutive patients (N = 43, aged 60 ± 10 years, 83% male) with chest pain and referred for quantitative coronary angiography (QCA) underwent HD-CCTA with radiation dose reduction measures, including prospective electrocardiographic triggering, reduction of additional tube on-time, and minimization of tube voltage and current. Intraluminal diameter stenosis ≥ 50% was considered significant. QCA served as the reference standard. The area under the receiver-operating-characteristic curve (AUC) was used to evaluate diagnostic accuracy. All scans demonstrated diagnostic image quality, with 99% (543/548) of included coronary segments interpretable by HD-CCTA. Median effective radiation dose was 2.8 mSv (interquartile range, 1.3-3.9). The AUC for the per-patient assessment for stenosis ≥ 50% was 0.90 (95% confidence interval [CI], 0.77-0.96), with sensitivity of 95% (95% CI, 85%-100%), specificity of 79% (95% CI, 63%-95%), positive predictive value of 78% (95% CI, 61%-95%), and negative predictive value of 95% (95% CI, 85%-100%). Compared with QCA, HD-CCTA with multiple dose reduction measures resulted in low radiation doses and high diagnostic accuracy to detect and exclude obstructive coronary artery disease.


Heterogeneous models for blood-cerebrospinal fluid barrier permeability to serum proteins in normal and abnormal cerebrospinal fluid/serum protein concentration gradients.
Cerebrospinal fluid (CSF)/serum concentration gradients (Q) of individual proteins (albumin, IgG, alpha 2-macroglobulin) have been studied in controls and in patients in whom the lumbar CSF flow is altered (medullary compression) or the blood-CSF barrier (BCB) function impaired (acute idiopathic polyneuropathy and acute meningoencephalitis). The analysis of relationships among protein Q has been performed by total and multiple regressions and the actual BCB permeability to individual proteins has been interpreted according to the accepted theoretical porous or vesicular BCB models. The exponential Q-IgG vs. Q-albumin total regression, and the poor Q-alpha 2-macroglobulin vs. Q-albumin regression found in controls, together with the different multiple regressions among proteins and the high Q-IgG vs. Q-albumin partial regression coefficients found in medullary compression, acute idiopathic polyneuropathy and acute meningoencephalitis, indicated that different permeability mechanisms can be postulated. Heterogeneous, fairly independent permeability BCB mechanisms maintain the normal CSF/serum protein concentration gradient. Pinocytotic vesicles or pores of radius exceeding 1000-1500 A, probably located at the capillary endothelium, account for the main serum-derived CSF protein fraction(s) with large hydrodynamic radius (R). A more selective endothelial vesicular transport with a radius of 250 A transfers a negligible amount of protein from serum into CSF. Proteins with small R also enter the CSF through a set of selective pores of radius 120 A, probably at the level of the choroidal epithelium. Pinocytotic vesicles with a radius of 250 A and increased rate of formation induce the accumulation of proteins below an obstruction of lumbar CSF flow. An increased formation rate of vesicles with a radius of 450 A can explain the increased capillary permeability in nerve roots in acute idiopathic polyneuropathy. Loss of selectivity was the main feature of BCB in acute meningoencephalitis, and it seemed to be due to pores or vesicles with a radius larger than 1000-1500 A. The heterogeneity of BCB mechanisms must be taken into account when the intrathecal synthesis of a protein, also derived from serum (for example IgG), has to be measured.


The knowledge, perceptions and practice of pharmacovigilance amongst community pharmacists in Lagos state, south west Nigeria.
Community Pharmacists both have an important responsibility in monitoring the ongoing safety of medicines and are widely accessible to do it. This study aims to investigate the knowledge, perceptions and practice of Pharmacovigilance amongst community pharmacists in Lagos State, South West Nigeria A cross-sectional observational survey was used in this study. A multistage random sampling technique was employed in the selection of 420 community pharmacies in Lagos. About 55% of respondents have ever heard of the word 'Pharmacovigilance' out of which less than half (representing only 18% of all respondents) could define the term 'Pharmacovigilance'. Forty percent of the respondents stated that patients reported ADRs to them at least once a month, and 20% reported to the relevant authorities. However only 3% of respondents actually reported an ADR to the National Pharmacovigilance Centre. The most important reason for poor reporting was lack of knowledge about how to report ADRs (44.6%).Meanwhile, 90% of respondents believed that the role of the pharmacists in ADR reporting was important. Most community pharmacists were willing to practice pharmacovigilance if they were trained. Community pharmacists in Lagos had poor knowledge about pharmacovigilance. Reporting rate was also poor. There is an urgent need for educational programs to train pharmacists about pharmacovigilance and ADR reporting.


Passive noise datasets at regolith sites.
The data presented in this article contain datasets of passive noise measurements at regolith sites in Adelaide, South Australia. The data were acquired using three component (3C) LE-3Dlite Lennartz seismometers with an eigenfrequency of 1 Hz. The data were acquired at eight sites across Adelaide׳s regolith in a hexagonal array layout. Four tests, each with a duration of 30 min, were conducted at different times. The ambient noise data can be used for both horizontal to vertical spectral ratio (HVSR) analysis and array analyses, which are essential to obtain the site fundamental frequency and the ellipticity of the fundamental mode Rayleigh waves at the measured site. The array analyses are useful to obtain the dispersion curves, which are needed to estimate the shear wave velocity profile.


