[Studies on hyperthermia by the use of a thermosensitizing drug].
Hyperthermic treatment using ACNU combined with a thermosensitizing drug, methylglyoxal-bis-guanylhydrazone (MGBG), was studied in human gastric cancer xenotransplanted into nude mice. In order to increase the intra-cellular MGBG content, intraperitoneal injection of alpha-difluoromethylornithine(DFMO) 1000 mg/kg was performed twice with an interval of 6 hours and 50 mg/kg of MGBG was given at the time of the second administration of DFMO. After 6 hours of MGBG administration, ACNU 20 mg/kg was given intraperitoneally and, subsequently a 23-minute hyperthermia was carried out in a water bath at 43.5 degrees C. After 48 hours a second hyperthermia was performed by the same method. Tumor weight was estimated using Battelle's Columbus Institute protocol and the inoculated tumors, which were extirpated 60 minutes after 3H-thymidine injection at a prescribed interval after cessation of hyperthermia, were assayed biochemically for the determination of DNA biosynthesis. In mice given ACNU, DFMO, MGBG plus heat, considerably superior results were obtained. Although the DFMO plus MGBG group was inferior in antitumor activity to the ACNU only or heat only group, the DFMO, MGBG plus heat group showed much the same antitumor effects, compared to the ACNU plus heat group. These data suggest that the thermosensitizing efficacy of MGBG may be applicable for clinical use.


HbA1c Predicts Time to Diagnosis of Type 1 Diabetes in Children at Risk.
Prediction of type 1 diabetes is based on the detection of multiple islet autoantibodies in subjects who are at increased genetic risk. Prediction of the timing of diagnosis is challenging, however. We assessed the utility of HbA1c levels in predicting the clinical disease in genetically predisposed children with multiple autoantibodies. Cord blood samples from 168,055 newborn infants were screened for class II HLA genotypes in Finland, and 14,876 children with increased genetic risk for type 1 diabetes were invited to participate in regular follow-ups, including screening for diabetes-associated autoantibodies. When two or more autoantibodies were detected, HbA1c levels were analyzed at each visit. During follow-up, multiple (two or more) autoantibodies developed in 466 children; type 1 diabetes was diagnosed in 201 of these children (43%, progressors), while 265 children remained disease free (nonprogressors) by December 2011. A 10% increase in HbA1c levels in samples obtained 3-12 months apart predicted the diagnosis of clinical disease (hazard ratio [HR] 5.7 [95% CI 4.1-7.9]) after a median time of 1.1 years (interquartile range [IQR] 0.6-3.1 years) from the observed rise of HbA1c. If the HbA1c level was ≥5.9% (41 mmol/mol) in two consecutive samples, the median time to diagnosis was 0.9 years (IQR 0.3-1.5, HR 11.9 [95% CI 8.8-16.0]). In conclusion, HbA1c is a useful biochemical marker when predicting the time to diagnosis of type 1 diabetes in children with multiple autoantibodies.


Effect of active sensitization on the bronchopulmonary responses to tachykinins in the guinea pig. Modulation by peptidase inhibitors.
The i.v. administration of substance P (SP, 0.25-16 micrograms/kg) or of the selective metabolic stable NK-1 agonist, [Glp6,Pro9]SP-(6-11) (septide, 0.03-0.25 microgram) to atropine-treated guinea pigs or to isolated perfused lungs triggered a dose-dependent bronchoconstriction, which was enhanced in animals actively sensitized to ovalbumin. In vivo, bronchial hyper-responsiveness was restricted to SP and to septide, inasmuch as neurokinin A (0.06-1 microgram/kg)- or capsaicin (0.5-32 micrograms/kg)-induced bronchoconstriction were not modified. In contrast, isolated lungs from sensitized guinea pigs exhibited an increased bronchoconstriction also in response to capsaicin (0.01-10 micrograms), which was inhibited by atropine in the medium. Pretreatment of actively sensitized guinea pigs either with indomethacin plus mepyramine, the lipoxygenase inhibitor BW A4C or with the platelet-activating factor antagonist SR 27417, did not modify bronchial hyper-reactivity to SP. Captopril (5 mg/kg i.v.), but not thiorphan (0.8 mg/kg i.v.), increased the SP-induced bronchoconstriction in actively sensitized animals, whereas both inhibitors were equally effective in nonsensitized guinea pigs. Thiorphan, however, did not modify the in vivo response to septide. Our results demonstrate that guinea pigs sensitized to ovalbumin exhibit bronchial hyperreactivity to SP, but not to neurokinin A, as compared to nonsensitized animals, suggesting a decrease in the neutral endopeptidase activity in the airways brought by the immunization. However, the results obtained by using septide indicate that other mechanisms may be involved in the bronchial hyper-reactivity to SP.


Formulation and Evaluation of Diclofenac Potassium Gel in Sports Injuries with and without Phonophoresis.
Background: Pain remains a global public heath priority. Phonophoresis, also known as sonophoresis or ultrasonophoresis, is when an ultrasound is used to maximize the effects of a topical drug. Purpose: The objective of this study was to test, in patients injured in sports or accidents (N = 200), the efficacy of diclofenac potassium (DK) 6%, 4%, and 2% formulated gels with and without phonophoresis in comparison with market available standard diclofenac sodium (DS or DN) gel. Methods: The patients were enrolled after informed consent. By using the lottery method, 100 patients were randomly segregated into five groups without phonophoresis and repeated similarly with phonophoresis at a frequency of 0.8 MHz, an intensity of about 1.5 W/cm2, and at continuous mode (2:1). Group-1 was treated with 6% DK gel, group-2 was treated with 4% DK gel, group-3 was treated with 2% DK gel, group-4 was treated with 4% DS gel and group-5 was given control gel three to four times a week for 4 weeks. The patients were screened by using NPRS and WOMAC scales. They were assessed on the baseline, 4th session, 8th session, 12th session, and 16th session. Results: Significant dose-dependently relief was observed in NPRS (Numeric Pain Rating Scale) and the WOMAC (Western Ontario McMaster Osteo-Arthritis) index for pain in disability and stiffness for each group treated with DK gel compared to DS gel. Phonophoresis increased these benefits significantly when used after topical application of DK gel or DS gel, and the dose-dependent effects of DK gel plus phonophoresis were stronger than the dose-dependent effects of DS gel plus phonophoresis. The faster and profounder relief was due to phonophoresis, which allows more penetration of the DK gel into the skin as compared to the direct application of DK gel in acute, uncomplicated soft tissue injury, such as plantar fasciitis, bursitis stress injuries, and tendinitis. In addition, DK gel with phonophoresis was well tolerated. Thus, in this personalized clinical setting, according to the degree of inflammation or injured-induced pain, disability, and stiffness, DK gel 6% with phonophoresis appeared more effective and thus more recommendable than DS gel 6% alone or DS gel 6% combined to phonophoresis.


Resveratrol Attenuates Subacute Systemic Inflammation-Induced Spatial Memory Impairment via Inhibition of Astrocyte Activation and Enhancement of Synaptophysin Expression in the Hippocampus.
The aim of this study was to investigate the role of resveratrol on subacute systemic inflammation-induced dysfunction of cognitive memory in mice and its underlying mechanism. Male ICR mice were trained in a water maze for four days of acquisition training and one day of probe trial. Subacute treatment with lipopolysaccharide (LPS) (1 mg/kg) by intraperitoneal injection for 5 days was used to establish a systemic inflammatory model. All mice were sacrificed after probe testing, then the expression of glial fibrillary acidic protein (GFAP), synaptophysin, and sirtuin1 (SIRT1) in hippocampi were determined using immunohistochemistry or western blot analysis. Morris water maze tests indicated that hippocampus-dependent spatial learning and memory were impaired in LPS-treated group. Resveratrol attenuated LPS-induced memory deficit in dose-dependent manner. Immunohistochemistry and western blot analysis revealed that LPS increased hippocampal GFAP expression and inhibited synaptophysin expression, which were prevented by resveratrol treatment. Treatment with LPS declined the SIRT1 protein expression in the hippocampus, which could be prevented by resveratrol. The protective effect of resveratrol could be abolished by a specific SIRT1 inhibitor. Our findings add new experimental data for potential therapeutic effects of resveratrol in the brain in a model of subacute systemic inflammation-induced astrocyte activation, synaptic alteration and cognitive decline.


[Treatment and management of intractable chronic pain patients--preface and comments].
Chronic intractable pain is well known to be very difficult in management. The mechanisms of intractable chronic pain are complicated. Therefore, such a patient is often involved with multiple pain mechanisms and needs multiple drugs which have different types of analgesic actions. This new insight into pain mechanisms is important in the diagnosis and treatments of chronic intractable pain patients and the concept of balanced analgesia is widely accepted. Therefore, the evaluation of many factors which modulate the pain behavior is important. Opioids such as morphine and other analgesics are sometimes useful for the treatment of chronic intractable pain. Nerve blocks and interventional treatments are also helpful.


A combined technique using a muscular flap and endobronchial stent to repair complex broncho-oesophageal fistulae supported by ECMO.
Certain broncho-oesophageal fistulae require surgical repair. Herein, we describe an innovative surgical technique combining intercostal flap and endobronchial stenting. Two patients, each with a with complex broncho-oesophageal fistula 2 years after radio-chemotherapy, were hospitalised for severe respiratory infection and extension of the fistula despite previous endoscopic treatment. The first patient presented with respiratory distress (ARDS). She had emergency surgery under extra corporeal membrane oxygenation: oesophagectomy and reconstruction of the left bronchus by a vascularised intercostal flap. Stenting was performed on day 10, due to persistence of the fistula. At 3 months the bronchus was healed, but the patient died of cerebral bleeding. For the second patient, repair was proposed before severe ARDS with the same surgical and ventilatory strategy and a stent was preventively inserted after surgery. After 3 months, the stent was removed and the left bronchus was healed. Complex post-radiotherapy broncho-oesophageal fistulae should be treated surgically before respiratory complications arise, by combining reconstruction with a vascularised flap and transient stenting.


Creation of Novel Cyclization Methods Using sp-Hybridized Carbon Units and Syntheses of Bioactive Compounds.
Some recent results on the development of new and reliable procedures for the construction of diverse ring systems based on the chemistry of sp-hybridized species, especially allene functionality, are described. This review includes: (i) synthesis of the multi-cyclic skeletons by combination of the π-component of allene with suitable other π-components such as alkyne, alkene, or additional allene under Rh-catalyzed conditions; (ii) synthesis of heterocycles as well as carbocycles by reaction of the sp-hybridized center of allene with some nucleophiles in an endo-mode manner; and (iii) total syntheses of natural products and related compounds from the sp-hybridized starting materials.


