[Organization and management of mountain rescues].
Mountain rescue is a matter for specialists. Specific training, a model of organisation under state control, emergency protocols and information and prevention campaigns have helped to improve morbidity and mortality rates in the mountains.


[Effects of autogenous periodontal ligament cell transplantation on periodontal tissue regeneration in dogs].
To evaluate the effect of autogenous periodontal ligament cell (PDL) transplantation in periodontal tissue regeneration. PDL cells derived from the same dog were cultured with alpha-MEM. 1 x 10(5) cells of first passage were allowed to attach to the collagen membrane for 24 hours. The membrane-cells were transplanted into periodontal defect in the same dog. Then the defects were covered with e-PTFE membranes. The defects covered only with e-PTFE were the controls. Eighteen teeth of 6 dogs for each group were included. The dogs were sacrificed after 6 weeks. The results showed that new bone formation (4.00 +/- 0.13) mm in test group was significantly higher than that of in control group (3.09 +/- 0.28) mm, P < 0.05. The new cementum formation in test group was better than control group (P < 0.05). The results suggested that PDL cell transplantation with guided tissue regeneration technique could enhance periodontal tissue regeneration in dogs.


The nerves to blood vessels supplying blood to nerves: the innervation of vasa nervorum.
Noradrenergic, serotoninergic and peptidergic nerves have been demonstrated in perivascular plexuses of vasa nervorum of sympathetic, parasympathetic and somatic nerve trunks. 5-Hydroxytryptamine-, vasoactive intestinal polypeptide- and substance P-containing fibers were found by immunohistochemistry to variable extents in whole mounts of the epineurium of sciatic, vagus and paravertebral sympathetic chains of rabbits. Innervation increased with age. This suggests an hitherto unsuspected role for these vasoactive substances in normal blood flow to nerves and in the genesis of experimental and human neuropathies.


Electrospun Microvasculature for Rapid Vascular Network Restoration.
Sufficient blood supply through neo-vasculature is a major challenge in cell therapy and tissue engineering in order to support the growth, function, and viability of implanted cells. However, depending on the implant size and cell types, the natural process of angiogenesis may not provide enough blood supply for long term survival of the implants, requiring supplementary strategy to prevent local ischemia. Many researchers have reported the methodologies to form pre-vasculatures that mimic in vivo microvessels for implantation to promote angiogenesis. These approaches successfully showed significant enhancement in long-term survival and regenerative functions of implanted cells, yet there remains room for improvement. This paper suggests a proof-of-concept strategy to utilize novel scaffolds of dimpled/hollow electrospun fibers that enable the formation of highly mature pre-vasculatures with adequate dimensions and fast degrading in the tissue. Higher surface roughness improved the maturity of endothelial cells mediated by increased cell-scaffold affinity. The degradation of scaffold material for functional restoration of the neo-vasculatures was also expedited by employing the hollow scaffold design based on co-axial electrospinning techniques. This unique scaffold-based pre-vasculature can hold implanted cells and tissue constructs for a prolonged time while minimizing the cellular loss, manifesting as a gold standard design for transplantable scaffolds.


Sex-related differences in long-term mortality and heart failure in a contemporary cohort of patients with NSTEACS. The cardiochus-HSUJ registry.
There is insufficient data regarding sex-related prognostic differences in patients with a non-ST elevation acute coronary syndrome (NSTEACS). We performed a sex-specific analysis of cardiovascular outcomes after NSTEACS using a large contemporary cohort of patients from two tertiary hospitals. This work is a retrospective analysis from a prospective registry, that included 5,686 consecutive NSTEACS patients from two Spanish University hospitals between the years 2005 and 2017. We performed a propensity score matching to obtain a well-balanced subset of individuals with the same clinical characteristics, resulting in 3,120 patients. Cox regression models performed survival analyses once the proportional risk test was verified. Among the study participants, 1,572 patients (27.6%) were women. The mean follow-up was 60.0 months (standard deviation of 32 months). Women had a higher risk of cardiovascular mortality compared with men (OR (Odds ratio) 1.27, CI (confidence interval) 95% 1.08-1.49), heart failure (HF) hospitalization (OR 1.39, CI 95% 1.18-1.63) and risk of all-cause mortality (OR 1.10, CI 95% 1.08-1.49). After a propensity score matching, female gender was associated with a significant reduction in the risk of total mortality (OR 0.77, CI 95% 0.65-0.90) with a similar risk of cardiovascular mortality (OR 0.86, CI 0.71-1.03) and HF hospitalization (OR 0.92, CI 95% 0.68-1.23). After baseline adjustment, the risk of all-cause mortality and cardiovascular mortality was lower in women, whereas the risk of HF remained similar among sexes. In a contemporary cohort of patients with NSTEACS, women are at similar risk of developing early and late HF admissions, and have better survival compared with men, with a lower risk of all-cause mortality and cardiovascular mortality. The implementation of NSTEACS guideline recommendations in women, including early revascularization, seems to be accompanied by improved early and long-term prognosis.


Microvascular density assessed by CD31 predicts clinical benefit upon bevacizumab treatment in metastatic colorectal cancer: results of the PassionATE study, a translational prospective Phase II study of capecitabine and irinotecan plus bevacizumab followed by capecitabine and oxaliplatin plus bevacizumab or the reverse sequence in patients in mCRC.
Targeted therapies offer novel opportunities to explore biomarkers based on their mode of action. Taking this into consideration, we evaluated six angiogenesis-related proteins as potential predictive biomarkers, which expression might predict the benefit of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC). This was a phase II multicenter, two-armed, randomized study, in which patients with mCRC were treated with XELIRI (capecitabine and irinotecan) plus bevacizumab followed by XELOX (capecitabine and oxaliplatin) plus bevacizumab (Arm A) or the reverse sequence (Arm B). Tissue expression level of six prespecified candidates [microvessel density assessed by CD31, PTEN, αV integrin, CD98hc, uPAR and NRP-1] was analyzed via immunohistochemistry. The prognostic impact on survival was quantified using the Cox regression model. The predictive potential for benefit from Arm A versus Arm B treatment was investigated by fitting an interaction between the biomarkers and treatment assignment within a multivariable Cox model. In total, 74 out of 126 patients were included in the analysis. The expression of PTEN, αV integrin, uPAR and NRP-1 was not associated with progression-free survival (PFS) or overall survival (OS). For the first time, we identified that patients with tumors expressing CD98hc had a longer PFS than patients without CD98hc-expression (p = 0.032). More importantly, and in accordance with previous studies, low microvessel density was found to be associated with a reduced PFS [adjusted HR per doubling of CD31-expression (p = 0.53, 95% confidence interval: 0.30-0.95, p = 0.034)]. These results can contribute to the development of a personalized strategy for the treatment of mCRC with bevacizumab.


Organ trafficking: scope and ethical dilemma.
The Israeli experience discloses the relationship between the traditional altruistic basis of organ donation and the new alternatives based on a utilitarian conception of unrelated compensated donation. Although organ trafficking in Israel was dramatically intensified, cadaveric and living-related donations decreased. Reforms in living donations, such as evaluation committees for unrelated directed donors, were insignificant in terms of meeting the demand of patients and reducing the volume of trafficking. It is our contention that battling organ trafficking should provide patients with a realistic alternative for kidney donations. Our model of regulated nondirect paid donations is planned to legalize significant compensation for the unrelated donors drawing individuals from falling into the trap of organ traders. This program, together with uncompromised penalties, would hopefully eradicate organ trafficking.


Engraftment of human adipose derived stem cells delivered in a hyaluronic acid preparation in mice.
To evaluate the implant of human adipose derived stem cells (ADSC) delivered in hyaluronic acid gel (HA), injected in the subcutaneous of athymic mice. Control implants -HA plus culture media was injected in the subcutaneous of the left sub scapular area of 12 athymic mice. ADSC implants: HA plus ADSC suspended in culture media was injected in the subcutaneous, at the contra lateral area, of the same animals. With eight weeks, animals were sacrificed and the recovered implants were processed for extraction of genomic DNA, and histological study by hematoxilin-eosin staining and immunufluorescence using anti human vimentin and anti von Willebrand factor antibodies. Not visualized at the injection site. An amorphous substance was observed in hematoxilin-eosin stained sections. Human vimentin and anti von Willebrand factor were not detected. No human DNA was detected. ADSC implants - A plug was visible at the site of injection. Fusiform cells were observed in sections stained by hematoxilin- eosin and both human vimentin and anti von Willebrand factor were detected by immunofluorescence. The presence of human DNA was confirmed. The delivery of human adipose derived stem cells in preparations of hyaluronic acid assured cells engraftment at the site of injection.


Construction of an EGF receptor-mediated histone H1(0)-based gene delivery system.
To construct an EGF receptor (EGF-R)-mediated histone H1(0)-based gene delivery system for gene therapy. A recombinant DNA containing histone H1(0), EGF-R ligand, and endosomalytic domains was constructed in a prokaryotic vector and expressed in E. coli. Expression of the beta-galactosidase (beta-gal) gene in the tumor cells and tissues was observed after transduction of the beta-gal gene packaged by purified fusion proteins in vitro and in vivo. As an extension of the research on previously reported chemically synthetic composite polypeptide gene delivery systems, this genetically engineered polypeptide has proved to be capable of targeting the beta-galactosidase (beta-gal) gene into EGF-R-positive cancer cells both in vitro and in vivo. We also studied the time course of beta-gal gene expression in tumor tissues delivered in vivo by this polypeptide vector. At 24 h after administration, expression of the beta-galactosidase gene in tumor reached peak levels. The dosage optimization of administered polyplex was also investigated. The optimal dose of polyplex per mouse was 1 microg DNA packaged by 3 microg of composite polypeptide. The genetically engineered polypeptide based on histone H1(0) is a promising gene delivery system targeting EGF-R.