[Expression Of DNA-Encoded Antidote to Organophosphorus Toxins in the Methylotrophic Yeast Pichia Pastoris].
A platform for the cloning and expression of active human butyrylcholinesterase (BuChE) in the yeast Pichia pastoris is first presented. Genetic constructs for BuChE gene expression, separately and in conjunction with a proline-rich peptide called proline-rich attachment domain (PRAD), are based on the vector pPICZαA. It is shown that the highest level of production is achieved in the expression of a BuChE gene without PRAD pPICZαA. It is found that one can obtain up to 125 mg of active enzyme from 1 L of culture medium at an optimal pH environment (pH 7.6), an optical seed culture density of 3 o.u., and an optimum methanol addition mode of (0.5% methanol in the first day and 0.2% thereafter from the second day).


Does a humoral correlate of protection exist for SARS-CoV-2? A systematic review.
A correlate of protection (CoP) is an immunological marker associated with protection against infection. Despite an urgent need, a CoP for SARS-CoV-2 is currently undefined. Our objective was to review the evidence for a humoral correlate of protection for SARS-CoV-2, including variants of concern. We searched OVID MEDLINE, EMBASE, Global Health, Biosis Previews and Scopus to January 4, 2022 and pre-prints (using NIH iSearch COVID-19 portfolio) to December 31, 2021, for studies describing SARS-CoV-2 re-infection or breakthrough infection with associated antibody measures. Two reviewers independently extracted study data and performed quality assessment. Twenty-five studies were included in our systematic review. Two studies examined the correlation of antibody levels to VE, and reported values from 48.5% to 94.2%. Similarly, several studies found an inverse relationship between antibody levels and infection incidence, risk, or viral load, suggesting that both humoral immunity and other immune components contribute to protection. However, individual level data suggest infection can still occur in the presence of high levels of antibodies. Two studies estimated a quantitative CoP: for Ancestral SARS-CoV-2, these included 154 (95% confidence interval (CI) 42, 559) anti-S binding antibody units/mL (BAU/mL), and 28.6% (95% CI 19.2, 29.2%) of the mean convalescent antibody level following infection. One study reported a CoP for the Alpha (B.1.1.7) variant of concern of 171 (95% CI 57, 519) BAU/mL. No studies have yet reported an Omicron-specific CoP. Our review suggests that a SARS-CoV-2 CoP is likely relative, where higher antibody levels decrease the risk of infection, but do not eliminate it completely. More work is urgently needed in this area to establish a SARS-CoV-2 CoP and guide policy as the pandemic continues.


A 62 kDa protein functions as estrogen receptor activation factor (E-RAF) in the goat uterus.
Goat uterine estrogen receptor activation factor, a 62 kDa protein existing in three molecular forms, E-RAF I, E-RAF IIA and E-RAF IIB, has been purified to homogeneity. The three forms are immunologically identical, but differ among themselves in their molecular Stokes radii and the sedimentation coefficients. The purified protein combines with the 4 S receptor-estrogen complex of the rat uterine cytosol to produce a 5 S receptor species. The E-RAF IgG cross-reacts with the nuclear 5 S receptor of the rat uterus but not with the cytoplasmic 4 S receptor. The E-RAF competes with the 5 S receptor for the DNA binding sites.


An update on pyelonephritis: role of contrast enhancement ultrasound (CEUS).
Acute pyelonephritis (APN) is a bacterial infection causing inflammation of the kidneys. Diagnosis is usually based on clinical and laboratory findings. Imaging is required if a complication is suspected in acute pyelonephritis to assess the nature and extent of the lesions and to detect underlying causes. CT represents the current imaging modality of choice in clinical practice. CEUS is an alternative that has been proven to be equally accurate in the detection of acute pyelonephritis renal lesions. CEUS allows us to distinguish small simple nephritic involvement from abscess complications and to follow their evolution over time during antibiotic therapy. The absence of ionizing radiation and the lack of nephrotoxicity make CEUS an ideal tool in the study of pyelonephritis.


Long time stability of 35 small endogenous biomolecules in dried urine spotted on various surfaces and environmental conditions.
Analysis of endogenous biomolecules is an important aspect of many forensic investigations especially with focus on DNA analysis for perpetrator/victim identification and protein analysis for body fluid identification. Recently, small endogenous biomolecules have been used for differentiation of synthetic "fake" urine from authentic urine and might be also useful for biofluid identification. Therefore, the aim of this study was to adapt and optimize a method for analysis of small EBs and to investigate long time stability of 35 small endogenous biomolecules (including acylcarnitines with their isomers and metabolites as well as amino acids with their metabolites) in spotted urine samples. Urine samples were spotted on seven different surfaces (Whatman 903 Protein Saver Cards, cotton swabs, cotton glove, denim, underwear, and smooth and rough flagstone) and stored under six environmental conditions (reference condition, sunlight, LED light, 4 °C, 37 °C, humidity of 95%). At certain time points (d0, d7, d28 and d56) samples were analyzed in triplicates by an optimized extraction and LC-HRMS approach. In addition, the urine marker Tamm-Horsfall-Protein was determined on cotton swabs at the same time points using a commercial lateral flow test. Twenty-one of 35 small endogenous biomolecules were stable on most materials/surfaces and under most storage conditions. Significant lower endogenous biomolecule peak areas were found for rough flagstone and underwear as well as for high humidity storage. Kynurenic acid proved to be photo labile. While high long time stabilities were found for 19 of 28 acylcarnitines, nine acylcarnitines showed aberrant stability patterns without evident structural reason. For Tamm-Horsfall-Protein degradation within 28 days was observed even under reference conditions. The presented study demonstrated the value of sensitive LC-HRMS analysis for small endogenous biomolecules / pattern. However, further studies will be indispensable for unambiguous body fluid identification by small endogenous biomolecules.


