Identification of optimal mother wavelets in survival prediction of lung cancer patients using wavelet decomposition-based radiomic features.
To identify the optimal mother wavelets in survival prediction of lung cancer patients using wavelet decomposition-based (WDB) radiomic features in CT images. The CT images of patients with histologically confirmed nonsmall cell lung carcinomas (NSCLCs) in training (Dataset T; n = 162) and validation (Dataset V; n = 143) datasets were analyzed for this study. The optimal mother wavelets were identified based on the impacts of the WDB radiomic features on the patient survival times. Four hundred and thirty-two three-dimensional WDB radiomic features were calculated from regions of interest (ROI) of 162 tumor contours. A Coxnet algorithm was used to select a subset of radiomic features (signature) based on the prediction of survival times with a fivefold cross validation. The impacts of the radiomic features on the patients' survival times were assessed by using a multivariate Cox proportional hazard regression (MCPHR) model. The major contribution of this study was to identify optimal mother wavelets based on a maximization of a novel ranking index (RI) incorporating the Coxnet cross-validated partial log-likelihood and the summation of the P-values of the radiomic features in the MCPHR model on Dataset T. The prognostic performance of the optimal mother wavelets was validated based on the concordance index (CI) of the MCPHR models when applied to Dataset V. The proposed approach was tested by using 31 mother wavelets from 6 wavelet families that were available in a commercially available software (Matlab® 2016b). The optimal mother wavelets were Symlet 5 and Biorthogonal 2.6 at 128 requantization levels, which yielded RIs of 4.27 ± 0.29 (3 features) and 6.50 ± 0.50 (5 features), respectively. The CIs of the MCPHR models of Symlet 5 were 0.66 ± 0.03 (Dataset T) and 0.64 ± 0.00 (Dataset V), whereas those of Biorthogonal 2.6 were 0.68 ± 0.03 (Dataset T) and 0.62 ± 0.02 (Dataset V). The radiomic signatures included the GLRLM-based LHL gray level nonuniformity feature that demonstrated statistically significant differences in stratifying patients with better and worse prognoses in Datasets T and V. This study has revealed the potential of Symlet and Biorthogonal mother wavelets in the survival prediction of lung cancer patients by using WDB radiomic features in CT images.


Effect of intensive blood pressure lowering on left ventricular hypertrophy in patients with hypertension: a meta-analysis of randomized trials.
Successful antihypertensive management can limit left ventricular hypertrophy (LVH) and improve the clinical prognosis. However, it remains unclear whether intensive blood pressure (BP) lowering has a greater effect on the occurrence and regression of LVH compared to standard BP lowering. We searched the electronic databases of PubMed, EMBASE and Web of Science from inception to 2 June 2023. Relevant and eligible studies were included. A random-effects model was used to estimate the pooled odds ratio (OR) and 95% confidence intervals (CI). Four RCTs including 20,747 patients met our inclusion criteria. The results demonstrated that intensive BP lowering was associated with a significantly lower rate of LVH (OR 0.85; 95%CI: 0.78-0.93; I2 48.6%) in patients with hypertension compared to standard BP lowering. Subgroup analysis revealed that the effect of intensive BP lowering on LVH was more pronounced in patients with high cardiovascular disease (CVD) risk factors (OR 0.82; 95%CI: 0.72-0.93; I2 57.9%). In addition, intensive BP lowering led to significant regression of LVH (OR 0.68; 95%CI: 0.52-0.88; I2 45.5%). Our study suggests that intensive BP lowering should be instigated as soon as possible for optimal control of BP and to prevent regression of LVH, especially in patients with high risk of CVD. However, caution is warranted when treating hypertensive patients with LVH to systolic blood pressure (SBP) targets below 130 mm Hg.


Hearts in the fire, heads in the fridge: a qualitative investigation into the temporal patterning of the precompetitive psychological response in elite performers.
Retrospective perceptions and causal beliefs regarding the temporal patterning of precompetitive psychological responses were examined in 12 elite rugby union players. Composite sequence analysis resulted in a series of temporal networks to describe participants' cognitive, affective, and behavioural responses in a time-to-event paradigm. Match-related cognitions remained stable in the lead up to competition, while perceptions of physical symptoms peaked at the onset of performance. Affective responses were associated with feelings of anxiety and tension in the early temporal phases but excitement, confidence, and efficacy in team-mates directly before competition. Behavioural themes described activities associated with technical and physical preparation, familiarization with environmental conditions, and strategies to control activation states early on or directly before competition. The findings highlight the idiosyncratic and dynamic nature of the temporal patterning of precompetitive responses and the influence that perceptions of the team have upon individual preparation for performance. Implications are discussed in the context of the type and timing of intervention for developing individual and team preparatory routines.