Effect of nimodipine on the autoregulation of cerebral blood flow studied by laser-Doppler flowmetry.
The present work examines whether nimodipine impairs autoregulation of CBF during hypotension. The CBF of 16 anesthetized rabbits was measured with a laser-Doppler flowmetry probe placed on the external surface of a plexiglas window, chronically inserted in the skull. Autoregulation was triggered by aortic bleeding. First, the effects of three doses of nimodipine (1, 3 and 10 micrograms/kg) and the solvent were studied in 10 rabbits in which MABP was maintained at 50 mmHg for one minute. Second, 10 micrograms/kg i.v. nimodipine was administered to 6 rabbits in which MABP was kept at 30 mmHg for one minute. Before bleeding, the 10 micrograms/kg dose significantly decreased MABP (from 96 +/- 11 mmHg to 81 +/- 11 mmHg, P < 0.01) and increased CBF (from 104 +/- 20% to 147 +/- 25%, P < 0.01) as compared to the solvent. In the first set of experiments, only the 10 micrograms/kg dose suppressed the autoregulatory vasodilation, but CBF was not different from control (84 +/- 17% versus 87 +/- 12%), probably because of the previous induced vasodilation. In the second set of experiments, active vasodilation occurred and the CBF during hypotension was not different from control (72 +/- 26% versus 65 +/- 11%). We conclude that under nimodipine the triggering of the active autoregulatory vasodilation is dependent on both the severity of hypotension and the previous nimodipine-induced vasodilation.


Women's knowledge of options for birth after Caesarean Section.
In Australia, the Caesarean Section rate has risen from 21.8% to 31.1% (2010) in a decade; in South Australia the rate was 32.2% in 2009. Caesarean Section is a life saving intervention in certain circumstances, but also a major surgical procedure with potential adverse effects on both mother and baby. The aim of this study was to ascertain the determinants of knowledge regarding options for subsequent birth in women who have experienced a previous Caesarean Section with a live baby. A sample of 33 women in South Australia who had a previous Caesarean Section were surveyed to assess their awareness of birth options and their advantages versus disadvantages as well as the possible factors influencing their information gathering and decision-making on birth options for their subsequent pregnancy. Most women perceived Caesarean Section to be major surgery but 69.6% were not aware that babies might have problems with breastfeeding, 60.6% did not know the rarity of uterine rupture during labour and/or birth and 48.5% were not aware that a caesarean may involve any complications for the baby at or after birth. Women's knowledge deficits relating to risks and benefits of birth options after previous caesarean can constrain them as most women chose caesarean rather than normal birth in their subsequent pregnancy.


Development and use of a computer system in a radiotherapy department: SISGRAD.
SISGRAD, the interactive computer system of the Antoine-Lacassagne Cancer Center Radiotherapy Department, has been operational since January 1982. It completes the computerized dosimetry system installed several years earlier and is fully integrated with the institution's central network. SISGRAD is in charge of surveillance of the radiotherapy treatments given by the Center's three radiotherapy units (1400 patients per year); it is also used for administrative purposes in the Department and physically connects all of the Department's operating stations. SISGRAD consists of a series of microcomputers connected to a common mass memory; each microcomputer is used as an intelligent console. SISGRAD was developed to guarantee that the treatments comply with prescriptions, to supply extemporaneous dosimetric data, to improve administrative work, and to supply banks with data for statistical analysis and research. SISGRAD actively intervenes to guarantee treatment quality and helps to improve therapy-related security factors. The present text describes the results of clinical use over a 4-year period. The consequences of integration of the system within the Department are analyzed, with special emphasis being placed on SISGRAD's role in the prevention and detection of errors in treatment prescription and delivery.


Clinicopathologic features of gastric cancer with synchronous and metachronous colorectal cancer in Korea: are microsatellite instability and p53 overexpression useful markers for predicting colorectal cancer in gastric cancer patients?
A large-scale study was performed to identify the risk factors for developing synchronous and metachronous colorectal cancer (CRC) in gastric cancer (GC) patients, including microsatellite instability (MSI) and p53 overexpression. A total of 1041 GC patients who underwent endoscopic resection or surgery and underwent colonoscopy simultaneously or during surveillance for GC were consecutively enrolled. Clinicopathologic characteristics, MSI, and p53 overexpression were compared between the GC patients with and those without synchronous and metachronous CRC. Of the 1041 patients, CRCs were detected in 67 (6.4 %) patients with GC. Forty-six (4.4 %) had synchronous CRC and 21 (2.0 %) had metachronous CRC. Univariate analysis indicated that age ≥63 years (P < 0.001), male sex (P = 0.005), and p53 overexpression (P = 0.040) were significantly associated with a higher incidence of CRC. However, body mass index, smoking, tumor location, tumor multiplicity, tumor histology, TNM stage, and MSI were not significantly associated with the incidence of CRC. Age ≥63 years (OR: 5.881; 95 % CI: 3.083-11.221; P < 0.001) and male sex (OR: 2.933; 95 % CI: 1.307-6.584; P = 0.009) were risk factors for CRC in GC patients according to multivariate analysis. GC patients who are male and/or ≥63 years old are recommended to receive colonoscopy to detect CRC. MSI and p53 overexpression were not useful molecular markers for predicting CRC in GC.


Aldo-keto Reductase Family 1 Member B 10 Mediates Liver Cancer Cell Proliferation through Sphingosine-1-Phosphate.
AKR1B10 is involved in hepatocarcinogenesis via modulation of fatty acid and lipid synthesis. AKR1B10 inhibition results in apoptosis of tumor cells whose lipids, especially phospholipids, were decreased by over 50%, suggesting involvement of phospholipids like sphingosine-1-phosphate (S1P) in AKR1B10's oncogenic function. Using a co-culture system, we found that co-culture of QSG-7701 (human hepatocyte) with HepG2 (hepatoma cell line) increases QSG-7701's proliferation, in which AKR1B10-S1P signaling plays a pivotal role. Consistent with previous findings, AKR1B10 mRNA and protein levels were higher in primary hepatocellular carcinoma (PHC) tissues than in peri-tumor tissues. Interestingly, the level of S1P was also higher in PHC tissues than in peri-tumor tissues. After analyzing the correlation between AKR1B10 mRNA expression in PHC tissues and the clinical data, we found that AKR1B10 mRNA expression was associated with serum alpha-fetoprotein (AFP), tumor-node-metastasis (TNM) stage, and lymph node metastasis, but not with other clinicopathologic variables. A higher AKR1B10 mRNA expression level is related to a shorter DFS (disease free survival) and OS (overall survival), serving as an independent predictor of DFS and OS in PHC patients with surgical resection.


Postoperative neurological complications in intradural extramedullary tumors: A 10-year experience of a single center.
Intradural extramedullary spinal cord tumors (IDEMs) cause neurological symptoms due to compression of the spinal cord and caudal nerves. The purpose of this study was to investigate the incidence of postoperative neurological complications after surgical resection of IDEM and to identify factors associated with such postoperative neurological complications. We retrospectively analyzed 85 patients who underwent tumor resection for IDEM between 2010 and 2020. We investigated the postoperative worsening of neurological disorders. The patients were divided into two groups: those with and without postoperative neurological complications. Patient demographic characteristics, tumor level, histological type, and surgery-related factors were also compared. The mean age at the time of surgery was 57.4 years, and histological analysis revealed 45 cases of schwannoma, 34 cases of meningioma, three cases of myxopapillary ependymoma, one case of ependymoma, one case of hemangioblastoma and one case of lipoma. There were five cases (5.8%) of postoperative neurological complications, and four patients improved within 6 months after surgery, and one patient had residual worsening. There were no statistically significant differences in age, sex, tumor location, preoperative modified McCormick Scale grade, histology, tumor occupancy, or whether fixation was performed in the presence or absence of postoperative neurological complications. All four cases of meningioma with postoperative neurological complications had preoperative neuropathy and meningiomas were located in the anterior or lateral thoracic spine. Neurological complications after surgical resection for IDEM occurred in 5.8% of patients. Meningiomas with postoperative neurological complications located anteriorly or laterally in the thoracic spine.


Risk-stratified outcomes with initial combination therapy in pulmonary arterial hypertension: Application of the REVEAL risk score.
The multinational AMBITION study demonstrated a 50% risk reduction in time to first clinical failure event (TtCF, a composite of death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) in treatment-naive Functional Class II and III PAH patients initiated on combination therapy (ambrisentan and tadalafil) vs monotherapy. A post-hoc analysis of AMBITION data by risk stratification, as determined by baseline REVEAL risk score, was undertaken to better assess the impact of combination therapy. Patients were randomized 2:1:1 to initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg vs either drug plus placebo, respectively. Baseline REVEAL risk scores in the 605 patients were grouped by low, intermediate, or high risk. Adjudicated outcomes (TtCF and post-hoc composite end-point of time to first PAH hospitalization or death) were assessed by risk group and treatment assignment. At baseline, risk groups were similarly represented across treatment assignments as low (16%), intermediate (46%), and high (38%) risk. Greater risk was associated with worse outcome. At each level of risk, patients on combination therapy had significantly fewer TtCF or PAH hospitalization/death events relative to those on monotherapy, and discontinuations due to adverse events were not higher on combination therapy. This post-hoc analysis comparing outcomes by REVEAL risk group has shown that, at all levels of risk, patients enrolled in AMBITION receiving initial combination therapy have superior outcomes and, even in those assessed as low risk, initial combination therapy was clinically beneficial.


The prescribing pattern of sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists in patient with type two diabetes mellitus: A two-center retrospective cross-sectional study.
The use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) in patients with type 2 diabetes mellitus (T2DM) remains limited, especially in those with other compelling indications. Thus, this study aimed to describe the prescribing patterns of GLP-1-RA and SGLT2i in patients with T2DM and to determine the factors that affect the prescribing of these medications. This multicenter retrospective cross-sectional study reviewed the electronic health records of adult patients diagnosed with T2DM who received care between January and December 2020. The patients were classified according to their compelling indications into "patients who are more likely" to benefit from SGLT2i or GLP-1 RA and "patients who are less likely" to benefit from them. They were then further categorized depending on whether these medications were prescribed. A total of 1,220 patients were included; most were female (56.9%). SGLT2i or GLP-1 RA were preferably prescribed in only 19% of the patients for reasons including BMI ≥ 27 kg/m2 (85.6%), uncontrolled T2DM (68.5%), high risk for ASCVD (23.9%), or established ASCVD (14%). The remaining 81.0% were underprescribed these agents. Patients at an older age or with a history of stroke or transient ischemic attack had higher odds of being underprescribed (OR 1.02; 95% CI: 1.01-1.03 and OR 2.86; 95% CI: 1.33-6.15), respectively. The results concur with those of previous studies highlighting the underutilization of GLP-1 RA and SGLT2i in patients with T2DM but also with compelling indications. To optimize the use of GLP-1 RA and SGLT2i for their additional benefits, prescribers need to assess the benefits of using these agents in patients who would likely benefit from them, regardless of DM control.