Regulation by synapsin I and Ca(2+)-calmodulin-dependent protein kinase II of the transmitter release in squid giant synapse.
1. Presynaptic or simultaneous pre- and postsynaptic voltage-clamp protocols were implemented in the squid giant synapse in order to determine the magnitude and time course of the presynaptic calcium current (ICa) and its relation to transmitter release before and after presynaptic injection of proteins. These included several forms of synapsin I, calcium-calmodulin-dependent protein kinase II (CaM kinase II) and avidin. 2. The quantities and location of these proteins were monitored by fluorescence video-enhanced microscopy during the electrophysiological measurements. 3. Presynaptic injection of dephosphorylated synapsin I inhibited synaptic transmission with a time course consistent with diffusion of the protein through the terminal and action at the active release zone. A mathematical model relating the diffusion of synapsin I into the terminal with transmitter release was developed to aid in the interpretation of these results. 4. Synapsin I inhibition of transmitter release was reversible. 5. The action of synapsin I was highly specific, as phosphorylation of the tail region only or head and tail regions prevented synapsin I from inhibiting release. 6. Injections of heat-treated synapsin I or of avidin, a protein with a size and isoelectric point similar to those of synapsin I, had no effect on transmitter release. 7. CaM kinase II injected presynaptically was found to facilitate transmitter release. This facilitation, which could be as large as 700% of the control response, was related to the level of penetration of the enzyme along the length of the preterminal A mathematical model of this facilitation indicates a reasonable fit between the distribution of CaM kinase II within the terminal and the degree of facilitation. 8. The overall shape of the postsynaptic response was not modified by either synapsin I or CaM kinase II injection. 9. The data suggest that, in addition to releasing transmitter, calcium also penetrates the presynaptic cytosol and activates CaM kinase II. When activated, CaM kinase II phosphorylates synapsin I, which reduces its binding to vesicles and/or cytoskeletal structures, enabling more vesicles to be released during a presynaptic depolarization. The amplitude of the postsynaptic response will then be both directly and indirectly regulated by depolarization induced Ca2+ influx. This model provides a molecular mechanism for synaptic potentiation.


A peptide of glutamic acid decarboxylase 65 can recruit and expand a diabetogenic T cell clone, BDC2.5, in the pancreas.
Self peptide-MHC ligands create and maintain the mature T cell repertoire by positive selection in the thymus and by homeostatic proliferation in the periphery. A low affinity/avidity interaction among T cells, self peptides, and MHC molecules has been suggested for these events, but it remains unknown whether or how this self-interaction is involved in tolerance and/or autoimmunity. Several lines of evidence implicate the glutamic acid decarboxylase 65 (GAD-65) peptide, p524-543, as a specific, possibly low affinity, stimulus for the spontaneously arising, diabetogenic T cell clone BDC2.5. Interestingly, BDC2.5 T cells, which normally are unresponsive to p524-543 stimulation, react to the peptide when provided with splenic APC obtained from mice immunized with the same peptide, p524-543, but not, for example, with hen egg white lysozyme. Immunization with p524-543 increases the susceptibility of the NOD mice to type 1 diabetes induced by the adoptive transfer of BDC2.5 T cells. In addition, very few CFSE-labeled BDC2.5 T cells divide in the recipient's pancreas after transfer into a transgenic mouse that overexpresses GAD-65 in B cells, whereas they divide vigorously in the pancreas of normal NOD recipients. A special relationship between the BDC2.5 clone and the GAD-65 molecule is further demonstrated by generation of a double-transgenic mouse line carrying both the BDC2.5 TCR and GAD-65 transgenes, in which a significant reduction of BDC2.5 cells in the pancreas has been observed, presumably due to tolerance induction. These data suggest that unique and/or altered processing of self Ags may play an essential role in the development and expansion of autoreactive T cells.


Facilities and services of postexposure prophylaxis in anti-rabies clinics: A national assessment in India.
The rabies postexposure prophylaxis (PEP) is provided through anti-rabies clinics in the country. It was considered important to assess their facilities under a nationwide multi-centric survey. The objective of this study is to assess the facilities available for PEP at the anti-rabies clinics and to ascertain the PEP provided at the anti-rabies clinics. The cross-sectional assessment was made from May 2017 to January 2018 in selected seven states of India. Thirty-five anti-rabies clinics from both Government and private; urban and rural areas from the states were assessed by an expert team using a pretested checklist for facilities and services available for PEP. On an average, 10 new animal bite cases were attended at each anti-rabies clinic per day. The cold chain facilities for rabies biologicals were satisfactory. The facilities for wound washing (54.3%) and the use of antiseptics to animal bite wounds were not adequate. Rabies vaccines were administered by intramuscular in 54.3% and by intradermal route in 45.7% of the cases. The vaccine stock-outs were reported only in the government sector (18.5%). The type of rabies immunoglobulin (RIG) used was equine (63.2%) and human (36.8%); given free of cost in 40% of Anti rabies clinics. The local wound infiltration of RIG was in practice at 58.6% of anti-rabies clinics. The stock-out of RIG was more in private (50%) hospitals than in Government (40.7%) hospitals. The facilities available for PEP at the anti-rabies clinics were inadequate and have to be improved across the country.


Dense assembly of Gd2O3:0.05X3+ (X = Eu, Tb) nanorods into nanoscaled thin-films and their photoluminescence properties.
This paper presents a simple and effective oil-water interfacial self-assembly strategy to fabricate monolayer and bilayer nanofilms of densely packed Gd2O3:0.05X(3+) (X = Eu, Tb) nanorods with characteristic luminescence properties. In this process, Gd2O3:0.05X(3+) (X = Eu, Tb) nanotubes synthesized by a hydrothermal method are dispersed in deionized water; then, a certain amount of n-hexane is added to produce a hexane-water interface. With n-butanol added as initiator, the nanotubes are gradually trapped at the interface to form a densely packed nanofilm. A monolayer nanofilm of densely packed Gd2O3:0.05Eu(3+) nanorods is obtained after annealing. In addition, the bilayer nanofilm composed of Gd2O3:0.05X(3+) (X = Eu, Tb) nanorods still retains the luminescence properties of each monolayer nanofilm. Moreover, the adhesion of the film on the substrate is very strong, which is extremely beneficial for its future applications.


Resistance to mTORC1 Inhibitors in Cancer Therapy: From Kinase Mutations to Intratumoral Heterogeneity of Kinase Activity.
Targeting mTORC1 has been thoroughly explored in cancer therapy. Following encouraging preclinical studies, mTORC1 inhibitors however failed to provide substantial benefits in cancer patients. Several resistance mechanisms have been identified including mutations of mTOR and activation of alternate proliferation pathways. Moreover, emerging evidence discloses intratumoral heterogeneity of mTORC1 activity that further contributes to a reduced anticancer efficacy of mTORC1 inhibitors. Genetic heterogeneity as well as heterogeneous conditions of the tumor environment such as hypoxia profoundly modifies mTORC1 activity in tumors and hence influences the response of tumors to mTORC1 inhibitors. Intriguingly, the heterogeneity of mTORC1 activity also occurs towards its substrates at the single cell level, as mutually exclusive pattern of activation of mTORC1 downstream effectors has been reported in tumors. After briefly describing mTORC1 biology and the use of mTORC1 inhibitors in patients, this review will give an overview on concepts of resistance to mTORC1 inhibition in cancer with a particular focus on intratumoral heterogeneity of mTORC1 activity.


An investigation into Merseyside General Dental Practitioners' interest in primary care research, their views on research and their training needs.
The aims of this investigation were to evaluate the interests of primary care dental practitioners within the Mersey Postgraduate Deanery in research and their views on research, their experience and research training needs. A questionnaire was sent to all practitioners in the Mersey Deanery asking for views on dental research, whether they had been involved in any research projects or had any research training, and whether they would be interested in research training and being part of a primary dental care research network. A total of 192 practitioners from the 1120 in the Mersey Deanery expressed an interest in being involved in primary care research. Most believed that primary care research was very important in providing a stronger evidence-base in dentistry and improved quality of dental care. Over 50% of respondents were interested in collaborative research, provided that their income and time could be protected and it was part of the normal working day. Almost 25% had some research experience and a number had undergone research training, ranging from informal training to part of a degree. A number of GDPs in the Mersey Deanery are interested in primary care research. With appropriate training, support and recognition within the new Personal Dental Services (PDS) contracts, there is a golden opportunity for more primary care dentists to participate in research. This, in time, will add to the evidence base in dentistry and should improve patient care.


Congenital diaphragmatic hernia prevents absorption of distal air space fluid in late-gestation rat fetuses.
We hypothesized that congenital diaphragmatic hernia (CDH) may decrease distal air space fluid absorption due to immaturity of alveolar epithelial cells from a loss of the normal epithelial Na+ transport, as assessed by amiloride and epithelial Na+ channel (ENaC) and Na-K-ATPase expression, as well as failure to respond to endogenous epinephrine as assessed by propranolol. Timed-pregnant dams were gavage fed 100 mg of nitrofen at 9.5-day gestation to induce CDH in the fetuses, and distal air space fluid absorption experiments were carried out on 22-day gestation (term) fetuses. Controls were nitrofen-exposed fetuses without CDH. Absorption of distal air space fluid was measured from the increase in 131I-albumin concentration in an isosmolar, physiological solution instilled into the developing lungs. In controls, distal air space fluid absorption was rapid and mediated by beta-adrenoceptors as demonstrated by reversal to fluid secretion after propranolol. Normal lung fluid absorption was also partially inhibited by amiloride. In contrast, CDH fetuses continued to show lung fluid secretion, and this secretion was not affected by either propranolol or amiloride. CDH lungs showed a 67% reduction in alpha-ENaC and beta-ENaC expression, but no change in alpha1-Na-K-ATPase expression. These studies demonstrate: 1) CDH delays lung maturation with impaired distal air space fluid absorption secondary to inadequate Na+ uptake by the distal lung epithelium that results in fluid-filled lungs at birth with reduced capacity to establish postnatal breathing, and 2) the main stimulus to lung fluid absorption in near-term control fetuses, elevated endogenous epinephrine levels, is not functional in CDH fetuses.


Intraobserver Error in Macromorphoscopic Trait Data,.
As part of a much larger investigation into the use of macromorphoscopic trait data by forensic anthropologists to estimate ancestry from unidentified skeletal remains, we conducted a fourteen-year (2002-2016) intraobserver error study. Motivated by the development of a large macromorphoscopic database-which will potentially utilize data collected in 2002-quantification of observer error, the impact of technological improvements in macromorphoscopic trait data collection and observer experience is necessary. To maximize comparisons between the two samples, ten macromorphoscopic traits were assessed. Results revealed three patterns of error relating to observer experience, the introduction of new technologies, and error inherent in the method. Overall, this study found the effect of error on macromorphoscopic trait analysis could be predicted and did not significantly impact their utility.