Reduced serum SIRT1 levels in patients with Parkinson's disease: a cross-sectional study in China.
Parkinson's disease (PD) is a movement disorder lacking of validated biomarkers. Experimental studies support the potential value of silent information regulator 1 (SIRT1) in neurodegeneration including PD. We aim to detect the serum levels of SIRT1 in PD patients in order to assess its value as a potential biomarker of PD. Fifty-eight PD patients and 91 healthy controls were included. Serum SIRT1 was determined by enzyme-linked immunosorbent assay (ELISA) and compared between controls and PD patients. Spearman correlation coefficient was analyzed to study the relationship between serum SIRT1 and clinical parameters in PD patients. Receiver operating characteristic (ROC) analysis was conducted to assess the diagnostic value of serum SIRT1 in PD identification. Serum SIRT1 was significantly reduced in PD patients compared with controls. According to the ROC curve, the optimal cut-off point was 0.47 ng/ml with the sensitivity of 71% and specificity of 71%. Serum SIRT1 level was related to age of onset, disease duration, Hoehn-Yahr staging scale (H-Y stage), Unified Parkinson's Disease Rating Scale III (UPDRS III), and Mini-Mental State Examination (MMSE). PD patients with cognitive impairment had lower serum SIRT1 than those with normal cognitive ability. Serum SIRT1 was reduced in PD patients and associated with disease severity and cognitive function. Our results indicate that SIRT1 may be a potential biomarker for PD.


Interaction of benz[a]pyrene diol epoxide with chromatin studied by flow linear dichroism.
Chromatin isolated from Ehrlich ascites cells was incubated with the tumourigenic compound (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenz[a]pyrene [(+)-anti-BPDE] at low ionic strength and the modified chromatin was analysed using flow linear dichroism (LD). The results confirm that (+)-anti-BPDE preferentially binds to the DNA in the linker regions, and furthermore show that the long axis of the bound pyrenyl chromophore is oriented parallel or close to parallel to the average orientation of the chromatin fiber axis. The data indicate that the binding geometry of (+)-anti-BPDE in chromatin is similar to that in pure DNA and deoxyguanosine-containing double-helical oligonucleotides.


Safety and efficacy of a basal-plus regimen with insulin glargine and insulin glulisine for elderly patients with high cardiovascular risk and type 2 diabetes mellitus.
To assess the safety and efficacy of a basal-plus (BP) regimen with insulin glargine (as basal insulin) and insulin glulisine (as prandial insulin) with the main meal for elderly patients with type 2 diabetes mellitus (DM2) and high cardiovascular risk, following standard clinical practice. An observational, retrospective study was conducted in 21 centres of internal medicine in Spain. The study included patients aged 65 years or older with DM2, undergoing treatment with a BP regimen for 4 to 12 months before inclusion in the study and a diagnosis of cardiovascular disease or high cardiovascular risk. The primary endpoint was the change in glycated haemoglobin (HbA1c) from the introduction of the glulisine to inclusion in the study. The study included 198 patients (mean age, 74±6.4 years; males, 52%). After at least 4 months of treatment with the BP regimen, started with the addition of glulisine, the mean HbA1c value decreased significantly (9±1.5% vs. 7.7±1.1%; P<.001), and almost 24% of the patients reached HbA1c levels of 7.5-8%. Furthermore, blood glucose levels under fasting conditions decreased significantly (190.6±73.2mg/dl vs. 138.9±38.2mg/dl; P<.001). A total of 35 patients (17.7%) had some hypoglycaemia during the month prior to the start of the study, and 2 cases (1.01%) of severe hypoglycaemia were detected. The BP strategy could significantly improve blood glucose control in patients 65 years of age or older with DM2 and high cardiovascular risk and is associated with a low risk of severe hypoglycaemia.


Metabolic regulation of apoproteins of high-density lipoproteins by estrogen and progesterone in the baboon (Papio sp).
To determine the metabolic regulation of the apoproteins of high-density lipoproteins (HDL) by estrogen and progesterone, 12 ovariectomized and hysterectomized baboons were fed a high cholesterol, high fat diet and were divided into four groups. One of these groups was the untreated control and the remaining three groups were treated with estrogen, progesterone, or a combination of both. After 10 months of treatment, there were significant differences in HDL apolipoprotein (apo) A-I and apo A-II levels in these groups. The apo A-I level was highest in baboons treated with the combination therapy, followed by those treated with estrogen. Baboons treated with progesterone and those in the control group had similar levels of apo A-I. Baboons treated with both estrogen and progesterone and estrogen alone had significantly higher levels of apo A-I than those in the control or progesterone group. Baboons treated with hormones had higher apo A-II levels than controls, and those treated with the combination therapy had the highest level. Metabolic studies suggested that both estrogen and progesterone increased apo A-I and apo A-II production. Progesterone also increased the fractional catabolic rate of apo A-I, but not of apo A-II. On the other hand, estrogen did not affect the fractional catabolic rate of either apo A-I or apo A-II. Thus, increased apo A-I content of HDL in baboons treated with both estrogen and progesterone or estrogen alone appears to be due to increased apo A-I synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)