Direct posterior endoscopic excision of atypical popliteal cyst: A case report.
Certain types of popliteal cysts do not possess the common pathophysiology of Baker's cysts, such as location or the presence of a one-way valve lesion. The traditional arthroscopic approach and excision of such atypical popliteal cysts are difficult because they do not communicate with the knee joint, especially when located behind the popliteal neurovascular structure. In this case report, we introduce a direct posterior endoscopic technique for the excision of atypical popliteal cysts when accessing them through the traditional arthroscopic approach is unfeasible. In this case, the popliteal cyst was not located between the gastrocnemius medial head and the semimembranosus muscle and did not communicate with the knee joint. Passage of the popliteal artery was observed running on the anteromedial side of the popliteal cyst. Therefore, a direct posterior endoscopic approach was decided for the surgical treatment of the popliteal cyst, and the atypical popliteal cyst was successfully excised without any complications. We also describe the possible advantages and pitfalls of the direct posterior endoscopic approach. Direct posterior endoscopic excision using an intra-cystic portal in the prone position is considered a safe and effective treatment method for atypical popliteal cysts.


Personalizing approaches to the management of metastatic hormone sensitive prostate cancer: role of advanced imaging, genetics and therapeutics.
To summarize contemporary and emerging strategies for the diagnosis and management of metastatic hormone sensitive prostate cancer (mHSPC), focusing on diagnostic testing and therapeutics. Literature review using PUBMED-Medline databases as well as clinicaltrials.gov to include reported or ongoing clinical trials on treatment for mHSPC. We prioritized the findings from phase III randomized clinical trials, systematic reviews, meta-analyses and clinical practice guidelines. There have been significant changes to the diagnosis and staging evaluation of mHSPC with the integration of increasingly accurate positron emission tomography (PET) imaging tracers that exceed the performance of conventional computerized tomography (CT) and bone scan. Germline multigene testing is recommended for the evaluation of patients newly diagnosed with mHSPC given the prevalence of actionable alterations that may create candidacy for specific therapies. Although androgen deprivation therapy (ADT) remains the backbone of treatment for mHSPC, approaches to first-line treatment include the integration of multiple agents including androgen receptor synthesis inhibitors (ARSI; abiraterone) Androgen Receptor antagonists (enzalutamide, darolutamide, apalautamide), and docetaxel chemotherapy. The combination of ADT, ARSI, and docetaxel chemotherapy has recently been evaluated in a randomized trial and was associated with significantly improved overall survival including in patients with a high burden of disease. The role of local treatment to the prostate with radiation has been evaluated in randomized trials with additional studies underway evaluating the role of cytoreductive radical prostatectomy. The staging and initial management of patients with mHSPC has undergone significant advances in the last decade with advancements in the diagnosis, treatment and sequencing of therapies.


Antibody-based approaches to coumarin analysis.
7-Hydroxycoumarin (7-HC) was chemically conjugated by diazo coupling to carrier proteins such as bovine serum albumin (BSA), thyroglobulin and ovalbumin. These conjugates were characterised by sodium dodecyl sulphate/polyacrylamide gel electrophoresis (SDS-PAGE) and high-performance liquid chromatography (HPLC). Rabbits were immunised using the 7-HC-BSA conjugate. The highest antibody titre achieved was 1:10,000, as determined by competitive enzyme-linked immunosorbent assay (ELISA). The resulting antibodies were purified by ammonium sulphate precipitation, followed by protein A affinity chromatography. Their purity was assessed by SDS-PAGE and HPLC. These antibodies have been used in the development of a competitive ELISA, an amperometric biosensor and an electrochemical immunoassay. Both the ELISA and amperometric biosensor have been successfully applied to the analysis of 7-HC and its glucuronide conjugate in human urine samples. Each of these antibody-based methods provides a novel approach to the analysis of the main metabolites of coumarin.


Mitochondrial oxidative phosphorylation and energetic status are reflected by morphology of mitochondrial network in INS-1E and HEP-G2 cells viewed by 4Pi microscopy.
Mitochondria in numerous cell types, especially in cultured cells, form a reticular network undergoing constant fusion and fission. The three dimensional (3D) morphology of these networks however has not been studied in detail to our knowledge. We have investigated insulinoma INS-1E and hepatocellular carcinoma HEP-G2 cells transfected with mitochondria-addressed GFP. Using 4Pi microscopy, 3D morphology changes responding to decreased oxidative phosphorylation and/or energetic status could be observed in these cells at an unprecedented 100 nm level of detail. In INS-1E cells cultivated at 11 mM glucose, the mitoreticulum appears predominantly as one interconnected mitochondrion with a nearly constant 262+/-26 nm tubule diameter. If cultured at 5 mM glucose, INS-1E cells show 311+/-36 nm tubules coexisting with numerous flat cisternae. Similar interconnected 284+/-38 nm and 417+/-110 nm tubules were found in HEP-G2 cells cultivated at 5 mM and hyperglycaemic 25 mM glucose, respectively. With rotenone inhibiting respiration to approximately 10%, disintegration into several reticula and numerous approximately 300 nm spheres or short tubules was observed. De-energization by uncoupling additionally led to formation of rings and bulky cisternae of 1.4+/-0.4 microm diameter. Rotenone and uncoupler acted synergically in INS-1E cells and increased fusion (ongoing with fission) forming bowl-like shapes. In HEP-G2 cells fission partially ceased with FCCP plus rotenone. Thus we have revealed previously undescribed details for shapes upon mitochondrial disintegration and clearly demonstrate that high resolution 3D microscopy is required for visualization of mitochondrial network. We recommend 4Pi microscopy as a new standard.


Engineering a "PEG-g-PEI/DNA nanoparticle-in- PLGA microsphere" hybrid controlled release system to enhance immunogenicity of DNA vaccine.
Controlled release strategies of DNA vaccine hold promise for the design of in vivo vaccination platforms, yet the formulation and sustained delivery still pose a substantial challenge. In this study, we developed a novel hybrid dual-particulate delivery system, nanoparticle-in-microsphere (NIM), to integrate the advantages of nano-sized polymer/DNA polyplex with the sustained-release microsphere for DNA vaccine delivery. The nano-sized cores, consisting of polyethylene glycol-graft-polyethylenimine (PEG-g-PEI)/DNA polyplexes, were formulated into PLGA microspheres using a solid-in-oil-in-water (S/O/W) emulsion. The PEG block was used as stabilizing excipient to make DNA soluble and stable in organic solvent to prevent the inactivation of DNA at aqueous-organic interface during encapsulation. The fashion of DNA in dry solid state greatly increased the encapsulation efficiency of DNA in NIMs. This new formulation exhibited a burst release less than 15% and then sustain release close to zero-order kinetics in physiological environment. In addition, the microspheres showed pH-sensitivity and degraded faster in lysosomal compartments, which contributed to the accelerated intracellular release kinetics of DNA. Finally, intramuscular injection of NIMs encoding HIV proteins elicited distinct humoral and cellular immune response in mice at low dose. These results thus may aid NIM-based vaccination towards more extensive clinical evaluations.


[The role of hyponatremia in the rapid onset of coma after Cyclophosphamide].
Cyclophosphamide is an alkylating agent used in routine pulmonary practice, particularly in the management of connectivitis-related diffuse interstitial lung disease. Common side effects are gastrointestinal disorders and immunosuppression, and a sudden and exceptional adverse effect is severe hyponatremia. A 78-year-old female patient treated for NSIP-OP in the context of an anti-synthetase syndrome was treated with Cyclophosphamide 15mg/kg. Twenty-four hours after the end of the infusion, she was diagnosed at home in a coma with comitial seizures. Biological assessment revealed severe hyponatremia at 109 mmol/l with blood hypo-osmolarity. The patient's condition rapidly improved following correction of the ionic disorder. Hyponatremia induced by low-dose Cyclophosphamide is a rare but serious adverse effect that requires special attention.


Do tracheas grow after slide tracheoplasty?
Slide tracheoplasty has become the surgical technique of choice for repair of congenital tracheal stenosis. Despite the initial reluctance regarding the ability of this "reconstructed" trachea to grow, the reduced morbidity and mortality have allowed slide tracheoplasty to be widely adopted. The aim of this study was to evaluate tracheal growth after slide tracheoplasty. This was a retrospective study. In follow-up bronchography performed 1, 6, 12, 18, and 24 months after slide tracheoplasty, we measured the cross-sectional areas of the midtrachea and distal trachea at each investigation and correlated the measurements with the anthropomorphic factors (body weight, height, and body surface). Fourteen patients were enrolled in this study. The midtracheal and distal tracheal cross-sectional areas significantly increased with time (p ≤ 0.0001). The average rates of midtracheal growth were 21.0 mm(2)year in the first 6 months and 8.0 mm(2)/year in the first 2 years, and the distal trachea grew 18.5 mm(2)/year and 8.4 mm(2)/year, respectively. Regression analysis showed that both the midtrachea and the distal trachea increase significantly with weight (r(2) = 0.257, p ≤ 0.0001), height (r(2) = 0.376, p ≤ 0.0001), and body surface area (r(2) = 0.315, p ≤ 0.0001). Balloon dilation did not significantly alter the tracheal growth in the first 2 years after slide tracheoplasty. Slide tracheoplasty does not inhibit tracheal growth. The reconstructed trachea grows faster in the first 6 months and slows in the following 18 months. There is a positive correlation between tracheal cross-sectional area and weight, height, and body surface area.


Preferences for pharmacist services to enhance medication management among people with diabetes in Indonesia: A discrete choice experiment.
To elicit patients' preferences for pharmacist services that can enhance medication management among people with diabetes in Indonesia. A discrete choice experiment (DCE) among 833 respondents with diabetes in 57 community health centers (CHCs) and three hospitals in Surabaya, Indonesia. Consultation was the baseline service. Four attributes of consultation and two attributes of additional services were used in the DCE profiles based on literature and expert opinion. The DCE choice sets generated were partially balanced and partially without overlap. Random effect logistic regression was used in the analysis. Respondents preferred a shorter duration of consultation and flexible access to the pharmacist offering the consultation. A private consultation room and lower copayment (fee) for services were also preferred. Respondents with experience in getting medication information from pharmacists, preferred to make an appointment for the consultation. Total monthly income and experience with pharmacist services influenced preferences for copayments. Differences in patients' preferences identified in the study provide information on pharmacist services that meet patients' expectations and contribute to improve medication management among people with diabetes. This study provides insight into evaluating and designing pharmacist services in accordance with the preferences of people with diabetes in Indonesia.