Clinical studies of ocular motility disturbances: Part 2. Risk factors for ischemic ocular motor nerve palsy [corrected].
A case-control study of 46 Japanese patients who were diagnosed by exclusion as having ischemic ocular motor nerve palsy and who exhibited spontaneous recovery within 4 months was done to evaluate the risk factors involved. We also evaluated the association between the number of risk factors and the spontaneous recovery or recurrence periods. Ischemic ocular motor nerve palsy is closely related to diabetes mellitus and coronary artery disease. Patients tended to be obese; many had two or more risk factors. Aging, in combination with two or more risk factors, seems to increase the likelihood of developing this disease. Diabetes mellitus is a particularly significant risk factor for this type of palsy, especially in combination with hypertension.


Growth Mixture Modeling: A Method for Identifying Differences in Longitudinal Change Among Unobserved Groups.
Growth mixture modeling (GMM) is a method for identifying multiple unobserved sub-populations, describing longitudinal change within each unobserved sub-population, and examining differences in change among unobserved sub-populations. We provide a practical primer that may be useful for researchers beginning to incorporate GMM analysis into their research. We briefly review basic elements of the standard latent basis growth curve model, introduce GMM as an extension of multiple-group growth modeling, and describe a four-step approach to conducting a GMM analysis. Example data from a cortisol stress-response paradigm are used to illustrate the suggested procedures.


[Forensic identification of floating shoulder injury].
To discuss forensic identification of floating shoulder injury (FSI). To analyze fifteen cases of FSI which were accepted from Jan. 1993 to Jan. 2006, including 15 shoulder neck fracture, 13 clavide stem fracture and 2 distal end clavide fracture, the function of shoulder joint was evaluated six months after injure considering the following three aspects: result of forensic examination such as X-ray photograph, CT and MRI, the injurers' symptom, objective sign and joint function, shoulder joint territory, degree of pain and local muscle power. Basing on the curative effect standard of Herscovic, all cases were divided into good. Modest, worst, which included 2, 4, 9 cases respectively; referring the standard of GA35-92, GB18667-2002, all cases were divided into six, seven, eight, nine and ten degree, which included 2,9,2,1,1 cases respectively. As a special powerful injure, FSI always companied with concurrent and multiple injure, and characterized by missed, incorrect and delayed diagnosis and infelicitous treatment, which lead to the high frequency and degree of injure. To prevent missed and incorrect forensic identification, we should have a full realization of the particularity of FSI, and evaluate the function of shoulder all-sidely, objectively and synseticaly.


Asthma control over 3 years in a real-life study.
This was a 3-year "real-life" study, during which patients' medication was increased and decreased to achieve sustained asthma control. Patients (282) were randomised to receive treatment with SAL 50microg, FP 250microg, or SFC 50/250microg via a Diskustrade mark inhaler, bid. A 12-month double-blind period was followed by a 2-year open phase. The physician increased or decreased patients' medication to achieve and maintain asthma control at regular clinical assessments using criteria based on the asthma treatment guidelines. On completion 73% (168/229) of the subjects were receiving SFC to maintain control of their asthma, compared with 21% (49/229) receiving FP and 5% (12/229) receiving SAL. Odds ratio for requiring increased treatment were 2.66 (p=0.002) for patients initially randomised to FP and 9.38 (p<0.0001) SAL, compared with SFC. Time until 25% of patients first required an increase in study medication was 6months for patients initially treated with SAL compared to 12months for FP and 21months for SFC. Symptoms and use of rescue medication improved first, followed rapidly by PEF with the greatest improvements occurring over the first year. Airway hyperresponsiveness continued to improve throughout the study. The majority of patients achieved and maintained control of asthma over a 3-year period with physician-driven medication changes. Patients treated with SFC were more likely to achieve control than patients treated with FP or SAL alone. Continuing improvements in airway hyperresponsiveness indicate the importance of maintaining treatment after clinical control of symptoms and lung function are achieved.


[Nuclear precursors for ceruloplasmin-coding messenger RNA from rat liver].
The distribution of the sequences coding for ceruloplasmin (CP) in rat liver heterogeneous nuclear RNA (hnRNA) was studied using highly specific CP cDNA as a hybridization probe. The content of CP-coding sequences in poly(A)-containing and poly(A)-free subfractions of hnRNA was shown to be respectively 1 and 27 equivalents of CP mRNA molecule per one hepatocyte. The gel electrophoresis of hnRNA under strongly denaturing conditions with the subsequent transfer of RNA to diazobenzyloxymethyl paper and hybridization with [32P]-cDNA probe showed that CP mRNA sequences were of multiple molecular weight distribution. In particular, 9.0, 6.6, 2.4 and 1.6 megadalton fractions of non-polyadenylate hnRNA carried CP-coding sequences while the only hand that hybridized to CP cDNA was detected in polyadenylated hnRNA. This band was of a molecular weight 1.1-1.2 megadaltons corresponding to that of cytoplasmic CP mRNA. The hybridization of high molecular weight hnRNA with full-length CP cDNA followed by the determination of the size of cDNA fragments protected against SI nuclease demonstrated that coding sequences of CP pre-mRNA are interrupted by intervening sequences.


DOG1 is commonly expressed in pancreatic adenocarcinoma but unrelated to cancer aggressiveness.
DOG1 (ANO1; TMEM16A) is a voltage-gated calcium-activated chloride and bicarbonate channel. DOG1 is physiologically expressed in Cajal cells, where it plays an important role in regulating intestinal motility and its expression is a diagnostic hallmark of gastrointestinal stromal tumors (GIST). Data on a possible role of DOG1 in pancreatic cancer are rare and controversial. The aim of our study was to clarify the prevalence of DOG1 expression in pancreatic cancer and to study its association with parameters of cancer aggressiveness. DOG1 expression was analyzed by immunohistochemistry in 599 pancreatic cancers in a tissue microarray format and in 12 cases of pancreatitis on large tissue sections. DOG1 expression was always absent in normal pancreas but a focal weak expression was seen in four of 12 cases of pancreatitis. DOG1 expression was, however, common in pancreatic cancer. Membranous and cytoplasmic DOG1 expression in tumor cells was highest in pancreatic ductal adenocarcinomas (61% of 444 interpretable cases), followed by cancers of the ampulla Vateri (43% of 51 interpretable cases), and absent in 6 acinus cell carcinomas. DOG1 expression in tumor associated stroma cells was seen in 76 of 444 (17%) pancreatic ductal adenocarcinomas and in seven of 51 (14%) cancers of the ampulla Vateri. Both tumoral and stromal DOG1 expression were unrelated to tumor stage, grade, lymph node and distant metastasis, mismatch repair protein deficiency and the density of CD8 positive cytotoxic T-lymphocytes in the subgroups of ductal adenocarcinomas and cancers of ampulla Vateri. Overall, the results of our study indicate that DOG1 may represent a potential biomarker for pancreatic cancer diagnosis and a putative therapeutic target in pancreatic cancer. However, DOG1 expression is unrelated to pancreatic cancer aggressiveness.


Unravelling the nature of the α-keratin EPR signal: an ab initio study.
Fingernail as a biodosimetry material, analyzed by the EPR technique, has attracted great attention in several experimental studies. One of the most challenging issues that should be addressed is additional signals, masking the radiation-induced signals (RIS) in EPR dosimetry analyses. In this work, we conducted a theoretical study of the RIS radicals and mechanisms to propose robust methods to distinguish the original signal from the irradiated nails' unwanted noise. Also, the proposed approach includes procedures to improve the accuracy of the dosimetry measurements. In our research, three categories of cysteine, DOPA and cystine radicals were considered due to their dominant abundance during the α-keratin reduction-oxidation processes. The SOMO-HOMO inversion is observed while investigating the electronic structure in these quasi-closed-shell systems. Furthermore, we demonstrated that the SOMO-HOMO gap is proportional to the spin localization. Indeed, new peaks in the EPR signals are not observed when the amino acid sequences are different. Moreover, the studied structures' neighborhood effect merely leads to a small change in the peak broadening of the EPR signals. On-the-fly magnetic parameter calculations were used to evaluate the system dynamics' effect on the broadening of the EPR signals in a molecular dynamics simulation. Comparing the calculated parameters with computational and experimental results in other studies helps assign low dose peaks to the corresponding tyrosyl phenoxyl radical.


Comparison of monoamine oxidase a in peripheral organs in nonsmokers and smokers.
Smokers have reduced levels of brain monoamine oxidase A (MAO A) leading to speculation that MAO A inhibition by tobacco smoke may underlie some of the neurophysiologic effects of smoking. Because smoking exposes peripheral organs as well as the brain to MAO A-inhibitory compounds, we determined whether smokers would also have reduced MAO A in peripheral organs. We measured MAO A in peripheral organs in a group of 9 smokers and compared it with a group of nonsmokers studied previously. MAO A was measured using PET and serial scans with the MAO A-specific radiotracers (11)C-clorgyline and deuterium-substituted (11)C-clorgyline ((11)C-clorgyline-D2) using the deuterium isotope effect to assess binding specificity. The time course of radiotracer in the arterial plasma was also measured and data from the tissue time-activity curves and the arterial input function were analyzed using a 3-compartment model to estimate k(3), which represents the rate-limiting step for the irreversible binding of labeled clorgyline to MAO A. Tracer uptake at plateau was reduced with deuterium substitution for the heart, lungs, and kidneys, indicating specificity for MAO. There was no difference in organ uptake at plateau between nonsmokers and smokers though, for the smokers, the efflux of tracer from peak uptake to plateau was slower for the lungs. The area under the time-activity curve for the arterial plasma was also significantly reduced for smokers versus nonsmokers and the reduction occurred in the first few minutes after radiotracer injection. Smokers had an approximately 50% reduction in k(3) when compared with nonsmokers; however, k(3) did not differ for nonsmokers and smokers for the heart and the kidneys. Because MAO A breaks down serotonin, norepinephrine, dopamine, and tyramine, and because the lung is a major metabolic organ in degrading some of these substances, reduced lung MAO A may contribute to some of the physiologic effects of smoking. This study also revealed that the concentration of the radiotracers in the arterial plasma is significantly lower for the smoker versus the nonsmoker and that this appears to be caused in part by retention of the radiotracer in lungs. If this is generally true for other substances that are administered intravenously, then this needs to be considered as a variable that may contribute to different short-term behavioral responses to intravenously administered drugs for nonsmokers versus smokers.