Developmental and nutritional regulation of the messenger RNAs for fatty acid synthase, malic enzyme and albumin in the livers of embryonic and newly-hatched chicks.
The mRNAs for fatty acid synthase and malic enzyme were almost undetectable in total RNA extracted from the livers of 16-day old chick embryos. Both mRNAs increased in abundance between the 16th day of incubation and the day of hatching. In neonates, fatty acid synthase mRNA level was dependent on nutritional status, increasing slowly if the chicks were starved and rapidly if they were fed. The abundance of malic enzyme mRNA decreased in starved neonatal chicks and increased in fed ones. When neonates were first fed and then starved, starvation caused a large decrease in the abundance of both mRNAs. Conversely, feeding, after a period of starvation, resulted in a substantial increase in both mRNAs. The relative abundances of fatty acid synthase and malic enzyme mRNAs correlated positively with relative rates of enzyme synthesis. Thus, nutritional and hormonal regulation of the synthesis of these two 'lipogenic' enzymes is exerted primarily at a pre-translational level. The abundance of albumin mRNA decreased significantly between the 16th day of incubation and the day of hatching but did not change thereafter in fed or starved chicks. The relative stability of albumin mRNA levels after hatching attests to the selectivity of the nutritional regulation of fatty acid synthase and malic enzyme mRNAs. The decrease in albumin mRNA which occurred between 16 days of incubation and hatching contrasts with the increase in albumin mRNA sequences which occurred during late gestation in the fetal rat (20). High levels of albumin in the chick embryo may be related to the lack of an analogue of mammalian alpha-fetoprotein in birds.


Identifying genetic components controlling fertility in the outcrossing grass species perennial ryegrass (Lolium perenne) by quantitative trait loci analysis and comparative genetics.
Mutational load and resource allocation factors and their effects on limiting seed set were investigated in ryegrass by comparative mapping genomics and quantitative trait loci (QTL) analysis in two perennial ryegrass (Lolium perenne) mapping families sharing common genetic markers. Quantitative trait loci for seed-set were identified on chromosome (LG) 7 in both families and on LG4 of the F2/WSC family. On LG7, seed-set and heading date QTLs colocalized in both families and cannot be unequivocally resolved. Comparative genomics suggests that the LG7 region is syntenous to a region of rice LG6 which contains both fertility (S5(n)) and heading date (Hd1, Hd3a) candidate genes. The LG4 region is syntenous to a region of rice LG3 which contains a fertility (S33) candidate gene. QTL maxima for seed-set and heading date on LG4 in the F2/WSC family are separated by c. 8 cm, indicating distinct genetic control. Low seed set is under the control of recessive genes at both LG4 and LG7 locations. The identification of QTLs associated with seed set, a major component of seed yield in perennial ryegrass, indicates that mutational load associated with these genomic regions can be mitigated through marker-assisted selection.


Acute Kidney Injury in Pediatric Diabetic Ketoacidosis.
To assess the incidence and clinical characteristics of acute kidney injury (AKI) and identify the associated risk factors for AKI in children with type 1 diabetes mellitus (T1DM) and diabetic ketoacidosis (DKA). This was a retrospective study performed over 15 y in a single Korean center. Children aged ≤18-y-old with T1DM and DKA were enrolled and divided into 2 groups according to the presence of AKI. This study included 90 episodes of DKA in 58 children with T1DM. AKI occurred in a total of 70 hospitalizations (77.8%) of 44 children: 18 (20.0%) with stage 1 AKI, 39 (43.3%) with stage 2 AKI, and 13 (14.4%) with stage 3 AKI. The number of AKI decreased to 28 (47.4%) and 13 (28.3%) after 12 h and 24 h of admission, respectively. The white blood cell count (P = 0.001) and anion gap levels (P = 0.025) were significantly higher and serum bicarbonate level (P = 0.004) was lower in the AKI group. Logistic regression analysis revealed that a longer duration of TIDM and high anion gap were independent predictors of developing severe AKI in pediatric DKA with T1DM (odds ratio, 1.225, P = 0.013; odds ratio, 1.130, P = 0.038). AKI frequently occurred in TIDM children with DKA. Longer duration of TIDM and elevated anion gap are associated with occurrence of severe AKI.


Preparation of pH-responsive stationary phase for reversed-phase liquid chromatography and hydrophilic interaction chromatography.
Novel pH-responsive polymer-grafted silica was successfully synthesized through the radical "grafting from" polymerization on azo initiator-immobilized silica. The immobilization of azo initiator onto the silica surface was achieved by the reaction of surface amino groups with 4,4'-azobis(4-cyanovaleric acid chloride). The polymer-grafted silica was prepared by stirring suspension of the azo initiator-immobilized silica in anhydrous dioxane containing acrylic acid (AAc) and butyl acrylate (BA). The resulting polymer-grafted silica was demonstrated to be pH responsive to hydrophobic/hydrophilic property by reversed-phase liquid chromatography (RPLC) and hydrophilic interaction chromatography (HILIC). In RPLC mode, the retention of aromatic compounds decreased with the increase in the pH of mobile phase. However, the opposite result was obtained in HILIC mode; the retention of soybean isoflavones was stronger with the mobile phase at higher pH. Finally, the separations of sulfonamides and soybean isoflavones were carried out in RPLC mode and the separation of some nucleotides was achieved in HILIC mode.


Detecting biologically relevant phosphates with locked salicylaldehyde probes in water.
This communication describes a disassembly based approach for the detection of biologically relevant di- and triphosphates in water using locked fluorescent salicylaldehyde probes.