Antibody response of nude (RNU/RNU) and hairy (RNU/+) rats to circulating cell surface components from human pancreatic cancer xenografts.
Homozygous nude rats (rnu/rnu) injected s.c. with 3 X 10(7) human pancreatic cancer cells from the GER cell line developed circulating antibody to GER cell surface, detected in a 125I binding assay against viable GER cells in vitro. Antibody titre rose with progressive xenograft growth. These antibodies showed no selectivity for GER cells when compared with a panel of other human cell lines. Heterozygous nude rats (rnu/+) immunised with serum from their GER xenograft-bearing nude relatives (rnu/rnu) also developed anti-GER cell surface antibodies. These antibodies showed some selectivity for GER and WAD (a second human pancreatic cancer cell line) when compared with other human cancer cells and lymphocytes. These findings show that some human pancreatic cancer cell surface components may persist independently in the circulation of xenograft bearing rnu/rnu rats despite the presence of antibody excess to other surface determinants from the same cells. It is suggested that differences in the relative immune competence of rnu/rnu and rnu/+ rats may offer a biological opportunity for enhancing the recognition of weak antigenic determinants which may have some useful selectivity for different types of human tumour cells.


The impact of cryoprotective media on cryopreservation of cells using loading trehalose.
The purpose of the present study was to assess the impact of cryoprotective media on cryopreservation of Paesun cells using loading trehalose. 30 mM trehalose was added after confluence of cells, and cultures were further incubated for 18 h at 37 °C. Cryoprotective media was "Cryocool" for the experiment, while MEM containing 10% FBS for the control. After thawing, these cells were examined with assaying the percentage of viable cells and the recovery rate; 89.2 ± 1.4% and 78.8 ± 3.2%, respectively in the experiment group, while 33.1 ± 2.9% and 21.5 ± 2.1%, respectively in the control group. Post-thaw cells of the experiment group were examined by assaying proliferation and susceptibility to virus lines; there were no significant differences between before and after cryopreservation, while cells of control group could not be recultured. In conclusion, the cryoprotective media impacts on the effectiveness of cryopreservation using loading trehalose.


Intracellular cytokine production by Th1/Th2 lymphocytes and monocytes of children with symptomatic transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD).
Intracellular expression of several cytokines was assessed in lymphocytes and monocytes of children with transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD). THI was characterized by an increased frequency of CD3+/CD4+ lymphocytes expressing tumour necrosis factor alpha (TNF-alpha), TNF-beta and interleukin 10 (IL-10), while in SIgAD elevated numbers of these cells containing TNF-alpha and interferon gamma (IFN-gamma) were observed. No changes in the number of CD4+ T cells expressing IL-4 in both diseases were noted. The proportion of CD33+ monocytes containing TNF-alpha both in THI and SIgAD was unchanged. The secretion of IL-12 by peripheral blood mononuclear cells (PBMCs) of patients with THI and SIgAD was significantly elevated and associated with an increased frequency of IL-12 expressing monocytes in THI but not in SIgAD. IL-18 secretion was slightly, but not significantly, elevated in both diseases. Intracellular Th1 and Th2 type cytokines within CD3+/CD4+ lymphocytes were also determined in the normal blood donors that showed high or low production of IgG and IgA in vitro. In low producers of IgG an increased proportion of CD3+/CD4+ cells expressing TNF-alpha and IFN-gamma was found, while in low IgA responders only elevated TNF-alpha positive CD3+/CD4+ cells were observed. These results suggest that THI and SIgAD may represent diseases with an excessive Th1 type response that is associated with an up-regulation of IL-12 secretion and, at least in THI, elevated numbers of monocytes expressing intracellular IL-12. Up-regulation of IL-12 may be the essential factor in the patomechanism(s) of these diseases as already described in common variable immunodeficiency (CVID).


Differences between effects of psychological versus pharmacological treatments on functional and morphological brain alterations in anxiety disorders and major depressive disorder: a systematic review.
The most prevalent mental disorders, anxiety and mood disorders, are associated with both functional and morphological brain changes that commonly involve the 'fear network' including the (medial) prefrontal cortex, hippocampus and amygdala. Patients suffering from anxiety disorders and major depressive disorder often show excessive amygdala and reduced prefrontal cortex functioning. It is, however, still unclear whether these brain abnormalities disappear or diminish following effective treatment. This review aims to compare the effects of psychotherapy and pharmacotherapy on functional and morphological brain measures in these disorders. Sixty-three studies were included, 30 investigating psychotherapy effects and 33 investigating pharmacotherapy effects. Despite methodological differences, results suggest a functional normalization of the 'fear network'. Pharmacotherapy particularly decreases over-activity of limbic structures (bottom-up effect) while psychotherapy tends to increase activity and recruitment of frontal areas (top-down effect), especially the anterior cingulate cortex. Additionally, pharmacotherapy, but not psychotherapy, has been associated with morphological changes, depending on the disorder. These findings suggest that both types of treatments normalize (functional) brain abnormalities each in specific ways.


Differences in advanced glycation endproducts (AGEs) in plasma from birds and mammals of different body sizes and ages.
Birds and mammals provide a physiological paradox: similar-sized mammals live shorter lives than birds; yet, birds have higher blood glucose concentrations than mammals, and higher basal metabolic rates. We have previously shown that oxidative stress patterns between mammals and birds differ, so that birds, generally, have lower blood antioxidant capacity, and lower lipid peroxidation concentration. There is a close association between oxidative stress and the production of carbohydrate-based damaged biomolecules, Advanced Glycation End-products (AGEs). In mammals, AGEs can bind to their receptor (RAGE), which can lead to increases in reactive oxygen species (ROS) production, and can decrease antioxidant capacity. Here, we used plasma from birds and mammals to address whether blood plasma AGE-BSA concentration is associated with body mass and age in these two groups. We found a statistically significantly higher average concentrations of AGE-BSA in birds compared with mammals, and we found a significantly positive correlation between AGE-BSA and age in mammals, though, this correlation disappeared after phylogenetic correction. We propose that the higher AGE concentration in birds is mainly attributable to greater AGE-production due to elevated basal glucose concentrations and decreased AGE-clearance given differences in glomerular filtration rates in birds compared with mammals. Additionally, due to the potential lack of an AGE receptor in birds, AGE accumulation may not be closely linked to oxidative stress and therefore pose a lesser physiological challenge in birds compared to mammals.


Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N2-(2-Ethoxy-4-(4-methyl-4 H-1,2,4-triazol-3-yl)phenyl)-6-methyl- N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine (BOS172722).
Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4- d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4- d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.


The effects of foot reflexology on back pain after coronary angiography: A randomized controlled trial.
Back pain is among the most common complaints of patients during the first hours after coronary angiography (CA), i.e. when they are restricted to complete bed rest. This study aimed to evaluate the effects of foot reflexology on back pain after CA. This randomized controlled trial was conducted in 2018-2019 on patients hospitalized in the post-angiography unit of Razi hospital, Birjand, Iran. Through convenience sampling, 120 patients were recruited and their demographic characteristics and baseline back pain intensity were assessed immediately after angiography using a demographic questionnaire and a visual analogue scale, respectively. Then, patients were randomly allocated to a control (n = 60) and a reflexology (n = 60) group through block randomization. Patients in the reflexology group received 8-min foot reflexology for each foot (16 min for both feet) while their counterparts in the control group solely received routine post-angiography care services. Back pain assessment was repeated for all participants immediately, two, four, and 6 h after the intervention. Data were analyzed using the SPSS software (v. 16.0). Back pain intensity significantly increased after angiography in both groups (P < 0.05). Yet, pain intensity in the reflexology group at all post-intervention measurement time points was significantly less than the control group (P < 0.001). Foot reflexology is effective in significantly reducing back pain after CA.


Intra-articular hyaluronic acid in knee osteoarthritis: clinical data for a product family (ARTHRUM), with comparative meta-analyses.
Viscosupplementation is widely practiced, to reduce pain in osteoarthritis (OA), using intra articular (IA) injections of hyaluronic acid (HA). In Europe, these products are class III medical devices, for which the Medical Device Regulation (MDR) requires clinical assessment, based on specific studies and/or a bibliographical review of equivalent devices. The purpose of this article is to present a comparative review between a family of devices (ARTHRUM, from LCA Pharmaceuticals, Chartres, France) and an extensive group of presumed equivalent IA HA devices or their controls, whose results have been published in Scientific journals. To meet the criteria used in most ARTHRUM studies, the Western Ontario and McMaster Universities' index sub-scores were selected for pain (WOMAC A), stiffness (WOMAC B) and function (WOMAC C). The main criterion was the variation of the WOMAC A score from T0 (date of inclusion) to T6 (6 months). The other WOMAC criteria were assessed at T1, T3, T6 and complemented by OMERACT-OARSI rates of responders to the treatment. Fifty articles were selected, containing treatment details on more than 12,000 patients. These were divided into three groups: ARTHRUM, EQUIVALENTS and CONTROLS. To get quantitative comparisons, meta-analyses were performed for each criterion individually. The 95% confidence interval of each difference from baseline, was used to assess the clinical relevance, with reference to a minimum validated in OA literature. Comparisons between groups and tolerance assessment completed the investigation. For the WOMAC A, B and C scores, the full 95% CI was always above the minimal perceptible clinical improvement (MPCI), in the ARTHRUM and EQUIVALENTS groups, but not for all criteria in the CONTROLS group. In the comparisons, both ARTHRUM and EQUIVALENTS groups were significantly better than the CONTROLS group for each criterion. The effect size (ES) on pain, for the ARTHRUM and EQUIVALENTS groups, varied from 0.28 to 0.56 and from 0.23 to 0.27, respectively. Overall, ARTHRUM was estimated always non-inferior to EQUIVALENTS, and sometimes statistically and clinically superior. The comparison of ARTHRUM clinical studies, with studies selected through bibliographic research, leads to the conclusion that the clinical efficacy of the ARTHRUM medical devices, to reduce pain and improve the function in knee OA, during a six-month period, is at least as great as those of equivalent products. With good tolerance results (lowest rate of adverse events, and none of them serious), the risk benefit ratio favours using viscosupplementation with ARTHRUM.