Diet and Physical Activity for Cardiovascular Disease Prevention.
Cardiovascular disease (CVD) is the leading cause of death in the United States. One-third of these deaths may be preventable through healthy lifestyle choices including diet and physical activity. The Mediterranean diet is associated with reduced cardiovascular mortality, whereas the Dietary Approaches to Stop Hypertension (DASH) eating plan is associated with a reduced risk of coronary artery disease. Substituting dietary saturated fat with polyunsaturated fatty acids is associated with improved cardiovascular outcomes, although exogenous supplementation with omega-3 fatty acids does not improve cardiovascular outcomes. There is an association between increased sodium intake and cardiovascular risk, but reducing dietary sodium has not consistently shown a reduction in cardiovascular risk. Physical activity recommendations for adults are at least 150 minutes of moderate-intensity aerobic activity per week, 75 minutes of vigorous-intensity aerobic activity per week, or an equivalent combination. Increases in physical activity by any level are associated with reduced cardiovascular risk. Introducing muscle-strengthening activities at least twice per week in previously inactive adults is associated with improved cardiovascular outcomes. Inactive adults without known CVD can gradually increase activity to a moderate-intensity level without consulting a physician. The U.S. Preventive Services Task Force recommends behavioral counseling to promote healthy diet and physical activity in adults at high risk of CVD. Evidence of benefit for counseling patients at average risk is less established.


Thyroid Surgery: To Drain or Not to Drain, That Is the Problem - A Randomized Clinical Trial.
We conducted a prospective, randomized study to evaluate the necessity of drainage after thyroid surgery. The patients (n = 215) were randomly assigned to be treated with suction drains (group 1; n = 108) or not (group 2; n = 107). The postoperative pain scores were significantly lower in the non-drained group than in the drained group of patients at postoperative days 0 and at 1. Hematomas, seromas, wound infections, transient biochemical hypoparathyroidism, and transient damage of the recurrent laryngeal nerve occurred more frequently in the drained group than in the non-drained group. The mean hospital stay was significantly shorter in the non-drained group than in the drained group. Routine drain emplacement after thyroidectomy is unnecessary.


Interplay between Protein Kinase C Epsilon and Reactive Oxygen Species during Myogenic Differentiation.
Reactive oxygen species (ROS) are currently recognized as a key driver of several physiological processes. Increasing evidence indicates that ROS levels can affect myogenic differentiation, but the molecular mechanisms still need to be elucidated. Protein kinase C (PKC) epsilon (PKCe) promotes muscle stem cell differentiation and regeneration of skeletal muscle after injury. PKCs play a tissue-specific role in redox biology, with specific isoforms being both a target of ROS and an up-stream regulator of ROS production. Therefore, we hypothesized that PKCe represents a molecular link between redox homeostasis and myogenic differentiation. We used an in vitro model of a mouse myoblast cell line (C2C12) to study the PKC-redox axis. We demonstrated that the transition from a myoblast to myotube is typified by increased PKCe protein content and decreased ROS. Intriguingly, the expression of the antioxidant enzyme superoxide dismutase 2 (SOD2) is significantly higher in the late phases of myogenic differentiation, mimicking PKCe protein content. Furthermore, we demonstrated that PKCe inhibition increases ROS and reduces SOD2 protein content while SOD2 silencing did not affect PKCe protein content, suggesting that the kinase could be an up-stream regulator of SOD2. To support this hypothesis, we found that in C2C12 cells, PKCe interacts with Nrf2, whose activation induces SOD2 transcription. Overall, our results indicate that PKCe is capable of activating the antioxidant signaling preventing ROS accumulation in a myotube, eventually promoting myogenic differentiation.


Schistosoma mansoni infection promotes SHIV clade C replication in rhesus macaques.
To evaluate the hypothesis that parasitic infections that induce T-helper type 2 (Th2) immune responses, such as schistosomiasis, upregulate HIV-1 replication. The effect of concomitant Schistosoma mansoni infection was tested in a primate model of acute and chronic simian-human immunodeficiency virus (SHIV) infection in rhesus macaques using a novel SHIV strain encoding the R5 env gene of a primary HIV clade C isolate from sub-Saharan Africa. S. mansoni-infected rhesus macaques and controls were exposed to SHIV to assess the effects of schistosomiasis on acute viral infection. Effects on chronic viral infection were evaluated by exposing virus-infected animals to parasites. S. mansoni infection was confirmed by the presence of parasite eggs in stool and eosinophilia. Viral RNA loads, cytokine and chemokine mRNA expression were measured by real time reverse transcription-PCR. S. mansoni coinfection increased the expression of Th2-associated cytokine responses and SHIV replication during both acute and chronic phases of SHIV infection. These results support the hypothesis that concomitant schistosomiasis upregulates replication of immunodeficiency viruses in coinfected hosts, raising the possibility that parasite-infected individuals may also be more susceptible to acquisition of HIV-1 infection.


A consensus method for the prediction of 'aggregation-prone' peptides in globular proteins.
The purpose of this work was to construct a consensus prediction algorithm of 'aggregation-prone' peptides in globular proteins, combining existing tools. This allows comparison of the different algorithms and the production of more objective and accurate results. Eleven (11) individual methods are combined and produce AMYLPRED2, a publicly, freely available web tool to academic users (http://biophysics.biol.uoa.gr/AMYLPRED2), for the consensus prediction of amyloidogenic determinants/'aggregation-prone' peptides in proteins, from sequence alone. The performance of AMYLPRED2 indicates that it functions better than individual aggregation-prediction algorithms, as perhaps expected. AMYLPRED2 is a useful tool for identifying amyloid-forming regions in proteins that are associated with several conformational diseases, called amyloidoses, such as Altzheimer's, Parkinson's, prion diseases and type II diabetes. It may also be useful for understanding the properties of protein folding and misfolding and for helping to the control of protein aggregation/solubility in biotechnology (recombinant proteins forming bacterial inclusion bodies) and biotherapeutics (monoclonal antibodies and biopharmaceutical proteins).


Sperm epigenetics in the study of male fertility, offspring health, and potential clinical applications.
The mammalian sperm contains a highly unique and specialized epigenetic landscape that offers a great degree of interesting research opportunities. One key discriminating feature of the mature sperm epigenome is that it, in theory, represents both remnant marks used throughout spermatogenesis to generate sperm cells competent to perform their function, but also marks that appear to be useful beyond fertilization. Key questions must be asked about the utility of these marks and the multiple purposes that may be served. It is this unique epigenetic landscape that has driven some labs to begin to study the links between aberrant sperm epigenetic patterns and various forms of infertility, from idiopathic to alterations in sperm motility, morphology, and viability and fertilization capacity. Because of the unique nature of the sperm epigenome and the patterns found in mature sperm that appear to reflect perturbations in spermatogenesis that may ultimately have effect on pregnancy outcomes, some researchers believe that these marks may provide predictive insight that can be exploited. Indeed, there is emerging data suggesting that the predictive power of DNA methylation and RNA signatures in sperm likely exceeds that which can be found with traditional assessments of male infertility. This review will focus on the utilization of the sperm epigenome as a potential diagnostic tool in the context of male infertility, as well as the potential difficulties associated with such an approach.


Difficulty of obtaining reproducibility in the Franklin and Dukes test for the detection of sperm-agglutinating antibodies in human sera.
The Franklin and Dukes (FD) test is used as a screening test for the determination of sperm-agglutinating antibodies and as a proof of therapeutic effects in cases of infertility, but various parameters of the FD test remain unclear and the application of different techniques has revealed highly different results. To test the statistical evidence for the FD technique, conditions regarded as optimal prerequisites were applied: a sperm concentration of 20 times 10(6)/ml was produced with Baker's buffer and serum dilutions were made with Baker's buffer, starting at 1:4. Only the standard deviation of parallel tests with one serum sample and one semen sample on the same day was found to be within an acceptable range. Using ejaculates of the same donor and the same serum sample on different days gave results that were not reproducible. The FD test should not, therefore, be used for quantification of sperm-agglutination antibodies except for a comparison in one test with one semen sample on the same day. Although the FD test only allowed a qualitative evaluation of sperm-agglutinating antibodies the % sperm agglutination was more informative than agglutination titres. For quantification of sperm-agglutinating antibodies, the FD test should be replaced by other techniques.


Diagnosis of oesophageal cancer by detection of minichromosome maintenance 5 protein in gastric aspirates.
Symptomatic oesophageal cancer is usually advanced and the prognosis poor. Lethality of symptomatic oesophageal cancer has motivated screening for these diseases earlier in their evolution, but reliable methods for early diagnosis remain elusive. We have demonstrated that dysregulated expression of minichromosome maintenance (MCM) proteins 2-7 is characteristic of early epithelial carcinogenesis, and that these key DNA replication initiation factors can be used as diagnostic markers for cervical and genito-urinary tract cancer. In this study, we investigated whether minichromosome maintenance protein 5 (Mcm5) can be used to detect oesophageal cancer cells in gastric aspirates. Two monoclonal antibodies raised against His-tagged human Mcm5 were used in a time-resolved immunofluorometric assay to measure Mcm5 levels in cells isolated from gastric aspirates of 40 patients undergoing gastroscopy for suspected or known oesophageal carcinoma or symptoms of dyspepsia. The test discriminated with high specificity and sensitivity between patients with and without oesophageal cancer (85% sensitivity (95% confidence interval (CI)=62-97%), 85% specificity (CI=66-96%)), as demonstrated by the large area under the receiver operating characteristics curve (0.93 (95% CI=0.85-0.99)). Elevated levels of Mcm5 in gastric aspirates are highly predictive of oesophageal cancer. This simple test for oesophageal cancer is readily automated with potential applications in primary diagnosis, surveillance and screening.


Involvement of dolichol phosphates as intermediates in the mannosyl and galactosyl transferases of rat testicular germ cell Golgi apparatus membranes.
Isolated Golgi apparatus membranes from the germinal elements (spermatocytes and early spermatids) of rat testis were examined for their ability to incorporate [14C]mannose and [14C]galactose into glycolipid and glycoprotein fractions. Transfer of mannose from GDP-[14C]mannose into a Lipid I fractions (GPD:MPP mannosyl transferase activity), identified as mannosyl phosphoryl dolichol, showed optimal activity at 1.5 mM manganese and at pH 7.5. Low concentrations of Triton X-100 (0.1%) stimulated transferase activity in the presence of exogenous dolichol phosphate (Dol-P); however, inhibition occurred at Triton X-100 concentrations greater than 0.1%. Maximal activity of this GDP:MPP mannosyl transferase occurred at 25 microM Dol-P. Activity using endogenous acceptor was 2.34 pmole/min/mg, whereas in the presence of 25 microM Dol-P the specific activity was 284 pmole/min/mg, a stimulation of 125-fold. Incorporation of mannose into a Lipid II (oligosaccharide pyrophosphoryl dolichol) and a glycoprotein fraction was also examined. In the absence of exogenous Dol-P, rapid incorporation into Lipid I occurred with a subsequent rise in Lipid II and glycoprotein fractions suggesting precursor-product relationships. Addition of exogenous Dol-P to galactosyl transferase assays showed only a minor stimulation, less than twofold, in all fractions. Over the concentration range of 9.4 to 62.5 micrograms/ml Dol-P, only 1% of radioactive product accumulated in the combined lipid fractions. These observations suggest that the mannose transfer involves Dol-P intermediates and also that spermatocyte Golgi membranes may be involved in formation of the oligosaccharide core as well as in terminal glycosylations.