Neurotensin enhances agonist-induced cAMP accumulation in PC3 cells via Ca2+ -dependent adenylyl cyclase(s).
A human prostate cancer cell line (PC3) with abundant neurotensin (NT) receptors was used to demonstrate that NT potentiated 3',5'-cyclic adenosine monophate (cAMP) accumulation in response to a variety of stimuli, including both direct forskolin (F) and indirect (prostaglandin, (PGE2), isoproterenol (ISO) and cholera toxin (CTx)) activators of adenylyl cyclase. Several mechanisms were investigated and our results indicated an effect on the rate of cAMP formation and not on degradation or extrusion. For each stimulus, NT enhanced efficacy without altering EC50. The effect of NT did not involve stimulatory G-protein (Gs)-activation or interference with a tonic inhibitory G-protein (Gi)-mediated inhibition. A similar response was obtained when NT was added with the stimulus or given as a two minute pulse which was removed prior to addition of stimulus. The potentiating activity disappeared with a t1,2 of approximately 15 min. NT transiently elevated cellular [Ca2+]i and its effects on cAMP could be mimicked by [Ca2+]i-elevating agents (uridine triphosphate (UTP), thapsigargin and ionomycin). Buffering cellular [Ca2+]i with 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA-AM) inhibited cAMP responses to ISO and F in presence and absence of NT. These data support the idea that NT potentiated cAMP formation in response to a variety of stimuli by facilitating the activation of Ca2+ -dependent adenylyl cyclases.


Chronic exposure to cadmium did not impair vitamin D metabolism in monkeys.
Vitamin D metabolism in primates with chronic exposure to cadmium was studied in relation to Itai-Itai disease. In a series of experiments, crab-eating monkeys were fed cadmium-contaminated rice (1.33 micrograms Cd/g) or a diet containing 3 micrograms/g cadmium chloride for 6 years. These treatments had no effect on the 1,25-dihydroxyvitamin D (1,25(OH)2D), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 25-hydroxyvitamin D (25(OH)D) in the serum. This is consistent with unchanged production of 1,25(OH)2D and 24,25(OH)2D by renal mitochondria prepared from the same animals. No indication of renal dysfunction was observed. In another series of experiments, rhesus monkeys were fed a diet containing 3, 10, 30, or 100 micrograms/g cadmium for 9 years. Serum vitamin D metabolites and renal production of 24,25(OH)2D also remained unchanged. In contrast, renal 25(OH)D-1-hydroxylase (1-hydroxylase), which is responsible for the production of 1,25(OH)2D, seemed to be suppressed in the animals fed 30 or 100 micrograms/kg cadmium-contaminated diet (no statistical significance). These animals had indications of mild renal dysfunction, and there was a strong negative correlation between 1-hydroxylase and urinary concentration of either protein or beta 2-microglobulin. These data suggest a slight change in the total enzyme activity, possibly due to mild renal dysfunction. Since substrate (25(OH)D) concentration is much lower and thus rate-limiting in vivo as compared with that in vitro assay system used in this study, the slight change of enzyme activity would not have been sufficient to affect the serum level of 1,25(OH)2D. No skeletal abnormality was observed in any of these animals. In view of these data, the length of cadmium exposure and the life span of animals as well as epidemiological data published elsewhere, factors other than cadmium may also be involved in the development of Itai-Itai disease.


Diabetes as a risk factor for herpes zoster infection: results of a population-based study in Israel.
Studies showed that diabetes mellitus (DM) is often accompanied by impaired cell-mediated immunity, which potentially may increase the risk for infectious diseases, including herpes zoster (HZ). However, data on the relation between DM and HZ are scarce. This case-control study explored the association between DM and HZ. This study was nested within a cohort of all members of a large health maintenance organization (HMO) in Israel. Cases totaled 22,294 members who were diagnosed with HZ between 2002 and 2006. Controls (n=88,895) were randomly selected from the remaining HMO population using frequency-matched age, sex, and duration of follow-up. Personal data on history of DM, lymphoma, leukemia, or AIDS, were obtained from computerized medical records. Adjusted analyses showed that the risk of HZ was associated with history of leukemia, lymphoma, use of steroids or antineoplastic medications, and AIDS, particularly among patients below 45 years of age. In a multivariate analysis, DM was associated with an increased risk of HZ (OR=1.53; 95% CI: 1.44-1.62). The data suggest that individuals with DM are at increased risk of HZ. Well-designed cohort studies may help to clarify the nature of this association.


Radiotherapy of salivary gland tumours.
Primary tumours of the salivary glands account for about 5 to 10% of tumours of the head and neck. These tumours represent a multitude of situations and histologies, where surgery is the mainstay of treatment and radiotherapy is frequently needed for malignant tumours (in case of stage T3-T4, nodal involvement, extraparotid invasion, positive or close resection margins, histological high-grade tumour, lymphovascular or perineural invasion, bone involvement postoperatively, or unresectable tumours). The diagnosis relies on anatomic and functional MRI and ultrasound-guided fine-needle aspiration for the diagnostic of benign or malignant tumors. In addition to patient characteristics, the determination of primary and nodal target volumes depends on tumor extensions and stage, histology and grade. Therefore, radiotherapy of salivary gland tumors requires a certain degree of personalization, which has been codified in the recommendations of the French multidisciplinary network of expertise for rare ENT cancers (Refcor) and may justify a specialised multidisciplinary discussion. Although radiotherapy is usually recommended for malignant tumours only, recurrent pleomorphic adenomas may sometimes require radiotherapy based on multidisciplinary discussion. An update of indications and recommendations for radiotherapy for salivary gland tumours in terms of techniques, doses, target volumes and dose constraints to organs at risk of the French society for radiotherapy and oncology (SFRO) was reported in this article.