Association between chronic pain and quality of life in long-term breast cancer survivors: a prospective analysis.
Pain is a leading cause of disability worldwide and is highly prevalent among breast cancer survivors. Pain and quality of life (QOL) are associated in breast cancer patients undergoing active treatment, but little is known about the relationship between the two in long-term survivors. We evaluated associations between pain information collected during a 5-year post-diagnosis follow-up survey and QOL assessed by the SF-36 during a 10-year post-diagnosis survey for 2828 participants in the Shanghai Breast Cancer Survival Study. The mean overall QOL score was 78.7 for the entire study population and decreased as pain severity and frequency measured at the 5-year timepoint increased (none: 81.9, mild: 75.9, moderate/severe: 70.4, infrequent: 76.7, frequent: 72.3; P < 0.001). Significant inverse associations were found between pain and all QOL domains, including pain at 10-years post-diagnosis after multivariate adjustments. Concurrent pain was significantly and strongly associated with QOL. Most of the associations between 5-years post-diagnosis pain and QOL at 10-years post-diagnosis persisted after further adjustment for concurrent pain. Pain is associated prospectively and concurrently with poor QOL among long-term breast cancer survivors. Programs to manage pain are needed to improve QOL among breast cancer survivors.


High expression of BTLA and B7-H4 on the surface of myeloid dendritic cells has a negative regulatory effect on their anti-tuberculosis immunity activity in pleural tuberculosis patients.
To investigate the effects of the surface markers B- and T-lymphocyte attenuator (BTLA) and B7 homologous body 4 (B7-H4) on expression of CD83, and Human Leukocyte Antigen-DR isotype (HLA-DR) that can activate dendritic cells (DCs). Flow cytometry was used to detect the co-expression of BTLA and B7-H4 on myeloid DCs (mDCs) in peripheral blood (PB) and pleural effusions (PE) in 15 volunteers and 20 tuberculous pleurisy (TP) patients. Co-expression of BTLA and B7-H4 (double positive (DP)) mDCs in PB and PE of TP patients were enhanced. The proportion of DP mDC in PB decreased markedly after 2 weeks treatment, but was still greater than in controls. Expression of CD83 and HLA-DR on DP mDCs was higher than on BTLA and B7-H4 double negative (DN) expressing mDCs in PB of different TP groups. Expression of CD83 on DP mDCs in PB and PE of TP patients was greater than that of controls. Expression of HLA-DR on DP mDCs in TP patient PB was lower than in TP PE and controls. In pleural tuberculosis (TB) patients, high expression of BTLA and B7-H4 promoted a high level of CD83 and HLA-DR, which had a negative regulatory effect on mDCs on anti-TB immunity.


BmCyclin B and BmCyclin B3 are required for cell cycle progression in the silkworm, Bombyx mori.
Cyclin B is an important regulator of the cell cycle G2 to M phase transition. The silkworm genomic database shows that there are two Cyclin B genes in the silkworm (Bombyx mori), BmCyclin B and BmCyclin B3. Using silkworm EST data, the cyclin B3 (EU074796) gene was cloned. Its complete cDNA was 1665 bp with an ORF of 1536 bp derived from seven exons and six introns. The BmCyclin B3 gene encodes 511 amino acids, and the predicted molecular weight is 57.8 kD with an isoelectric point of 9.18. The protein contains one protein damage box and two cyclin boxes. RNA interference-mediated reduction of BmCyclin B and BmCyclin B3 expression induced cell cycle arrest in G2 or M phase in BmN-SWU1 cells, thus inhibiting cell proliferation. These results suggest that BmCyclin B and BmCyclin B3 are necessary for completing the cell cycle in silkworm cells.


Intrasphincteric anastomotic urethroplasty allows preservation of continence in men with bulbomembranous urethral strictures following benign prostatic hyperplasia surgery.
Injury to the external sphincter during urethroplasty at or near the membranous urethra can result in incontinence in men whose internal sphincter mechanism has been compromised by previous benign prostatic hyperplasia (BPH) surgery. We present outcomes of a novel reconstructive procedure, incorporating a recent anatomic discovery revealing a connective tissue sheath between the external sphincter and membranous urethra, which provides a surgical plane allowing for intrasphincteric bulbo-prostatic urethroplasty (ISBPA) with continence preservation. Stricture at or near the membranous urethra after transurethral resection (TURP) or open simple prostatectomy (OSP) was reconstructed with ISBPA. The bulbomembranous junction is approached dorsally with a bulbar artery sparing approach and the external sphincter muscle is carefully reflected, exposing the wall of the membranous urethra. Gentle blunt dissection along this connective tissue plane allows separating the muscle away up to the prostatic apex, where healthy urethra is found for anastomosis. From January 2010 to August 2019, 40 men (18 after TURP and 22 after OSP) underwent ISBPA at a single institution. Mean age was 67 years (54-82). Mean stricture length was 2.6 cm (1-6) with obliterative stricture identified in 10 (25%). At a mean follow-up of 53 months (10-122), 36 men (90%) are free of stricture recurrence and 34 (85%) were completely dry or using one security pad. This novel intrasphincteric urethroplasty technique for stricture following BPH surgery is feasible and safe, allowing successful reconstruction with continence preservation in most patients. A larger series and reproduction in other centers is needed.


Stable thin films and hollow spheres composing chiral polyaniline composites.
Chiral polyaniline composite (CPAC) thin films were fabricated by self-assembly using diazoresin (DR) and CPAC. The weak linkage between the DR and CPAC of the film will convert to covalent bonds under UV irradiation or heating, and the thin film becomes very stable toward polar solvents and electrolyte aqueous solutions. Core-shell particles with stable DR/CPAC shell and polystyrene (PS) core can be prepared by similar methods. After the PS core is removed by chemical etching, stable DR/CPAC hollow spheres were obtained. Circular dichroism spectra and cyclic voltammetry measurements show that the DR/CPAC thin films are chirally active and possess good electrochemical stability.


Chemical and cytological changes during the autolysis of yeasts.
Cell suspensions of Sacharomyces cerevisiae, Kloeckera apiculata and Candida stellata were autolyzed in phosphate buffer, pH 4.5, for up to 10 days. Cell dry weights decreased by 25-35% after 10 days. Based on initial cell dry weight, the soluble autolysate consisted of: carbohydrate (principally polysaccharide) 3-7%; organic acids 3-6%; protein 12-13%; free amino acids 8-12%; nucleic acid products 3-5%; and lipids 1-2%. The main organic acids in autolysates were propionic, succinic and acetic and the main amino acids were phenylalanine, glutamic acid, leucine, alanine and arginine. Approximately 85-90% of cellular RNA and 25-40% of cellular DNA were degraded during autolysis. Both neutral lipid and phospholipid components were degraded, with neural lipids but not phospholipids being found in autolysates. Scanning and transmission electron micrographs showed retention of cell wall structure and shape during autolysis, but there was extensive intracellular disorganization within S. cerevisiae and C. stellata. There were differences in the autolytic behavior of K. apiculata compared with S. cerevisiae and C. stellata.


National cervical cancer burden estimation through systematic review and analysis of publicly available data in Pakistan.
Cervical cancer is a major cause of cancer-related deaths among women worldwide. Paucity of data on cervical cancer burden in countries like Pakistan hamper requisite resource allocation. To estimate the burden of cervical cancer in Pakistan using available data sources. We performed a systematic review to identify relevant data on Pakistan between 1995 to 2022. Study data identified through the systematic review that provided enough information to allow age specific incidence rates and age standardized incidence rates (ASIR) calculations for cervical cancer were merged. Population at risk estimates were derived and adjusted for important variables in the care-seeking pathway. The calculated ASIRs were applied to 2020 population estimates to estimate the number of cervical cancer cases in Pakistan. A total of 13 studies reported ASIRs for cervical cancer for Pakistan. Among the studies selected, the Karachi Cancer Registry reported the highest disease burden estimates for all reported time periods: 1995-1997 ASIR = 6.81, 1998-2002 ASIR = 7.47, and 2017-2019 ASIR = 6.02 per 100,000 women. Using data from Karachi, Punjab and Pakistan Atomic Energy Cancer Registries from 2015-2019, we derived an unadjusted ASIR for cervical cancer of 4.16 per 100,000 women (95% UI 3.28, 5.28). Varying model assumptions produced adjusted ASIRs ranging from 5.2 to 8.4 per 100,000 women. We derived an adjusted ASIR of 7.60, (95% UI 5.98, 10.01) and estimated 6166 (95% UI 4833, 8305) new cases of cervical cancer per year. The estimated cervical cancer burden in Pakistan is higher than the WHO target. Estimates are sensitive to health seeking behavior, and appropriate physician diagnostic intervention, factors that are relevant to the case of cervical cancer, a stigmatized disease in a low-lower middle income country setting. These estimates make the case for approaching cervical cancer elimination through a multi-pronged strategy.


Comparative study of glial marker proteins in the hypoplastic cerebellum of jaundiced Gunn rats.
The behavior of marker proteins of glial cells [alpha-enolase, beta-S100 protein, and glial fibrillary acidic protein (GFAP)] was investigated quantitatively by using enzyme immunoassay systems during the development of cerebellar hypoplasia in jaundiced Gunn rats. A neuronal marker protein, gamma-enolase, was also measured as a reference. At postnatal day 8 corresponding to the early stage of cerebellar damage, the amount of beta-S100 on a protein basis was significantly higher in jaundiced homozygotes (jj) than in control nonjaundiced heterozygotes (j+), whereas no differences in alpha- and gamma-enolases and GFAP were observed between the two groups of rats. At days 15 and 30, which correspond, respectively, to the advanced and late stages of cerebellar damage, the three glial proteins, especially GFAP, were higher and the neuronal protein was lower in the jj rat cerebellum than in the control. These results are consistent with the reported histological observations that neuronal cells are vulnerable and damaged by bilirubin, whereas glial cells seem to be less sensitive. On the other hand, the amounts of beta-S100 and alpha-enolase per cerebellum were significantly lower in jj rats at days 15 and 30, as in the case of gamma-enolase, whereas that of GFAP remained at the same level as the control at day 15 and showed a slight but significant decrease at day 30. The possibility is suggested that beta-S100 and GFAP may be available as biochemical indicators of glial cells, especially in the early and advanced stages of cerebellar damage, respectively, but that alpha-enolase is less available.