Effects of degradable osteosynthesis plates of MgYREZr alloy on cell function of human osteoblasts, fibroblasts and osteosarcoma cells.
The aim was to evaluate the biocompatibility of osteosynthesis plates of the MgYREZr/WE43 alloy by using human cells in vitro. Eluates of degradable magnesium osteosynthesis plates as well as halved plates were used for incubation with human osteoblasts, fibroblasts and osteosarcoma cells. The cell viability was evaluated by using FDA/PI-Staining and LDH analysis. Cell proliferation was assessed by MTT, WST-Test and BrdU-ELISA. Scanning electron microscope was used for investigation of the cell adhesion. The number of devitalized cells in all treatment groups did not significantly deviate from the control group. According to MTT results, the number of metabolically active cells was not significantly affected by the addition of the eluates. The number of metabolically active cells was reduced by 24 to 38% compared to the control on incubation in direct contact with the osteosynthesis plates. The proliferation of the cells was inhibited by the addition of the eluates. While the eluate of the half-hour elution has only a very small effect, the 24 h eluate significantly inhibits proliferation by 23-25% compared to the control. The roughened surface of the magnesium osteosynthesis plate after incubation showed adherent cells. However, some areas of the plates were also free of adherent cells. WE43 based magnesium alloys showed favorable biocompatibility considering the viability of the cells evaluated; however, proliferation rates were reduced in a time dependent manner, especially in fibroblast group. This might be a potential clinical benefit of magnesium osteosynthesis plates and their superiority to titanium, thus the fibroblastic ingrowth might negatively influence the bone-plate contact.


Serum creatine phosphokinase concentrations after intramuscular chlordiazepoxide and its solvent.
Serum creatine phosphokinase (CPK) concentrations were determined in healthy volunteers for the first 48 hours after intramuscular injection of 50 mg chlordiazepoxide hydrochloride or of its solvent alone. Intramuscular injection of both the drug solution and its solvent was painful and caused CPK elevations. The CPK rise due to the drug solution was 33 per cent higher than that due to the solvent alone, but the difference was not significant. The pH of the solvent preparation is low and it contains high concentrations of propylene glycol. The pain and muscle damage due to injection of the solvent could be due to its acidity and its high osmolarity. Problems associated with intramuscular injections of water-insoluble drugs are not resolved by the use of such solvent preparations.


The optimal diagnostic methods for COVID-19.
As the world continues to study and understand coronavirus disease (COVID-19), existing investigations and tests have been used to try and detect the virus to slow viral transmission and its global spread. A 'gold-standard' investigation has not yet been identified for detection and monitoring. Initially, computed tomography (CT) was the mainstay investigation as it shows the disease severity and recovery, and its images change at different stages of the disease. However, CT has been found to have limited sensitivity and negative predictive value in the early stages of the disease, and the value of its use has come under debate due to whether its images change the treatment plan, the risk of radiation, as well as its practicality with infection control. Therefore, there has been a shift to the use of other imaging modalities and tests, such as chest X-rays and ultrasound. Furthermore, the use of nucleic acid-based testing such as reverse-transcriptase polymerase chain reaction (RT-PCR) have proven useful with direct confirmation of COVID-19 infection. In this study, we aim to review and analyse current literature to compare RT-PCR, immunological biomarkers, chest radiographs, ultrasound and chest CT scanning as methods of diagnosing COVID-19.


Diabetic retinopathy and HLA antigens in type 2 diabetes mellitus.
Diabetic retinopathy is the most common complication of diabetes mellitus. No single predisposing factor has been identified, and genetic factors may play a role in the development of severe retinopathy. In this study, we investigated the association between diabetic retinopathy and HLA antigens in type 2 diabetes mellitus. This study was conducted at the retina unit of the Department of Ophthalmology of Ondokuz Mayis University between October 1999 and March 2000, and included 46 diabetics with non-proliferative retinopathy and 30 with proliferative retinopathy, with 30 nondiabetic controls. HLA class I (A, B, C) antigens were studied by Terasaki's microlymphocytotoxicity test and HLA class II (DR, DQ) typing was carried out using a polymerase chain reaction-sequence specific primer. HLA-DR4 and DQ8 frequencies were higherin patients with non-proliferative retinopathy than those with proliferative retinopathy, and HLA-DR7 frequency was higher in patients with proliferative retinopathy than non-proliferative cases (p<0.05). No significant differences in HLA antigens were found between patient groups and controls. The differences in HLA antigen frequencies between patients with and without proliferative retinopathy suggest a genetic contribution to diabetic retinopathy.


Methylation differences of the neuronatin gene promoter region in liver between normal and cloned pigs.
Abnormal phenotypes in cloned pigs can be partly due to changes in epigenetic modifications such as methylation levels of promoter CpG islands. Neuronatin is an imprinted gene, conserved in human, pig, cattle and mouse, which is expressed exclusively from the paternal allele. Three CpG islands located in the promoter region of the porcine neuronatin gene have the potential to regulate the gene expression by cytosine methylation. To illustrate whether neuronatin was differentially expressed among nuclear transfer macroglossia-positive and nuclear transfer macroglossia-negative pigs and in vitro-fertilized pigs, we detected its expression level by qRT-PCR and further quantified methylation levels by pyrosequencing DNA from the liver. The results showed that neuronatin was expressed at a significantly higher level in livers of nuclear transfer macroglossia-positive pigs compared with normal cloned and in vitro-fertilized pigs. Livers of nuclear transfer macroglossia-positive pigs also had a significantly lower methylation level at CpG island 2 and CpG island 3 in the promoter region.


Reduced dietary potassium reversibly enhances vasopressor response to stress in African Americans.
Acute vasopressor responses to stress are adrenergically mediated and hence potentially subject to differential modulation by dietary potassium and sodium. The greater vasopressor responsiveness in blacks compared with whites might then be consequent not only to a high dietary salt intake but also to a marginally reduced dietary potassium intake. Under controlled metabolic conditions, we compared acute vasopressor responses to cold and mental stress in black and white normotensive men during three successive dietary periods: (1) while dietary potassium was reduced (30 mmol K+/70 kg per day) and salt was restricted (10 to 14 days); (2) while salt was loaded (15 to 250 mmol Na+/70 kg per day) (7 days); and (3) while salt loading was continued and potassium was either supplemented (70 mmol K+/70 kg per day) (7 to 21 days) in 9 blacks and 6 whites or continued reduced (30 mmol K+/70 kg per day) (28 days) in 4 blacks (time controls). At the lower potassium intake, cold-induced increase in forearm vascular resistance in blacks was twice that in whites during both salt restriction and salt loading. Normalization of dietary potassium attenuated cold-induced increases in both forearm vascular resistance and systolic and diastolic blood pressures in blacks but only in systolic pressure in whites. In blacks but not in whites, normalization of dietary potassium attenuated mental stress-induced increases in systolic and diastolic pressures. In normotensive blacks but not whites, a marginally reduced dietary intake of potassium reversibly enhances adrenergically mediated vasopressor responsiveness to stress. That responsiveness so enhanced over time might contribute to the pathogenesis of hypertension in blacks.


Drug use and mental health problems among prison inmates--results from a nation-wide prison population study.
Prisons all over the western world are known to be inhabited by a biased sample of the population. More information is needed on how problems in diverse areas interact. The present study investigated how general welfare deficiencies, drug use and mental health problems were related in a representative prison population. Data stem from a level-of-living survey among a nationwide representative sample of Norwegian prison inmates. The sample was drawn randomly from the official register of prison inmates. Data were collected through structured personal interviews (computer assisted). Analyses presented in this paper are based on the male part of the sample (n=225). Only 24% of male prisoners were affected by neither drug use problems nor mental health problems. Investigating the relationship between variables indicated an increasing accumulation of childhood stressors and general welfare deficiencies with increasing drug use and mental health problems. As health problems are intertwined with more general social problems, health promotion among prison inmates is clearly a multidisciplinary task, requiring close collaboration between different service providers and systems of care.


The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells.
Lymphocyte signaling cascades responsible for anti-tumor cytotoxicity and inflammatory cytokine production must be tightly regulated in order to control an immune response. Disruption of these cascades can cause immune suppression as seen in a tumor microenvironment, and loss of signaling integrity can lead to autoimmunity and other forms of host-tissue damage. Therefore, understanding the distinct signaling events that exclusively control specific effector functions of "killer" lymphocytes (T and NK cells) is critical for understanding disease progression and formulating successful immunotherapy. Elucidation of divergent signaling pathways involved in receptor-mediated activation has provided insights into the independent regulation of cytotoxicity and cytokine production in lymphocytes. Specifically, the Fyn signaling axis represents a branch point for killer cell effector functions and provides a model for how cytotoxicity and cytokine production are differentially regulated. While the Fyn-PI(3)K pathway controls multiple functions, including cytotoxicity, cell development, and cytokine production, the Fyn-ADAP pathway preferentially regulates cytokine production in NK and T cells. In this review, we discuss how the structure of Fyn controls its function in lymphocytes and the role this plays in mediating two facets of lymphocyte effector function, cytotoxicity and production of inflammatory cytokines. This offers a model for using mechanistic and structural approaches to understand clinically relevant lymphocyte signaling.


Dietary restriction started after spinal cord injury improves functional recovery.
Spinal cord injury typically results in limited functional recovery. Here we investigated whether therapeutic dietary restriction, a multi-faceted, safe, and clinically-feasible treatment, can improve outcome from cervical spinal cord injury. The well-established notion that dietary restriction increases longevity has kindled interest in its potential benefits in injury and disease. When followed for several months prior to insult, prophylactic dietary restriction triggers multiple molecular responses and improves outcome in animal models of stroke and myocardial infarction. However, the efficacy of the clinically-relevant treatment of post-injury dietary restriction is unknown. Here we report that "every-other-day fasting" (EODF), a form of dietary restriction, implemented after rat cervical spinal cord injury was neuroprotective, promoted plasticity, and improved behavioral recovery. Without causing weight loss, EODF improved gait-pattern, forelimb function during ladder-crossing, and vertical exploration. In agreement, EODF preserved neuronal integrity, dramatically reduced lesion volume by >50%, and increased sprouting of corticospinal axons. As expected, blood beta-hydroxybutyrate levels, a ketone known to be neuroprotective, were increased by 2-3 fold on the fasting days. In addition, we found increased ratios of full-length to truncated trkB (receptor for brain-derived neurotrophic factor) in the spinal cord by 2-6 folds at both 5 days (lesion site) and 3 weeks after injury (caudal to lesion site) which may further enhance neuroprotection and plasticity. Because EODF is a safe, non-invasive, and low-cost treatment, it could be readily translated into the clinical setting of spinal cord injury and possibly other insults.