[Production and characteristics of monoclonal antibodies reacting with human-type M. tuberculosis].
Monoclonal antibodies to M. tuberculosis were produced by hybrid technology. They were described via enzyme immunoassay and immunoblotting. It was shown that these antibodies should be included into IgG class. Besides, they are oriented towards and antigen with a molecular weight of 20 kDa, react with H37Rv at a concentration of 12 ng/ml and with BCG at a concentration of 50 micrograms/ml and fail to react with M. Intracellulare, M. Scrofulaceum and E. coli.


Increased patellofemoral pressure after TKA: an in vitro study.
Considering the discrepant results of the recent biomechanical studies, the purpose of this study was to simulate dynamic muscle-loaded knee flexion with a large number of specimens and to analyse the influence of total knee arthroplasty (TKA) without and with patellar resurfacing on the patellofemoral pressure distribution. In 22 cadaver knee specimens, dynamic muscle-loaded knee flexion (15°-90°) was simulated with a specially developed knee simulator applying variable muscle forces on the quadriceps muscles to maintain a constant ankle force. Patellofemoral pressures were measured with flexible, pressure-sensitive sensor foils (TEKSCAN) and patellofemoral offset with an ultrasound motion-tracking system (ZEBRIS). Measurements were taken on the native knee, after total knee arthroplasty and after patellar resurfacing. Correct positioning of the patellar implant was examined radiologically. The maximal patellofemoral peak pressure partly increased from the native knee to the knee with TKA with intact patella (35°-90°, p < 0.012) and highly increased (twofold to threefold) after patellar resurfacing (20°-90°, p < 0.001). Concurrently, the patellofemoral contact area decreased and changed from a wide area distribution in the native knee, to a punctate area after TKA with intact patella and a line-shaped area after patellar resurfacing. Patellar resurfacing led to no increase in patellar thickness and patellofemoral offset. Despite correct implantation of the patellar implants and largely unchanged patellofemoral offset, a highly significant increase in pressure after patellar resurfacing was measured. Therefore, from a biomechanical point of view, the preservation of the native patella seems reasonable if there is no higher grade patellar cartilage damage.


Surgically related upper cervical spine canal anatomy in children.
MRI studies of the upper spines of 121 children were evaluated to precisely define the sagittal anatomy at C1 in the pediatric population. The diameters of the spinal cord, bony canal, space available for the cord (SAC), dens+atlanto-dens interval (ADI), and "free" space were measured. The results demonstrate an accelerated growth in the C1 canal, dens + ADI, and SAC during the first four years after birth. Steel's rule of thirds was shown to roughly hold true throughout childhood. Neonates have an average SAC diameter of 12.4 mm, a value less than the 13 mm dimension commonly used to define relative stenosis in children.


Associations between frailty trajectories and frailty status and adverse outcomes in community-dwelling older adults.
The association between frailty and adverse outcomes has been clearly defined. Frailty is associated with age, but different frailty evolution patterns might determine the incidence of adverse outcomes at older ages. So far, few observational studies have examined how distinct frailty trajectories could be associated with differences in the risk of adverse events and assessing whether frailty trajectories could define risk of death, hospitalization, worsening, and incident disability better than one-off assessment. Our hypothesis is that prospective increases in frailty levels are associated with higher risk of adverse events compared with subjects that prospectively decreased frailty levels. Participants' data were taken from the Toledo Study of Healthy Ageing. Frailty was evaluated using the Frailty Trait Scale 5 (FTS5), being 0 the lower (the most robust) and 50 the highest (the frailest) score. FTS5 scores at baseline and follow-up (median 5.04 years) were used to construct frailty trajectories according to group-based trajectory modelling (GBTM). Multivariate Cox proportional hazard and logistic regression models were used to explore associations between frailty status and trajectory membership and the adverse outcomes. Deaths were ascertained through the Spanish National Death Index. Disability was evaluated through the Katz Index. Hospitalization was defined as first admission to Toledo Hospital. Nine hundred and seventy-five older adults (mean age 73.14 ± 4.69; 43.38% men) were included. GBTM identified five FTS5 trajectories: worsening from non-frailty (WNF), improving to non-frailty (INF), developing frailty (DF), remaining frail (RF), and increasing frailty (IF). Subjects belonging to trajectories of increasing frailty scores or showing consistently higher frailty levels presented with an increased risk of mortality {DF [hazard ratio (HR), 95% confidence interval (CI)] = 2.01 [1.21-3.32]; RF = 1.92 [1.18-3.12]; IF = 2.67 [1.48-4.81]}, incident [DF (HR, 95% CI) = 2.06 (1.11-3.82); RF = 2.29 (1.30-4.03); IF = 3.55 (1.37-9.24)], and worsening disability [DF (HR, 95% CI) = 2.11 (1.19-3.76); RF = 2.14 (1.26-3.64); IF = 2.21 (1.06-4.62)], compared with subjects prospectively showing decreases in frailty levels or maintaining low FTS5 scores. A secondary result was a significant dose-response relationship between baseline FTS5 score and adverse events. Belonging to trajectories of prospectively increasing/consistently high frailty scores over time are associated with an increased risk of adverse outcomes compared with maintaining low or reducing frailty scores. Our results support the dynamic nature of frailty and the potential benefit of interventions aimed at reducing its levels on relevant and burdensome adverse outcomes.