Myopathy is a prominent feature in Marinesco-Sjögren syndrome: A muscle computed tomography study.
Marinesco-Sjögren syndrome (MSS) is an autosomal recessive multiorgan disorder showing clinical and genetic heterogeneity. The key features of MSS include cerebellar ataxia, early bilateral cataracts, delayed motor development, and varying degrees of mental retardation. Patients with a subtype of MSS with myoglobinuria and neuropathy have been linked to chromosome 18qter, and recently a locus for classical MSS has been localized on chromosome 5q31. To determine the importance of myopathy in this disorder apart from the CNS based disability and to establish the pattern of muscle involvement and degree of its severity. Muscle computed tomography (CT) investigations were carried out in nine Finnish MSS patients homozygous for markers around the MSS locus on chromosome 5q31. Patients with severe clinical disability showed severe and generalized muscle degeneration. Muscle CT findings in patients with relatively severe clinical picture were characterized by severe involvement of the posterior thoracic and pelvic muscles, and almost all thigh muscles. In the legs the peronei and posterior compartment muscles were severely degenerated. The group of patients with moderate severity of disease showed the same pattern of involved muscle, albeit with lower degree of muscle degeneration. Patients with MSS linked to chromosome 5q31 have a severe progressive myopathy, the extent of which may remain largely unrecognized because of the CNS involvement.


Comparison of the uptake of health assessment items for Aboriginal and Torres Strait Islander people and other Australians: implications for policy.
Health Assessment (HA) items were introduced in 1999 for Aboriginal and Torres Strait Islander people aged at least 55 years and all Australians aged over 75 years. In 2004 a new item was introduced for HAs among adult Aboriginal and Torres Strait Islander people aged 15-54 years. The new item has been applauded as a major policy innovation however this enthusiasm has been tempered with concern about potential barriers to its uptake. In this study we aim to determine whether there are disparities in uptake of HA items for Aboriginal and Torres Strait Islander people compared to other Australians. The analysis was based on Health Insurance Commission data. Indigenous status was ascertained based on the item number used. Logistic regression was used to compare uptake of HA items for older people among Aboriginal and Torres Strait Islander people compared to other Australians. Adjustments were made for dual eligibility. Uptake of the HA items for older people was compared to the uptake of the new item for Aboriginal and Torres Strait Islander people aged 15-44 years. Our analyses suggest a significant and persistent disparity in the uptake of items for older patients among Aboriginal and Torres Strait Islander people compared to other Australians. A similar disparity appears to exist in the uptake of the new adult Aboriginal and Torres Strait Islander HA item. Further engagement of primary care providers and the community around the uptake of the new HA items may be required to ensure that the anticipated health benefits eventuate.


From Mendel to epigenetics: History of genetics.
The origins of genetics are to be found in Gregor Mendel's memoir on plant hybridization (1865). However, the word 'genetics' was only coined in 1906, to designate the new science of heredity. Founded upon the Mendelian method for analyzing the products of crosses, this science is distinguished by its explicit purpose of being a general 'science of heredity', and by the introduction of totally new biological concepts (in particular those of gene, genotype, and phenotype). In the 1910s, Mendelian genetics fused with the chromosomal theory of inheritance, giving rise to what is still called 'classical genetics'. Within this framework, the gene is simultaneously a unit of function and transmission, a unit of recombination, and of mutation. Until the early 1950s, these concepts of the gene coincided. But when DNA was found to be the material basis of inheritance, this congruence dissolved. Then began the venture of molecular biology, which has never stopped revealing the complexity of the way in which hereditary material functions.


Dominance in a human adolescent group.
Primatological concepts and methods are applied to a 5-week, naturalistic observational study of six 13-year-old boys in a summer camp. The purpose is to illustrate similarities between a human adolescent group and other primate groups in the establishment and stability of a dominance hierarchy, indices and frequencies of dominance interactions, and characteristics of dominance relations. A hierarchy was evident after 3 days of camp and remained operative throughout the 5 weeks, becoming more stable over time. The dominance rank-order was significantly related to athletic ability, leadership, and bed position but not to trail position, popularity, body surface area, and physical maturity. The possible social effects of the dominance hierarchy are also discussed.


ESCRT-I Component VPS23A Is Targeted by E3 Ubiquitin Ligase XBAT35 for Proteasome-Mediated Degradation in Modulating ABA Signaling.
A myriad of abiotic stress responses in plants are controlled by abscisic acid (ABA) signaling. ABA receptors can be degraded by both the 26S proteasome pathway and vacuolar degradation pathway after processing via the endosomal sorting complex required for transport (ESCRT) proteins. Despite being essential for ABA signaling, the upstream regulators of ESCRTs remain unknown. Here, we report that the ESCRT-I component VPS23A is an unstable protein that is degraded via the ubiquitin-proteasome system (UPS). The UEV domain of VPS23A physically interacts with the two PSAP motifs of XBAT35, an E3 ubiquitin ligase, and this interaction results in the deposition of K48 polyubiquitin chains on VPS23A, marking it for degradation by 26S proteasomes. We showed that XBAT35 in plants is a positive regulator of ABA responses that acts via the VPS23A/PYL4 complex, specifically by accelerating VPS23A turnover and thereby increasing accumulation of the ABA receptor PYL4. This work deciphers how an ESCRT component is regulated in plants and deepens our understanding of plant stress responses by illustrating a mechanism whereby crosstalk between the UPS and endosome-vacuole-mediated degradation pathways controls ABA signaling.


Helix rotation model of the flagellar rotary motor.
A new model of the flagellar motor is proposed that is based on established dynamics of the KcsA potassium ion channel and on known genetic, biochemical, and biophysical facts, which accounts for the mechanics of torque generation, force transmission, and reversals of motor rotation. It predicts that proton (or in some species sodium ion) flow generates short, reversible helix rotations of the MotA-MotB channel complex (the stator) that are transmitted by Coulomb forces to the FliG segments at the rotor surface. Channels are arranged as symmetric pairs, S and T, that swing back and forth in synchrony. S and T alternate in attaching to the rotor, so that force transmission proceeds in steps. The sense of motor rotation can be readily reversed by conformationally switching the position of charged groups on the rotor so that they interact with the stator during the reverse rather than forward strokes. An elastic device accounts for the observed smoothness of rotation and a prolonged attachment of the torque generators to the rotor, i.e., a high duty ratio of each torque-generating unit.


Differential virulence of infectious hematopoietic necrosis virus (IHNV) isolated from salmonid fish in Gangwon Province, Korea.
The present study investigated the virulence and expression of innate immunity genes in isolates of infectious hematopoietic necrosis virus (IHNV) in Gangwon province, South Korea, by challenging rainbow trout, Atlantic salmon, and coho salmon. Eight IHNV isolates were used to infect RTG-2 cells for viral replication using plaque assays. Three isolates with the highest replication rates, the RtPc0314g and RtPc0314c isolates of the JRt-Shizuoka type and the RtPc0816g isolate of the JRt-Nagano type, were experimentally infected into the fish. In rainbow trout, both RtPc0314c and RtPc0314g isolates showed 100% cumulative mortality while the RtPc0816g isolate showed 60% cumulative mortality for 14 days. In contrast, all three isolates showed <60% cumulative mortality in Atlantic salmon and coho salmon. The expression of G genes in the kidney was higher than that in the spleen-infected fish, with the highest expression observed in the kidneys of rainbow trout. The relative expression levels of innate immunity genes were higher in rainbow trout than in Atlantic salmon and coho salmon. The expression level of immunoglobulin M increased until day 7, and the expression of type I interferon was higher in the spleen than in other tissues. The expression of Mx-1 was higher in the kidney and liver than other tissues. These results indicate that IHNV isolates from Gangwon province show host-specific virulence in rainbow trout and that their virulence and replication were higher in JRt-Shizuoka type than in JRt-Nagano type isolates.


Loss of intraoperative evoked responses during dorsal column surgery associated with isolated postoperative sensory deficit.
Two patients underwent surgery for the removal of dermoid tumors that involved the dorsal aspect of the spinal cord. Both patients were monitored with intraoperative posterior tibial nerve somatosensory evoked potentials (SSEPs). In each case, the surgical procedure was nearly complete when an abrupt and persistent loss of SSEPs occurred. Although minor recovery of waveforms was present by the end of the operation, the SSEP waveforms remained strikingly abnormal. Neither patient had a postoperative motor deficit, although both had evidence of dorsal column dysfunction. These observations suggest that, during dorsal column surgery, even dramatic SSEP loss may not be associated with motor pathway injury, but rather, may correlate better with postoperative dorsal column dysfunction. The possible implications for intraoperative monitoring of SSEPs during dorsal column surgical procedures are discussed.


Discrepancies of MRI findings between recumbent and upright positions in atlantoaxial lesion. Report of two cases.
Two cases of atlantoaxial (A-A) instability that showed different MRI findings between supine and upright positions are presented. The upright MRI represented the findings corresponding to their symptoms. In A-A lesions, conventional MR images taken in the supine position do not always explain the pathophysiological consequences. The MR images taken in the upright position disclose the actual spinal pathophysiology with gravitational effects.


Analysis of the proteolysis of bioactive peptides using a peptidomics approach.
Identifying the peptidases that inactivate bioactive peptides (e.g., peptide hormones and neuropeptides) in mammals is an important unmet challenge. This protocol describes a recent approach that uses liquid chromatography-mass spectrometry (LC-MS) peptidomics to identify endogenous cleavage sites of a bioactive peptide; it also addresses the subsequent biochemical purification of a candidate peptidase on the basis of these cleavage sites and the validation of the candidate peptidase's role in the physiological regulation of the bioactive peptide by examining a peptidase-knockout mouse. We highlight the successful application of this protocol in the discovery that insulin-degrading enzyme (IDE) regulates physiological calcitonin gene-related peptide (CGRP) levels, and we detail the key stages and steps in this approach. This protocol requires 7 d of work; however, the total time for this protocol is highly variable because of its dependence on the availability of biological reagents such as purified enzymes and knockout mice. The protocol is valuable because it expedites the characterization of mammalian peptidases, such as IDE, which in certain instances can be used to develop novel therapeutics.