Thrombophilic mechanisms of OCs.
Oral contraceptives (OCs) have minor effects on procoagulant and anticoagulant factors. Clotting factor changes that are associated with the use of low-androgenic OCs include a 10% to 20% increase in fibrinogen, variable effects on factor VII, an increase in fibrinopeptide A, and a 10% to 20% decrease in protein S (in comparison, levels of protein S decrease approximately 70% during pregnancy). Although these acquired changes can be statistically significant between OC users and nonusers, there is no evidence that they are clinically significant. In contrast, increased risk of venous thrombosis has been associated with inherited deficiencies in protein S and protein C, which are both natural anticoagulant proteins. In addition, activated protein C (APC) resistance can occur via a mutation of factor V, known as factor V Leiden, which is present in 5% of the general population and 20-40% of patients with venous thrombosis. In one study, the combination of OC use and factor V Leiden positivity was associated with a 35-fold increased risk of venous thrombosis compared with controls. However, the absolute risk of venous thrombosis in this group was low; the incidence of venous thrombosis was 28.5 events per 10,000 women-years in women with both factors (in comparison, pregnancy was associated with an incidence of 5.9 per 10,000 women-years). Even if venous thrombosis could be totally prevented in OC users with the Leiden mutation, there would be little impact on the total number of cases of venous thrombosis; therefore, routine screening for factor V Leiden or APC resistance prior to starting women on OCs does not seem to be warranted.


Synthesis and structural characterization of a gamma-Keggin-type dimeric silicotungstate with a bis(mu-hydroxo) dizirconium core [(gamma-SiW10O36)2Zr2(mu-OH)2]10-.
A novel dinuclear zirconium sandwich-type silicotungstate cluster of [(gamma-SiW(10)O(36))(2)Zr(2)(mu-OH)(2)](10-) (1) was synthesized by the reaction of a divacant lacunary gamma-Keggin silicotungstate [gamma-SiW(10)O(36)](8-) with ZrOCl(2).8H(2)O. The anion consisted of two [gamma-SiW(10)O(36)](8-) units sandwiching a diamond Zr(2)(mu-OH)(2) core, and each zirconium atom in 1 was six-coordinated to two mu-OH ligands and four oxygen atoms of two [gamma-SiW(10)O(36)](8-) units. The Zr(2)(mu-OH)(2) core in 1 reacted with methanol to give the corresponding monomethoxo derivative [(gamma-SiW(10)O(36))(2)Zr(2)(mu-OH)(mu-OCH(3))](10-) (2).


Role of sn-2 acyl group of phosphatidylcholine in determining the positional specificity of lecithin-cholesterol acyltransferase.
Although human plasma lecithin-cholesterol acyltransferase (LCAT) is believed to be specific for the sn-2 position of phosphatidylcholine (PC), our recent studies showed that it derives a significant percent of acyl groups from the sn-1 position of certain PC species. To understand the physicochemical basis for this altered positional specificity, we determined the effect of sn-2 acyl group of PC on the enzyme activity and utilization of 16:0 from the sn-1 position by purified human and rat LCATs. Positional isomers of PC containing 16:0 at sn-2 were better substrates for human LCAT than the corresponding sn-1-16:0 isomers, whereas the reverse was true for rat LCAT. The positional specificity of human LCAT varied greatly depending on the nature of the acyl group at sn-2. The sn-1 contribution from various sn-1-16:0-2-acyl PCs for cholesteryl ester (CE) synthesis was 1.0% from 16:0-16:0, 1.4% from 16:0-20:5, 7.3% from 16:0-18:1, 47.0% from 16:0-20:3, 49.9% from 16:0-20:4, 54.9% from 16:0-22:6, and 72.3% from 16:0-18:0. There was a linear relationship between the percentage of 16:0 CE formed (from sn-1 position) and the acyl chain length at sn-2 position (r = 0.94). Rat LCAT also transferred some 16:0 from sn-1 position of 16:0-22:6, 16:0-20:3, and 16:0-18:0 PCs, but not from the other natural PCs tested. The phospholipase A activity of both LCATs in the presence of 16:0-20:4 PC showed the same positional specificity as CE synthesis, indicating that the specificity is determined at the formation of acyl-enzyme intermediate. These results show that the positional specificity of LCAT is influenced by the structure of PC, especially the chain length of the sn-2 acyl group.


Adnexal masses in pregnancy: a review of eight cases undergoing surgical management.
Our purpose was to determine maternal and foetal outcome in patients undergoing surgery for a pelvic mass in pregnancy. Maternal and foetal records (outcomes) of eight cases of adnexal masses associated with intrauterine pregnancy that required laparotomy or aspiration or that were diagnosed incidentally at the time of caesarean section were reviewed. The review was performed on patients who were seen with an adnexal mass in pregnancy from January 1994 to February 2001. We included patients with simple or complex masses > or = 6 cm that were persistent on ultrasonographic evaluation and patients with adnexal masses with complications (torsion, haemorrhage). We excluded cysts that spontaneously resolved by 16 weeks' gestation. Eight patients of 16,472 deliveries were identified with adnexal masses that satisfied the above criteria. Six patients underwent laparotomy in the first and/or the second trimester of pregnancy. In two of them emergency laparotomy were done due to torsion or haemorrhage as a complication of the adnexal masses. In all patients benign ovarian tumors were found. Two patients underwent transvaginal aspiration of simplex cysts due to subtorsion in the first trimester of gestation (negative results on cytological study). All of these eight patients had term deliveries. Two patients, due to obstetrical reasons, underwent caesarean section. The incidence of an adnexal mass during pregnancy in our population is consistent with what has been reported in the literature. We emphasize that transvaginal aspiration and drainage of symptomatic simplex cysts in the first trimester and percutaneous cysts in the second trimester can avert laparotomy. Our data support a randomised clinical study to determine optimal management of an adnexal mass in pregnancy.


An unusual cause of posterior tibial tendon degeneration.
A case demonstrating a mechanical cause of posterior tibial tendon degeneration is reported. The possible etiologies for degeneration of the posterior tibial tendon are discussed.


Association of N-nitrosodimethylamine exposure with cognitive impairment based on the clues of mice and humans.
N-nitrosodimethylamine (NDMA) is an environmental and food contaminant, but limited data to concern whether NDMA has adverse effects on the brain. This study first determined the concentration of NDMA in foods from aquaculture markets in Shenzhen, then analyzed the effects on C57BL/6 mice and further evaluated on the urine samples of elderly Chinese residents with normal cognition (NC, n = 144), cognitive decline (CD, n = 116) and mild cognitive impairment (MCI, n = 123). The excessive rate of NDMA in foods was 3.32% (27/813), with a exceeding range of 4.78-131.00 μg/kg. Behavioral tests showed that 60 days treatment of mice with 3 mg/kg NDMA reduced cognitive performance. Cognitive impairment in human was significantly associated with sex, educational levels, length of residence in Shenzhen, household registration, passive smoking, rice, fresh vegetables, bacon products. NDMA was detected in 55.4% (212/383) of urine samples, with a median concentration of 0.23 μg/L (1.20 × 10 -7-157.39 μg/L). The median concentration for NC, CD and MCI were 0.32, 0.27, and 0 μg/L, respectively. The urinary NDMA concentration had a strong negative correlation with cognitive impairment (Kendall's Tau-b = -0.89, P = 0.024). The median estimated daily intake (EDI) of NDMA was determined to be 6.63 ng/kg-bw/day. Taken together, there appears to be an association between NDMA and human and murine cognition, which provides a new clue to Alzheimer's disease (AD).


Transport properties of ferrofluids.
Long-time self-diffusion coefficients of ferrofluid suspensions are derived from an effective Langevin equation approach. The dependences of these transport properties on the volume fraction of particles and the strength of interparticle interaction are investigated. Strong reduction of the rotational and the translational Brownian motion of the particles is manifested upon increase of particle-particle interaction or ferrofluid concentration.


Configuration of Inactive and Active Polysomes of the Developing Down Feather.
Inactive four-ribosome polyribosomes, insensitive to ribonuclease, have the form of tight symmetrical squares and appear in feather cells during the early and intermediate periods of development. When, on the 13th day of incubation, the inactive polyribosomes become sensitive to ribonuclease and can then synthesize protein, the squares open up so that the four-ribosome polysomes are strung out in the configuration characteristic of functioning polysomes.


Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death.
Inflammatory-activated glia are seen in numerous central nervous system (CNS) pathologies and can kill nearby neurons through the release of cytotoxic mediators. Glia, when activated, can express the inducible isoform of nitric oxide synthase (iNOS) producing high levels of nitric oxide (NO), which can kill neurons in certain conditions. We show, however, that inflammatory activation of glia in a mature culture of cerebellar granule neurons and glia causes little or no neuronal death under normal (21%) oxygen conditions. Similarly, hypoxia (2% oxygen) or low levels of an NO donor (100 microM DETA/NO) caused little or no neuronal death in nonactivated cultures. If inflammatory activation of glia or addition of NO donor was combined with hypoxia, however, extensive neuronal death occurred. Death in both cases was prevented by the N-methyl-D-aspartate (NMDA) receptor blocker MK-801, implying that death was mediated by the glutamate receptor. Low levels of NO were found to increase the apparent K(M) of cellular oxygen consumption for oxygen, probably due to NO-induced inhibition of mitochondrial respiration, in competition with oxygen, at cytochrome oxidase. Necrotic death, induced by hypoxia plus DETA/NO, was increased further by deoxyglucose, an inhibitor of glycolysis, suggesting that necrosis was mediated by energy depletion. Hypoxia was found to be a potent stimulator of microglia proliferation, but this proliferation was not significant in inflammatory-activated cultures. These results suggest that low levels of NO can induce neuronal death under hypoxic conditions, mediated by glutamate after NO inhibition of respiration in competition with oxygen. Brain inflammation can thus sensitize to hypoxia-induced death, which may be important in pathologies such as stroke, neurodegeneration, and brain aging.


Uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): Results of an open label, randomized and controlled clinical trial, among multibacillary patients.
Leprosy control is based on early diagnosis and multidrug therapy. For treatment purposes, leprosy patients can be classified as paucibacillary (PB) or multibacillary (MB), according to the number of skin lesions. Studies regarding a uniform treatment regimen (U-MDT) for all leprosy patients have been encouraged by the WHO, rendering disease classification unnecessary. An independent, randomized, controlled clinical trial conducted from 2007 to 2015 in Brazil, compared main outcomes (frequency of reactions, bacilloscopic index trend, disability progression and relapse rates) among MB patients treated with a uniform regimen/U-MDT (dapsone+rifampicin+clofazimine for six months) versus WHO regular-MDT/R-MDT (dapsone+rifampicin+clofazimine for 12 months). A total of 613 newly diagnosed, untreated MB patients with high bacterial load were included. There was no statistically significant difference in Kaplan-Meyer survival function regarding reaction or disability progression among patients in the U-MDT and R-MDT groups, with more than 25% disability progression in both groups. The full mixed effects model adjusted for the bacilloscopic index average trend in time showed no statistically significant difference for the regression coefficient in both groups and for interaction variables that included treatment group. During active follow up, four patients in U-MDT group relapsed representing a relapse rate of 2.6 per 1000 patients per year of active follow up (95% CI [0·81, 6·2] per 1000). During passive follow up three patients relapsed in U-MDT and one in R-MTD. As this period corresponds to passive follow up, sensitivity analysis estimated the relapse rate for the entire follow up period between 2·9- and 4·5 per 1000 people per year. Our results on the first randomized and controlled study on U-MDT together with the results from three previous studies performed in China, India and Bangladesh, support the hypothesis that UMDT is an acceptable option to be adopted in endemic countries to treat leprosy patients in the field worldwide. ClinicalTrials.gov: NCT00669643.


Circulatory dynamics during dental extractions in normal, cardiac and transplant patients.
The authors conducted a study to evaluate the relationship between the circulatory dynamics of patients with heart disease and these patients' cardiac status when undergoing dental extractions. Subjects with minimal heart disease, or MHD; with severe heart disease, or SHD; or who received a heart transplant, or TRAN; as well as control, or NOR, subjects were enrolled in the study. The authors recorded subjects' systolic blood pressure, or SBP; diastolic blood pressure, or DBP; and heart rate, or HR, while they were under basal conditions and during postanesthesia and dental extraction periods. The authors estimated a general linear model and performed analysis of variance. Under basal conditions, MHD subjects did not show significantly different mean blood pressure values compared with NOR subjects but did show slightly significantly higher mean HR values. Mean DBP and HR values were significantly higher in SHD and TRAN subjects than in MHD and NOR subjects, while SBP values in SHD subjects were significantly lower than those in MHD, TRAN and NOR subjects. During dental extraction sessions, SBP, DBP and HR mean values increased significantly compared with basal conditions and post-anesthesia periods in MHD and NOR subjects. SHD and TRAN subjects showed no significant time-dependent variation during dental extraction sessions in any circulatory parameter. MHD subjects had cardiovascular responses to stress similar to those of NOR subjects, while SHD and TRAN subjects had similar slight and dulled cardiac responses. Patients with SHD may not be able to adapt their cardiac performance to an emotional stress such as a dental appointment, while it seems to be easier for MHD and TRAN patients. Managing TRAN patients is relatively easier than managing SHD patients.


Morphological and biochemical changes of LLC-PK1 cells during adaptation to glucose-free culture conditions.
The established renal epithelial cell line LLC-PK1 retained in tissue culture several differentiated properties of renal proximal tubular cells. By adapting LLC-PK1 cells to glucose-free culture conditions, we recently succeeded in isolating a gluconeogenic strain of LLC-PK1 cells capable of growing in the absence of hexoses. In contrast to the parental wild type, the isolated strain expressed fructose-1,6-bisphosphatase activity and was, therefore, designated LLC-PK1-FBPase+. Besides the differences in glucose metabolism, the isolated gluconeogenic substrain differs form the parental wild type with respect to morphological appearance and the expression of apical membrane marker enzymes. LLC-PK1-FBPase+ cells display a drastic accumulation of autophagic vacuoles, disappearance of apical membrane alkaline phosphatase activity, and increased gamma-glutamyltranspeptidase activity. In order to find out whether or not a low alkaline phosphatase activity in combination with the enhanced formation of autophagic vacuoles is related to a change in apical membrane surface, we utilized a combined light and electron microscopic morphometric procedure to determine the absolute amount of organelle volumes and membrane surface areas. This stereologic approach shows that LLC-PK1-FBPase+ cells display a tenfold increase in the volume of autophagic vacuoles and the lysosomal compartment. Analysis of lysosomal enzyme activities, however, revealed no changes as compared to wild-type cells. The apical membrane surface of gluconeogenic cells was found to be increased by 80%. Karyotype analysis revealed that LLC-PK1 wild-type cells were diploid, whereas FBPase+ cells exhibited polyploidy with a high percentage of tetraploid nuclei. Culturing LLC-PK1-FBPase+ cells in the presence of 5 mM glucose does not abolish the morphological and biochemical changes described, indicating the stability of the FBPase+ strain.


Simultaneous Occurrence of Rosai-Dorfman Disease and Nodal Marginal Zone Lymphoma in a Patient with Sjögren's Syndrome.
We present an exceptionally rare case of co-occurrence of Rosai-Dorfman disease (RDD) and nodal marginal zone lymphoma (NMZL) in a 60-year-old Caucasian female with a 20-year course of Sjögren's syndrome (SS). In response to treatment for lymphoma, the patient presented a short positive response, followed by a rapid progression of the disease accompanied by the development of the peripheral facial nerve palsy. We failed to detect Epstein-Barr virus (EBV) in the NMZL/RDD sample by EBV-encoded RNA (EBER) in situ hybridization but identified genomic DNA of EBV by polymerase chain reaction. A second biopsy revealed EBV-positive diffuse large B-cell lymphoma (DLBCL), not otherwise specified. The identical clonal immunoglobulin heavy chain gene rearrangements in the NMZL and DLBCL pointed to their clonal relationship. Though the role of EBV in the pathogenesis of some lymphomas is well-known, there have been only few cases of EBV-induced transformation of low-grade B-cell lymphoma into high-grade lymphoma and no cases of a patient with an NMZL background. To our knowledge, this is the first report of a concomitant occurrence of RDD and NMZL in a SS patient.


Effects of heat stroke on surface ECG: a study on clinical outcomes.
Classic heat stroke is associated with high in-hospital mortality and morbidity. The relation between the ECG findings in heat stroke and the clinical outcomes of these patients has not been studied. The aim of this study was to describe the electrocardiographic features in patients with classic heat stroke and to determine if there is any correlation of ECG findings with in-hospital outcomes. We performed a retrospective study on 50 patients with classic heat stroke during summer months of 2016-2018. All 12-lead electrocardiographic recordings obtained from these patients were subjected to in-depth analysis. Statistical analysis was done to determine the correlation of electrocardiographic findings with in-hospital outcomes. 37 patients were in sinus rhythm, while supraventricular arrhythmias including atrial fibrillation (n=6), ectopic atrial tachycardia (n=4) and atrial flutter (n=2) were observed in the rest. There was a high prevalence of QTc prolongation, low voltage P waves, conduction defects like incomplete right bundle branch block and repolarisation abnormalities. The ratio of QRS voltage in the limb leads to that in precordial leads was ≤0.5 in nearly three-fourths of the patients. Among the observed electrocardiographic features, low P-wave voltage (<0.01 mV) in lead II was found to have statistically significant correlation with adverse in-hospital outcome (OR 8.93, p=0.04), after adjustment for clinical covariates. There was high incidence of atrial arrhythmias in patients with classic heat stroke. A low P-wave voltage (<0.01 mV) in lead II was predictive of adverse in-hospital outcome in this cohort of patients.


[SP-selectin and beta-TG as serum markers of platelet activation in menopausal women with depression].
During activation, blood platelets (PLT) release a number of micromolecular compounds, of which P-selectin and beta-thromboglobulin (beta-TG) are considered the major markers of the activation. The activated platelets and the released micromolecular compounds actively participate in thromboembolic disorders frequently observed in menopause. Low estrogen level in menopausal women is a common cause of depressive disorders. The aim of the study was to compare the state of PLT activation in menopausal women with and without depression. The assessment of PLT activation was based on the concentration of sP-selectin and beta-TG as serum markers of the activation. Among 65 menopausal women examined, 16 (approx. 25%) had depression. PLT activation was assessed on the basis of sP-selectin and beta-TG levels. The investigation was performed in the low-platelet citrate serum obtained from venous blood collected onto anticoagulant. The levels of beta-TG and sP-selectin were determined using the immunoenzymatic method, with ELISA Kit reagents. In all the women, both with and without depression, the levels of beta-TG and sP-selectin several times exceeded the accepted norms. The concentration of beta-TG was statistically significantly higher (p < 0.05) in women with depression as compared to those with no depressive disorders. Menopausal women suffering from depression show enhanced intravascular platelet activation. High beta-TG level in women with depression indicates higher risk of thromboembolic disorders in comparison with depression-free women in menopause.


Dichotic listening using Mandarin CV-words of six plosives and vowel /a/.
Available data on dichotic listening using tonal Chinese words have been limited, and conflicting results on a right-ear advantage (REA) have been reported. The current study developed a set of Mandarin CV-words based on the Bergen dichotic listening paradigm. The test materials consisted of two sets of stimuli. The English set, derived from the iDichotic application, consisted of six nonsense syllables with plosives conjugated to /a/. The Mandarin set had these 6 CV-syllables spoken as real words according to the Mandarin phonology. Study sample: Forty young, native Mandarin speakers were tested dichotically with both sets of test materials. Twenty participants were right-handed, and the other twenty were left-handed. Fourteen participants were randomly selected to repeat the test with the Mandarin set. The mean difference of correct recognition responses between two ears indicated a REA with both sets of stimuli for the right-handers, but not for left-handers. For the right-handers, performance with the Mandarin set was significantly better than performance with the English set. Dichotic listening with the Mandarin set had strong correlation between two time points, r = 0.8. Performance using the Mandarin set is reliable in dichotic listening; a REA is observed for the right-handers.