Total "internal" hemipelvectomy.
Several authors have described resections of tumorbearing parts of the pelvis including reconstructive plastic surgery. With extensive tumor growth present mutilating hemipelvectomies often have been the last resort. Even the most sophisticated prostheses hardly ever enabled the patients to walk again. We have therefore performed total "internal" hemipelvectomies in three cases. The necessary substitute consisted of half a pelvis made of polyacetal resin produced from a given model. The model's measures and shape was established by computer tomograms thus resulting in an individually shaped pelvis half. The operative procedure aims at the maintenance of osseous muscular insertions and origins and their reconstruction. Utmost care has to be taken in avoiding damage to nerves and vessels. Fixation of the implant is performed by screws aiming through the sacroiliac joint into ala and corpus of the sacrum and corticocancellous grafts incorporated in the implant. The symphyses are united by means of plate fixation. The hip joint is substituted by a total prosthesis. With the procedure described we have managed three cases of extensive malignant tumors of the pelvis. One patient suffered a nerve lesion and skin necrosis with infection. The two remaining patients are capable of weight-bearing and standing on the inflicted leg alone.


Methylphenidate in the management of asthenia in breast cancer patients treated with docetaxel: results of a pilot study.
The objectives of this pilot study were to evaluate the safety and efficacy of the central nervous system stimulant methylphenidate in the management of asthenia in breast cancer patients treated with docetaxel. Patients with early breast cancer who presented asthenia >3 on the Visual Analogue Scale (VAS) after the first cycle of docetaxel-based chemotherapy were included. Patients received two additional cycles of chemotherapy, one with methylphenidate (10 mg bid) and the other without methylphenidate. Asthenia was evaluated using VAS and the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale. Distress was assessed using the Hospital Anxiety and Depression Scale (HADS), and quality of life using FACT-F. Ten patients were included and evaluated for efficacy and safety. Overall, cycles with methylphenidate were better tolerated than those without methylphenidate in terms of asthenia (VAS, p = 0.004; FACT-F, p = 0.027) and quality of life (FACT-F, p = 0.047). No significant differences were observed in terms of distress (HADS, p = 0.297). Six (60%) patients continued with methylphenidate after study end. Main adverse events during study were palpitations and insomnia (30% of patients each). This pilot study suggests that methylphenidate may reduce asthenia and improve quality of life in breast cancer patients treated with docetaxel.


Developmental DSP4 effects on cortical Arc expression.
Activity Regulated Cytoskeleton Associated Protein (Arc) is an immediate early gene that is critical to brain plasticity. In this study, norepinephrine's regulation of Arc expression was examined during different stages of postnatal development. Rats were injected with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a selective noradrenergic neurotoxin, during preadolescence (PND 0 or 13), adolescence (PND 23 or 48) or adulthood (PND 60). After each DSP4 treatment, brains were harvested later in development and Arc mRNA levels analyzed with in situ hybridization. Rats lesioned with DSP4 during preadolescence showed no differences in Arc level compared to saline treated controls. In contrast, adolescence was a time of changing Arc mRNA response to DSP4. Rats lesioned during early adolescence showed Arc expression increases, while rats lesioned during late adolescence showed dramatic Arc expression decreases. Decreases in Arc level caused by late adolescent DSP4 were similar to those found in lesioned adults. These findings highlight a qualitatively different regulation of Arc expression by norepinephrine according to developmental stage, and indicate that mature regulation is not intact until late adolescence. These data point to important developmental differences in norepinephrine's regulation of brain plasticity. These differences may underlie contrasting psychotropic responses in children and adolescents compared to adults.


Catheter-free discharge on first postoperative day after bipolar transurethral resection of prostate: clinical outcomes of 100 cases.
Our center has adopted a protocol for catheter-free first postoperative day discharge after bipolar transurethral resection of the prostate. We present the immediate, 1-month and 6-month outcomes of our first 100 cases following this protocol. All bipolar transurethral resection of the prostate patients followed the protocol regardless of indications and background comorbid conditions. Bladder irrigation was stopped in the evening after transurethral resection of the prostate, and the catheter was removed at 06.00 hours. All patients were discharged on the first postoperative day. They were reviewed at 1 month and 6 months with the International Prostate Symptom Score and uroflowmetry. The mean age of the study population was 70.8 years. A total of 40 patients had urinary retention and were on an indwelling catheter before transurethral resection of the prostate. A total of 14 patients had other surgeries in the same setting as the transurethral resection of the prostate. The mean resection weight was 32.7 g. The mean irrigation time and catheter time were 4.2 h and 15.0 h, respectively. The improvement in terms of International Prostate Symptom Score, quality of life score, peak flow rate and post-void residual volume was comparable with those reported in the literature for bipolar transurethral resection of the prostate. Similarly, early and late complication rates also compared favorably with the literature. The perioperative cost was significantly reduced. Catheter-free first postoperative day discharge after bipolar transurethral resection of the prostate is safe with good clinical outcomes and cost savings.