A novel method for analysing key corticosteroids in polar bear (Ursus maritimus) hair using liquid chromatography tandem mass spectrometry.
This paper presents the development and evaluation of a methodology for extraction, clean-up and analysis of three key corticosteroids (aldosterone, cortisol and corticosterone) in polar bear hair. Such a methodology can be used to monitor stress biomarkers in polar bears and may provide as a useful tool for long-term and retrospective information. We developed a combined pressurized liquid extraction (PLE)-solid phase extraction (SPE) procedure for corticosteroid extraction and clean-up followed by high pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS) analysis. This procedure allows for the simultaneous determination of multiple steroids, which is in contrast to previous polar bear studies based on ELISA techniques. Absolute method recoveries were 81%, 75% and 60% for cortisol, corticosterone and aldosterone, respectively. We applied the developed method on a hair sample pooled from four East Greenland polar bears. Herein cortisol and corticosterone were successfully determined in levels of 0.32±0.02ng/g hair and 0.13±0.02ng/g hair, respectively. Aldosterone was below limit of detection (LOD<0.17ng/g). The cortisol hair concentration found in these East Greenland polar bears was consistent with cortisol levels previously determined in the Southern Hudson Bay and James Bay in Canada using ELISA kits.


A possible role for the high mobility group box transcription factor Tcf-4 in vertebrate gut epithelial cell differentiation.
The Wingless (Wg)/Wnt signaling pathway activates High Mobility Group (HMG)-box transcription factors of the T-cell Factor (Tcf)/Lymphoid Enhancer Factor (LEF) subfamily and mediates diverse functions in development, possibly including endoderm and gut differentiation. Determinants of tissue specificity in the response to Wg/Wnt signaling remain unknown. We have identified Tcf-4 as the predominant Tcf/LEF factor in the developing mouse gut. During fetal development, Tcf-4 mRNA expression is restricted to gut epithelium and specific regions of the brain, the thalamus and roof of the midbrain. In adults, expression is widespread, with highest levels observed in the liver, an endodermally derived organ, and persists in the gastrointestinal tract. Murine Tcf-4 has multiple RNA splice variants with consequently significant heterogeneity in sequences 3' to the HMG box. Microinjection of mRNA or plasmid DNA encoding Tcf-4 into Xenopus embryos results in ectopic expression of molecular markers of endoderm and differentiated gut epithelium in isolated animal cap explants. Taken together, these findings point to a potentially important function for Tcf-4 in development of the vertebrate gastrointestinal tract.


Hospitalization and ambulatory care in imported-malaria: evaluation of trends and impact on mortality. A prospective multicentric 14-year observational study.
Hospitalization is usually recommended for imported malaria. The goal of the present study is to evaluate the evolution in clinical pathways while measuring their impact on mortality. This is a 14-year prospective observational study divided into three periods. We evaluated for adult (≥15 years) and paediatric (<15 years) case trends in severity, clinical pathways (hospitalization in medical ward (MW) or intensive care unit (ICU), ambulatory care) and mortality. In total, 21,386 imported malaria cases were included, 4269 of them were paediatrics (20 %). Rises in severe forms for adults [from 8 % in period 1-14 % in period 3 (p = 0.0001)] and paediatrics [from 12 to 18 % (p < 0.0001)] were found. For adults, MW admission rates decreased [-15 % (CI 95 % -17; -13)] while ambulatory care [+7 % (CI 95 % 5-9)] and ICU admission rates [+4 % (CI 95 % 3-5)] increased. For paediatrics, increase in ICU admissions (+3 %) was shown. We did not observe any change in overall mortality during the study periods, whether among adults or children, regardless of care pathway. The present study indicates a changing management of imported malaria in adults, with an increasing trend for ambulatory care. The absence of change in mortality for adults indicates that ambulatory care can be proposed for adults presenting non-severe imported malaria.


Simple enucleation and radiotherapy in the treatment of the pleomorphic salivary adenoma of the parotid gland.
A series of 76 patients with a primary pleomorphic salivary adenoma treated by simple extracapsular enucleation and high energy radiation between 1963 and 1976 is presented. Analysis of the results has shown a very low incidence of complications with only minimal cosmetic deformity. Of the 76 patients, only 5 have been lost to follow-up, 3 patients have died of causes unrelated to the tumour and only 1 patient has developed a recurrence. Further local excision in this patient showed the histological appearances of adenocarcinoma.


Evaluating approved and alternative treatments against an oxytetracycline-resistant bacterium responsible for European foulbrood disease in honey bees.
European foulbrood (EFB) is a disease of honey bee larvae caused by Melissococcus plutonius. In North America, oxytetracycline (OTC) is approved to combat EFB disease though tylosin (TYL) and lincomycin (LMC) are also registered for use against American foulbrood disease. Herein, we report and characterize an OTC-resistant M. plutonius isolate from British Columbia, Canada, providing an antimicrobial sensitivity to the three approved antibiotics and studying their abilities to alter larval survival in an in vitro infection model. Specifically, we investigated OTC, TYL, and LMC as potential treatment options for EFB disease using laboratory-reared larvae infected with M. plutonius. The utility of the three antibiotics were compared through an experimental design that either mimicked metaphylaxis or antimicrobial intervention. At varying concentrations, all three antibiotics prevented clinical signs of EFB disease following infection with M. plutonius 2019BC1 in vitro. This included treatment with 100 μg/mL of OTC, a concentration that was ~ 3× the minimum inhibitory concentration measured to inhibit the strain in nutrient broth. Additionally, we noted high larval mortality in groups treated with doses of OTC corresponding to ~ 30× the dose required to eliminate bacterial growth in vitro. In contrast, TYL and LMC were not toxic to larvae at concentrations that exceed field use. As we continue to investigate antimicrobial resistance (AMR) profiles of M. plutonius from known EFB outbreaks, we expect a range of AMR phenotypes, reiterating the importance of expanding current therapeutic options along with alternative management practices to suppress this disease.


Expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tissue in correlation with adipocyte cell volume, serum TNF-alpha, soluble serum TNF-receptor-2 concentrations and C-peptide level.
The aim of the study was to evaluate the expression of tumor necrosis factor (TNF)-alpha protein in the subcutaneous and visceral adipose tIssue in correlation with adipocyte cell Volume, serum TNF-alpha, soluble TNF-receptor-2 (sTNFR-2) and indirect parameters of insulin resistance in overweight/obese and lean healthy persons. A cross-sectional case-control study was used. Twenty-eight overweight/obese probands with normal glucose tolerance (BMI>27 kg/m(2)) and 15 lean people (BMI<25 kg/m(2)), all of them undergoing planned surgical operation, participated in the study. Two to four grams of subcutaneous and visceral adipose tIssue were removed and studied using semi-quantitative immunohistochemical staining of the TNF-alpha protein. Serum TNF-alpha, sTNFR-2 (ELISA) and fasting C-peptide (RIA) were measured. TNF-alpha protein was expressed in adipocytes of both depots. The expression was evaluated visually and found to be greater in the obese patients. Significantly higher serum TNF-alpha (5.58+/-0.87 pg/ml vs 4.21+/-0.55, mean+/-s.d., P<0.01, Mann-Whitney) and sTNFR-2 levels (7.84+/-3.56 ng/ml vs 4.59+/-1.35, P=0.005) were found in the obese subgroup in correlation with the fasting C-peptide level (r=0.49, P=0.003; and r=0.74, P=0.001) and the C-peptide/ blood glucose ratio (r=0.47, Spearman, P=0.005; and r=0.70, P=0.001). The cell Volume of both adipocyte depots was found to have a significant positive correlation with serum TNF-alpha and sTNFR-2 levels in the total group of patients (subcutaneous: r=0.52, P=0.0003; r=0.69, P<0.0001; visceral: r=0.65, P<0.0001; r=0.63, P<0.0001) and in both subgroups. Adipocyte cell Volume of both the subcutaneous and visceral fat depots may be determinants of TNF-alpha, sTNFR-2 production and obesity-linked insulin resistance.


Adenosine A1 receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle.
Adenosine receptors (AR; A1, A2A, A2B, and A3) contract and relax smooth muscle through different signaling mechanisms. Deciphering these complex responses remains difficult because relationships between AR subtypes and various end-effectors (e.g., enzymes and ion channels) remain to be identified. A1AR stimulation is associated with the production of 20-hydroxyeicosatetraenoic acid (20-HETE) and activation of protein kinase C (PKC). 20-HETE and PKC can inhibit large conductance Ca2+/voltage-sensitive K+ (BK) channels that regulate smooth muscle contraction. We tested the hypothesis that activation of A1AR inhibits BK channels via a PKC-dependent mechanism. Patch clamp recordings and Western blots were performed using aortae of wild type (WT) and A1AR knockout (A1KO) mice. There were no differences in whole-cell K+ current or α and β1 subunits expression between WT and A1KO. 20-HETE (100 nM) inhibited BK current similarly in WT and A1KO mice. NECA (5'-N-ethylcarboxamidoadenosine; 10 μM), a non-selective AR agonist, increased BK current in myocytes from both WT and A1KO mice, but the increase was greater in A1KO (52±15 vs. 17±3%; p<0.05). This suggests that A1AR signaling negatively regulates BK channel activity. Accordingly, CCPA (2-chloro-N(6)-cyclopentyladenosine; 100 nM), an A1AR-selective agonist, inhibited BK current in myocytes from WT but not A1KO mice (81±4 vs. 100±7% of control; p<0.05). Gö6976 (100 nM), a PKCα inhibitor, abolished the effect of CCPA to inhibit BK current (99±3% of control). These data lead us to conclude that, in aortic smooth muscle, A1AR inhibits BK channel activity and that this occurs via a mechanism involving PKCα.


Altitudinal neglect following traumatic brain injury: a case report.
We present an analysis of altitudinal neglect in a patient who following traumatic brain injury showed extinction to a visual stimulus presented in the lower field when another stimulus was simultaneously presented in the upper field. When estimating the midpoint of vertically-oriented rods presented below eye level using visual cues, tactile/kinesthetic cues or a combination of these cues, she consistently pointed higher than control subjects did. She showed less severe impairments when the rods were presented at or above eye level. When estimating the midpoint between two clicks presented above and below her head, she pointed higher than did control subjects. These deficits cannot be accounted for by sensory or motor disorders and appear to be due to a disorder in attending to stimuli in the lower half to space.