Predictors of Mortality Among Adult HIV-Infected Patients Taking Antiretroviral Therapy (ART) in Harari Hospitals, Ethiopia.
Despite the world has made efforts, the reduction of acquired immunodeficiency syndrome (AIDS) related mortality by giving antiretroviral therapy (ART), still HIV/AIDS is killing people while they are on ART. However, the current progress and associated factors of mortality among ART-taking patients are hardly available. Therefore, this study was aimed to determine predictors of mortality among HIV-infected adult patients after starting antiretroviral therapy in Harar Hospitals, Harari region, Ethiopia. A facility-based retrospective cohort study was employed with randomly selected 610 medical records of HIV patients on antiretroviral therapy (ART). Adjusted hazard ratio (AHR) with 95% confidence interval (CI) was used to identify predictors of mortality using multivariate Cox proportional hazard model. Among 610 medical records analyzed with a total of 1410.7 follow-up years, 67 (11%) deaths were found giving an overall mortality rate of 4.75 per 100 person-years. The independent predictor of mortality identified was ambulatory/bedridden functional status (AHR=2.48; 95% CI: 1.43-4.28), taking other than Tenofovir-based regimen (AHR=2.5,95% CI; 1.04-5.94), not taking isoniazid preventive therapy (IPT) (AHR=2.8; 95% CI: 1.61,4.71), hemoglobin <11g/dl (AHR=3.33,95% CI 1.94-5.69), and poor adherence to ART (AHR= 3.62, 95% CI: 1.87-7.0). This study demonstrated that poor ART adherence, not taking IPT, and initiating ART with a non-Tenofovir-based regimen and low hemoglobin count were significantly associated with the risk of death. For this reason, addressing these all significant predictors is essential to prevent early death.


Accuracy of percentage of signal intensity recovery and relative cerebral blood volume derived from dynamic susceptibility-weighted, contrast-enhanced MRI in the preoperative diagnosis of cerebral tumours.
Conventional magnetic resonance imaging (MRI) is the technique of choice for diagnosis of cerebral tumours, and has become an increasingly powerful tool for their evaluation; however, the diagnosis of common contrast-enhancing lesions can be challenging, as it is sometimes impossible to differentiate them using conventional imaging. Histopathological analysis of biopsy specimens is the gold standard for diagnosis; however, there are significant risks associated with the invasive procedure and definitive diagnosis is not always achieved. Early accurate diagnosis is important, as management differs accordingly. Advanced MRI techniques have increasing utility for aiding diagnosis in a variety of clinical scenarios. Dynamic susceptibility-weighted contrast-enhanced (DSC) MRI is a perfusion imaging technique and a potentially important tool for the characterisation of cerebral tumours. The percentage of signal intensity recovery (PSR) and relative cerebral blood volume (rCBV) derived from DSC MRI provide information about tumour capillary permeability and neoangiogenesis, which can be used to characterise tumour type and grade, and distinguish tumour recurrence from treatment-related effects. Therefore, PSR and rCBV potentially represent a non-invasive means of diagnosis; however, the clinical utility of these parameters has yet to be established. We present a review of the literature to date.


Temperature-Controlled Rotational Epitaxy of Graphene.
When graphene is placed on a crystalline surface, the periodic structures within the layers superimpose and moiré superlattices form. Small lattice rotations between the two materials in contact strongly modify the moiré lattice parameter, upon which many electronic, vibrational, and chemical properties depend. While precise adjustment of the relative orientation in the degree- and sub-degree-range can be achieved via careful deterministic transfer of graphene, we report on the spontaneous reorientation of graphene on a metallic substrate, Ir(111). We find that selecting a substrate temperature between 1530 and 1000 K during the growth of graphene leads to distinct relative rotational angles of 0°, ± 0.6°, ±1.1°, and ±1.7°. When modeling the moiré superlattices as two-dimensional coincidence networks, we can ascribe the observed rotations to favorable low-strain graphene structures. The dissimilar thermal expansion of the substrate and graphene is regarded as an effective compressive biaxial pressure that is more easily accommodated in graphene by small rotations rather than by compression.


Machine learning algorithms to identify cluster randomized trials from MEDLINE and EMBASE.
Cluster randomized trials (CRTs) are becoming an increasingly important design. However, authors of CRTs do not always adhere to requirements to explicitly identify the design as cluster randomized in titles and abstracts, making retrieval from bibliographic databases difficult. Machine learning algorithms may improve their identification and retrieval. Therefore, we aimed to develop machine learning algorithms that accurately determine whether a bibliographic citation is a CRT report. We trained, internally validated, and externally validated two convolutional neural networks and one support vector machine (SVM) algorithm to predict whether a citation is a CRT report or not. We exclusively used the information in an article citation, including the title, abstract, keywords, and subject headings. The algorithms' output was a probability from 0 to 1. We assessed algorithm performance using the area under the receiver operating characteristic (AUC) curves. Each algorithm's performance was evaluated individually and together as an ensemble. We randomly selected 5000 from 87,633 citations to train and internally validate our algorithms. Of the 5000 selected citations, 589 (12%) were confirmed CRT reports. We then externally validated our algorithms on an independent set of 1916 randomized trial citations, with 665 (35%) confirmed CRT reports. In internal validation, the ensemble algorithm discriminated best for identifying CRT reports with an AUC of 98.6% (95% confidence interval: 97.8%, 99.4%), sensitivity of 97.7% (94.3%, 100%), and specificity of 85.0% (81.8%, 88.1%). In external validation, the ensemble algorithm had an AUC of 97.8% (97.0%, 98.5%), sensitivity of 97.6% (96.4%, 98.6%), and specificity of 78.2% (75.9%, 80.4%)). All three individual algorithms performed well, but less so than the ensemble. We successfully developed high-performance algorithms that identified whether a citation was a CRT report with high sensitivity and moderately high specificity. We provide open-source software to facilitate the use of our algorithms in practice.


Computational modelling of the graft-tunnel interaction in single-bundle ACL reconstructed knee.
Tunnel enlargement and graft failure are common complications associated with ACL reconstruction. The mechanical interaction between the graft and the tunnel aperture may play a more important role. This study aims to evaluate graft position within femoral tunnel and the graft force under external loads. An FE model of the femur-graft-tibia complex was constructed from CT images of an anatomically reconstructed knee specimen. The model was subjected to kinematics of passive flexion extension, anterior/posterior translation, internal/external rotation and valgus kinematics, which were collected from experimental testing. Graft shift and rotation of graft-tunnel contact region during flexion/extension and external loadings were recorded and compared to experimental measurements. Model showed that the graft shifted in the femoral tunnel during flexion and under external loads. The graft-tunnel contact area rotated by up to 55° during flexion from full extension to 90° of extension implying that the so-called "wiper effect" occurs during most of flexion angles. Different regions of the femoral tunnel aperture, particularly the anterior region, were under significantly more contact force from the graft than other areas of the aperture during the anterior translation test, potentially leading to femoral tunnel enlargement to the anterior side of the aperture.


[Long-term outcome of patients with hypertrophic obstructive cardiomyopathy post percutaneous transluminal septal ablation].
Objective: To evaluate the long-term outcome of patients with hypertrophic obstructive cardiomyopathy(HOCM) after percutaneous transluminal septal ablation(PTSMA). Methods: HOCM patients who underwent PTSMA and surgical myectomy at the Chest Hospital of Shanghai Jiao Tong University from April 2001 to February 2019 were included in this retrospective analysis. Patients were divided into PTSMA group and surgical myectomy group. In addition, patients undergoing PTSMA were further divided into HOCM-PTSMA non-survivor group and HOCM-PTSMA survivor group. The general clinical information, procedural/surgical information and complications during hospitalization were compared between groups. Multivariate Cox regression model was used to analyze the independent risk factors for all-cause death in HOCM patients after PTSMA. Results: A total of 104 patients with HOCM who underwent PTSMA were enrolled. Mean age of the patients was (54±15) years old, including 41 females (38.7%). The follow-up time was 37.5(14.3, 76.8) months. At the last follow-up, 12 patients died (HOCM-PTSMA non-survivor group) and 92 were alive(HOCM-PTSMA survivor group). The proportion of patients with NYHA function class Ⅲ/Ⅳ was higher(P=0.036), and the posterior wall of the left ventricle was thicker(P=0.006) in the HOCM-PTSMA non-survivor group than in the HOCM-PTSMA survivor group. The immediate success rate of PTSMA in this cohort was 66%(70/104). The amount of absolute alcohol during the operation in the HOCM-PTSMA non-survivor group was (2.9±0.8) ml, which tended to be higher as compared to that in the HOCM-PTSMA survivor group((2.4±1.0)ml, P=0.056). Kaplan-Meier survival curve analysis showed that patients with HOCM who underwent PTSMA had an all-cause mortality-free survival rate of 90.1%, 78.3%, and 56.9% at 5, 10 and 15 years, and a HOCM-free survival rate of 91.3%, 79.4% and 57.7% at 5, 10 and 15 years, respectively. Multivariate Cox regression analysis showed that age≥ 65 years was an independent risk factor for all-cause death after PTSMA in patients with HOCM (HR=2.697, 95%CI 1.292-18.977, P=0.020). There were 32 patients in the surgical myectomy group. The proportion of patients with NYHA function class Ⅲ/Ⅳ was higher than that in the PTSMA group(P<0.001), while age, gender, and major comorbidities(atrial fibrillation, coronary heart disease, hypertension, and diabetes) as well as the left atrium dimension were all similar between the two groups(all P>0.05). Patients in the surgical myectomy group were followed up for 38.0(17.6, 64.2)months, and no deaths occurred during the follow-up period. Kaplan-Meier survival curve analysis showed that there were no statistically significant differences in all-cause-free and HOCM-free survival rates between patients in PTSMA group and surgical myectomy group(P=0.089 and 0.110, respectively). Conclusion: PTSMA is safe and effective for the treatment of patients with HOCM, and the long-term survival rate of patients after PTSMA is similar as patients undergoing classical surgical myectomy surgery.


Membrane potential changes during mitogenic stimulation of mouse spleen lymphocytes.
By monitoring differences in accumulation of the lipophilic cation [(3)H]tetraphenylphosphonium in media containing low or high potassium concentrations [Lichtshtein, D., Kaback, H. R. & Blume, A. J. (1979) Proc. Natl. Acad. Sci. USA 76, 650-654], the membrane potential of lymphocytes from various sources has been estimated. On the basis of this method, the potential of normal mouse spleen lymphocytes (T and B cells) is -65 +/- 2 mV (mean +/- SEM, interior negative). During the course of mitogenic stimulation by concanavalin A, lipopolysaccharide, or fetal calf serum, the membrane potential of murine spleen lymphocytes changes systematically according to the following pattern: (i) early depolarization lasting 2-3 hr, (ii) repolarization over the next 7 hr, and (iii) a final hyperpolarization phase during the last 24-48 hr. During repolarization and hyperpolarization, moreover, there is a direct correlation between the membrane potential and DNA synthesis, as judged by [(3)H]thymidine incorporation. By using isolated T and B cells, it is observed that concanavalin A depolarizes T cells only, whereas lipopolysaccharide depolarizes B cells only. Thus, both mitogens exhibit the same specificity for depolarization as for mitogenic stimulation. On the basis of these observations, it is suggested that the transition of lymphocytes from a resting state to mitotic activity is initiated by depolarization of the plasma membrane.