L-DOPA increases noradrenaline turnover in central and peripheral nervous systems.
The ability of L-3,4-dihydroxyphenylalanine (L-DOPA) to release noradrenaline (NA) from peripheral and CNS neurons was studied using isolated rat vas deferens and in vivo frontal cortex microdialysis. Application of L-DOPA (30 microM) to vas deferens increased basal NA efflux but not electrical field stimulation-evoked release of NA when the tissue was pretreated with an inhibitor of MAO-B (clorgyline 1 microM) or an inhibitor of MAO-A and MOA-B (AGN-1133 1 microM). No effect on NA efflux was seen when the tissue was treated with rasagiline (0.005 microM; selective inhibitor of MAO-B), but rasagiline, AGN-1133 and clorgyline increased basal efflux of dopamine (DA) following L-DOPA. In microdialysis experiments, systemic administration of L-DOPA/carbidopa combination (50/12 mg.kg(-1)) increased the efflux of 3,4-dihydroxyphenylglycol and 3-methoxy,4-hydroxyphenylglycol but reduced that of NA. Microdialysate levels of NA, however were increased following L-DOPA/carbidopa when desipramine (1 microM) was infused locally via the probe, or following systemic administration of yohimbine (2 mg.kg(-1)). The data are consistent with the hypothesis that administration of L-DOPA is followed by increased axoplasmatic levels of DA which release NA from storage sites into the free cytoplasmatic pool.


The histone-deacetylase inhibitor Trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells.
Effective treatment for hepatocellular carcinoma is urgently needed. The histone-deacetylase inhibitor Trichostatin A (TSA) was shown to induce apoptosis in non-hepatic cells at submicromolar concentrations. However, the effect of TSA on hepatoma cells is unknown. The hepatoma cells HepG2, MH1C1, Hepa1-6 and Hep1B as well as human fibroblasts (control cells) were exposed to TSA (10(-6) to 10(-9)M). Cell proliferation was assessed by measuring DNA-synthesis and cell numbers. Apoptosis was quantified by flow cytometry and by the TdT-mediated dUTP nick-end labeling method. Expression patterns of cell cycle- and/or apoptosis-associated p27, p21(cip/waf), bax, bcl-2, cyclin A and (pro)-caspase 3 were studied using quantitative Western blotting. Activation of caspase 3 was analyzed via a colorimetric assay. 10(-6)M TSA inhibited DNA-synthesis by 46% (HepG2) to 64% (MH1C1) after 24h, inducing a G(2)/M-phase arrest and apoptosis. TSA increased activation of caspase 3 and expression of cyclin A, p2l(cip/waf), bax and (pro)-caspase 3, while bcl-2 was downregulated. Human fibroblasts remained unaffected. TSA inhibits hepatoma cell growth in vitro, which are otherwise particularly resistant to chemotherapy. Its anti-proliferative activity is paralleled by a comparable rate of apoptosis. TSA may be a promising agent for treatment of hepatocellular carcinoma in vivo.


Lung uptake of 131I-metaiodobenzylguanidine in sheep. An in vivo measurement of pulmonary metabolic function.
Circulating biogenic amines are known to be cleared by the mammalian lung. Their lung uptake is considered as an indicator of pulmonary endothelial integrity. Unfortunately, their use as markers of pulmonary metabolic function in human pathology is precluded by their biological effects and by the type of radiolabeling (3H and 14C), making them harmful for repeat injections and unfit for scintigraphy. Metaiodobenzylguanidine (MIBG) is structurally related to the neuron blocking agent guanethidine, devoid of significant biological effects, and has been shown to be extracted by the same active sodium dependent, saturable transport as norepinephrine in perfused rat lungs in vitro. We studied the single pass lung extraction of 131I-MIBG in five awake and five anaesthetised sheep using the standard double indicator dilution technique with 99mTc-human serum albumin (HSA) as an intravascular reference tracer. Intravenous bolus injection of increasing doses of MIBG up to 400 nmol resulted in a significant (F ratio = 7.778, P less than 0.0001) dose dependent decrease of MIBG extraction in both awake and anaesthetised sheep, without significant differences of extraction values between the two groups. For the 10 sheep, the averaged percentage single pass pulmonary uptake of MIBG at the peak of the dilution curve decreased from 32% +/- 3% (mean +/- SE, n = 27 measurements) with 20 nmol to 18% +/- 2% (n = 32) with 400 nmol. Estimates of the apparent Michaelis-Menten constant (Km) averaged 2 +/- 1.2 microM (n = 7), whereas estimates of the apparent maximum velocity of removal (Vmax) was 1.1 +/- 0.5 mumol/min (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)


Peripherally inserted central catheter in haematopoietic stem cell transplantation. Infusion of haematopoietic cells and complications.
To analyze the incidence of complications related to the central peripheral insertion catheter and the viability of the infusion of haematopoietic stem cells through volumetric perfusion pumps. Prospective descriptive study that includes all patients who received a haematopoietic transplant in the Haematology Service of the Hospital Clínico de Valencia between January and December 2016 (n=73). All of them received a central peripheral insertion catheter. SPSS™ v22 was used to perform the descriptive analysis of the main variables using a confidence interval of 95%. The student's t-test was used to compare the means of two independent samples assuming unequal variances. The 63% (n=73) of the catheters remained without problems throughout the procedure. Fever of unknown origin (28.8%) was the main cause of catheter removal. The median number of days for haematological recovery was 12.5 for the autologous transplants and 15 for the allogeneic transplants. The central peripheral insertion catheter presents few complications related to insertion. The administration of haematopoietic cells through these catheters with volumetric perfusion pumps does not imply a delay in haematological recovery. Good acceptance by the patient is confirmed.