The relationship between perinatal exposure to dioxins and serum steroid hormone levels in preschool-aged children at an e-waste region in China.
Perinatal exposure to dioxins affects steroid hormone synthesis. The purpose of the present study was to evaluate the associations between perinatal exposure to dioxins and serum steroid hormone levels in preschool-aged children from an e-waste recycling region in China. In the present study, we enrolled 50 pairs of mothers and infants from the Taizhou, Luqiao region in 2015. Of the 50 pairs of mothers and infants, 42 pairs participated in this study when the children were 4 years old. We measured breast milk dioxin concentrations using high-resolution gas chromatography/mass spectrometry. Additionally, we used liquid chromatography-tandem mass spectrometry to measure the concentrations of progesterone, testosterone, androstenedione (A-dione), and dehydroepiandrosterone (DHEA) in serum samples from the 4-year-old children. We used multivariate linear regressions to assess the associations between dioxin congeners and steroid hormones. Results were reported as beta estimates and 95% confidence intervals by bootstrapping. We observed sex-related differences between breast milk dioxins and serum steroid hormone levels in 4-year-old children. An increase in breast milk dioxins was associated with a decrease in testosterone in serum samples from boys. Similarly, an increase in breast milk dioxins was associated with a decrease in progesterone levels in serum samples from girls. However, dioxins were not associated with changes in the levels of testosterone, DHEA, or A-dione in girls. Based on these results, we conclude that perinatal exposure to dioxins modifies steroidogenesis in preschool-aged children. However, the long-term impact of dioxins requires further large-scale studies to assess these effects in school-going children and adolescents.


How translational modeling in oncology needs to get the mechanism just right.
Translational model-based approaches have played a role in increasing success in the development of novel anticancer treatments. However, despite this, significant translational uncertainty remains from animal models to patients. Optimization of dose and scheduling (regimen) of drugs to maximize the therapeutic utility (maximize efficacy while avoiding limiting toxicities) is still predominately driven by clinical investigations. Here, we argue that utilizing pragmatic mechanism-based translational modeling of nonclinical data can further inform this optimization. Consequently, a prototype model is demonstrated that addresses the required fundamental mechanisms.


[Animal nutrition for veterinarians--actual cases: tulip bulbs with leaves (Tulipa gesneriana)--an unusual and high risk plant for ruminant feeding].
14 cattle (mainly younger ones) of a total of 50 extensively kept Galloways died within 6 weeks in late winter 2001/02. According to the owner's report, grass growth had been rather poor; therefore, the herd was fed additionally hay as well as large amounts of tulip onions. In the microbiological examination a highly reduced hygienic quality of the roughage could be detected. In the rumen contents of two dissected young cattle parts of tulip onions were found. According to pertinent literature, tulip onions (in particular their external layers) contain variant-specific amounts of anti-nutritive substances; main active agents are tulipin (a glycoprotein), tuliposid A and B, and lectins. They may cause intensive mucosal irritation, accompanied by reduced feed digestion and body-weight gains, drooling, vomiting and diarrhea. This case report underlines risks caused by feeding of plants originally not destined as forage, if their active ingredients and effects are unknown or remain unconsidered.


Fructose Consumption Alters Biogenic Amines Associated with Cardiovascular Disease Risk Factors.
Cardiovascular diseases (CVD) are the major cause of mortality worldwide, whose most prominent risk factor is unhealthy eating habits, such as high fructose intake. Biogenic amines (BAs) perform important functions in the human body. However, the effect of fructose consumption on BA levels is still unclear, as is the association between these and CVD risk factors. This study aimed to establish the association between BA levels and CVD risk factors in animals that consumed fructose. Male Wistar rats received standard chow (n=8) or standard chow + fructose in drinking water (30%) (n=8) over a 24-week period. At the end of this period, the nutritional and metabolic syndrome (MS) parameters and plasmatic BA levels were analyzed. A 5% level of significance was adopted. Fructose consumption led to MS, reduced the levels of tryptophan and 5-hydroxitryptophan, and increased histamine. Tryptophan, histamine, and dopamine showed a correlation with metabolic syndrome parameters. Fructose consumption alters BAs associated with CVD risk factors.


Does presentation format influence visual size discrimination in tufted capuchin monkeys (Sapajus spp.)?
Most experimental paradigms to study visual cognition in humans and non-human species are based on discrimination tasks involving the choice between two or more visual stimuli. To this end, different types of stimuli and procedures for stimuli presentation are used, which highlights the necessity to compare data obtained with different methods. The present study assessed whether, and to what extent, capuchin monkeys' ability to solve a size discrimination problem is influenced by the type of procedure used to present the problem. Capuchins' ability to generalise knowledge across different tasks was also evaluated. We trained eight adult tufted capuchin monkeys to select the larger of two stimuli of the same shape and different sizes by using pairs of food items (Experiment 1), computer images (Experiment 1) and objects (Experiment 2). Our results indicated that monkeys achieved the learning criterion faster with food stimuli compared to both images and objects. They also required consistently fewer trials with objects than with images. Moreover, female capuchins had higher levels of acquisition accuracy with food stimuli than with images. Finally, capuchins did not immediately transfer the solution of the problem acquired in one task condition to the other conditions. Overall, these findings suggest that--even in relatively simple visual discrimination problems where a single perceptual dimension (i.e., size) has to be judged--learning speed strongly depends on the mode of presentation.


[Hypokalemia can accelerate the development of cerebrovascular and cardiovascular disease].
Hypokalaemia is known to precipitate cardiac arrhythmias. Hypokalaemia can also give rise to adverse cardiovascular effects not related to arrhythmias. This article presents an evaluation of the relevant literature describing adverse effects of hypokalaemia and beneficial effects of potassium supplementation on cerebrovascular and cardiovascular disease. Diuretics-induced hypokalaemia may offset the beneficial effects of blood pressure reduction on cardiovascular events. In several epidemiological studies high intake of potassium in the food was associated with reduced risk of developing a stroke. Fruit and vegetables contain potassium, and an inverse correlation between intake of these nutrients and stroke has been described. In spontaneously hypertensive rats, potassium supplementation in the diet markedly reduced the risk of death, brain haemorrhage and infarct. Potassium reduces oxidative stress and proliferation of smooth muscle cells, i.e. factors involved in the development of atherosclerosis, and may have an antithrombotic effect.


Spiroiminodihydantoin is a major product in the photooxidation of 2'-deoxyguanosine by the triplet states and oxyl radicals generated from hydroxyacetophenone photolysis and dioxetane thermolysis.
[reaction: see text] Photolysis of hydroxyacetophenone and thermolysis of the corresponding dioxetane afford spiroiminodihydantoin rather than 4,8-dihydro-4-hydroxy-8-oxo-2'-deoxyguanosine (4-HO-8-oxodG) through the oxidation of 2'-deoxyguanosine (dG) by triplet-excited hydroxyacetophenone and the peroxyl radicals derived thereof by alpha cleavage and subsequent oxygen trapping. The structure of the spiroiminodihydantoin is assigned by the SELINQUATE NMR technique, which unequivocally establishes the spirocyclic connectivity.


Fabrication and characterization of bioactive β-Ca2SiO4/PHBV composite scaffolds.
A key challenge in tissue engineering is the construction of a scaffold with adequate properties which would mimic extracellular matrix (ECM) to induce the cells' efficient adhesion, proliferation and proper differentiation. Novel β-Ca2SiO4/PHBV composite scaffolds were fabricated by integrating β-Ca2SiO4 nanoparticles with PHBV backbone via a modified solvent casting-particulates leaching method, which generates interconnected porous structure and the high porosity, about 87%, of these scaffolds. Compared with PHBV scaffolds, β-Ca2SiO4/PHBV composite scaffolds facilitate the adhesion of human osteoblast-like MG-63 cells due to their increased hydrophilicity. The β-Ca2SiO4/PHBV composite scaffolds containing 2.5 or 5% β-Ca2SiO4 nanoparticles significantly enhance the proliferation of MG-63 cells by stimulating the transcription of the transforming growth factor-β1 (TGF-β1) and bone morphogenetic protein-7 (BMP-7) genes. These scaffolds also induce early differentiation via promoting the transcription of alkaline phosphatase (ALP). The results suggest the potential application of β-Ca2SiO4/PHBV composites in bone tissue engineering.


The psychiatric clinical nurse specialist/nurse practitioner: an example of a combined role.
The purpose of this article is to provide an historical overview of the clinical nurse specialist and nurse practitioner roles in psychiatric nursing. This article is written as a follow-up to that of Dyer, Hammill, Regan-Kubinski, Yurick, & Kobert, (1997), Archives of Psychiatric Nursing, 11, 2-11, in which a new paradigm for delivering comprehensive mental and general health services is conceptualized, i.e., the psychiatric-primary care nurse practitioner role. In this article an alternative model is presented: the psychiatric clinical nurse specialist/nurse practitioner role. Similarities and differences in the two roles are discussed.


Nonrandomized Clinical Trial of the Effectiveness of a Laxative Treatment Protocol to Time of First Bowel Movement After Uterine Artery Embolization Procedure: A Pilot Study.
The purpose of this pilot study was to determine the efficacy of a proactive laxative protocol for constipation prevention in patients undergoing uterine artery embolization (UAE). A nonrandomized clinical trial. A nonrandomized trial study design was piloted using a convenience sample of 35 patients undergoing UAE in the course of 1 year. There was a statistically significant difference (P < .0001) in time of first bowel movement after UAE when patients followed a proactive laxative protocol. A combination of senna and stool softener taken twice a day for 2 days preoperatively was associated with a shorter time to first bowel movement postoperatively. This pilot study supports the benefits of a proactive laxative protocol in helping achieve procedural recovery uncomplicated by constipation in patients undergoing UAE.


Ambiguities in the relationship between gonadal steroids and reproduction in axolotls (Ambystoma mexicanum).
Axolotls (Ambystoma mexicanum) are aquatic salamanders that are widely used in research. Axolotls have been bred in laboratories for nearly 150 years, yet little is known about the basic biology of reproduction in these animals. We investigated the effects of changing day length, time of year, and food availability on levels of circulating estradiol and androgens in adult female and male axolotls, respectively. In addition, we examined the effects of these variables on the mass of ovaries, oviducts, and eggs in females and on mass of testes in males relative to each individual's body weight, to calculate a form of gonadosomatic index (GSI). In both sexes, GSI was not correlated with levels of circulating steroids. In female axolotls, estradiol levels were influenced by food availability, changes in day length, and season, even when animals were held at a constant temperature and day length was decorrelated with calendar date. In addition, the mass of ovaries, oviducts, and eggs varied seasonally, peaking in the winter months and declining during the summer months, even though our animals were not breeding and shedding eggs. In males, levels of androgens appeared to vary independently of external conditions, but GSI varied dramatically with changes in day length. These results suggest that reproduction in axolotls may vary seasonally, as it does in many other ambystomid species, although both male and female axolotls are capable of reproducing several times each year. The physiological basis of this ability remains enigmatic, given the indications of seasonality contained in our data.