Contact Effect of ReS2/Metal Interface.
Rhenium disulfide (ReS2) has attracted immense interest as a promising two-dimensional material for optoelectronic devices owing to its outstanding photonic response based on its energy band gap's insensitivity to the layer thickness. Here, we theoretically calculated the electrical band structure of mono-, bi-, and trilayer ReS2 and experimentally found the work function to be 4.8 eV, which was shown to be independent of the layer thickness. We also evaluated the contact resistance of a ReS2 field-effect transistor using a Y-function method with various metal electrodes, including graphene. The ReS2 channel is a strong n-type semiconductor, thus a lower work function than that of metals tends to lead to a lower contact resistance. Moreover, the graphene electrodes, which were not chemically or physically bonded to ReS2, showed the lowest contact resistance, regardless of the work function, suggesting a significant Fermi-level pinning effect at the ReS2/metal interface. In addition, an asymmetric Schottky diode device was demonstrated using Ti or graphene for ohmic contacts and Pt or Pd for Schottky contacts. The ReS2-based transistor used in this study on the work function of ReS2 achieved the possibility of designing the next-generation nanologic devices.


Impact of clinical trials on neurosurgical practice: an assessment of case volume.
To evaluate the effect of important trials on the practice of neurosurgery. We hypothesized that evidence from trials addressing the management of intracranial aneurysms (International Subarachnoid Aneurysm Trial [ISAT]) and nontraumatic intracerebral hemorrhages (Surgical Trial in Intracerebral Hemorrhage [STICH]) and vertebral augmentation for osteoporotic vertebral body fractures had a significant impact on the frequency of the corresponding neurosurgical procedures. A Medicare administrative database was queried for corresponding Common Procedural Terminology codes and units billed per calendar year. The effects of ISAT and STICH were evaluated using a generalized linear model. The effect of the vertebral augmentation study was evaluated using a t test. After publication of ISAT in 2002, the rate of increase in proportion of cerebral aneurysms that were treated with embolization (Common Procedural Terminology code 61624) per year increased from 3.9% to 5.5% (P = 0.01). After publication of STICH in 2005, the number of craniotomies performed for intracerebral hematoma decreased from 2341 in 2002 to 1646 in 2011 (P = 0.03). After 2 publications in 2009, performance of vertebral augmentation decreased from a high of 99,961 in 2009 per year to 77,108 in 2013 (P = 0.002). Randomized clinical trials remain the gold standard in the medical community to demonstrate efficacy, but their true impact relies on rapid and extensive assimilation into everyday medical practice. However, the described methodology establishes a temporal relationship only and does not prove causation. Nonetheless, trends in procedural volume suggest that the results of these select randomized clinical trials had a significant effect on neurosurgical practice affecting Medicare patients within an interval of a few years.


OrthoGraphics. A two-dimensional surgical planning system.
Presurgical planning is a useful means of attaining consistent and predictable surgical results. The range of intraoperative errors is narrowed, and surgical time and materials are minimized. Computer-assisted presurgical planning is an extremely valuable tool for reconstructive foot surgery. A versatile, self-taught software program that permits longitudinal tracking of deformities and visualization of multiple surgical options, i.e., base wedge versus neck osteotomy, is effective in terms of cost, speed, accessibility, documentation, research, and education. The concept of CAD in presurgical planning is not new to other surgical specialties, but as of this date, it has not been implemented fully by podiatric surgeons. The cost factor for office computer use has decreased significantly over the years, and it is highly unusual to locate an office today that does not employ a computer in some aspect of office operation. The additional hardware and OrthoGraphics software at this date may represent between a $6000 and $20,000 investment, depending on how sophisticated an office operation is desired. It is of particular interest that one optical disk in the ICS can hold up to 1000 patient records with nearly 4000 radiographs. In addition, a 35-mm slide-creating interface is available along with the opportunity to modify existing programs to create custom software to meet special needs. It would appear that the teaching applications of this type of system are most compatible with the podiatric medical college clinical curriculum as a component of instructional programs in both biomechanics and surgery.


Impact of Preformed Donor-Specific Anti-HLA-Cw and Anti-HLA-DP Antibodies on Acute Antibody-Mediated Rejection in Kidney Transplantation.
Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2 years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21-4.45 (p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA's MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08-1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA.


Oxymatrine improves intestinal epithelial barrier function involving NF-κB-mediated signaling pathway in CCl4-induced cirrhotic rats.
Accumulating evidence suggests that intestinal epithelial barrier dysfunction plays an important role in the pathogenesis of hepatic cirrhosis and its complications such as gastrointestinal injury and hepatic encephalopathy. To date, there is no cure for cirrhosis-associated intestinal mucosal lesion and ulcer. This study aimed to investigate the effect of oxymatrine on intestinal epithelial barrier function and the underlying mechanism in carbon tetrachloride (CCl4)-induced cirrhotic rats. Thirty CCl4-induced cirrhotic rats were randomly divided into treatment group, which received oxymatrine treatment (63 mg/kg), and non-treatment group, which received the same dose of 5% glucose solution (vehicle). The blank group (n = 10 healthy rats) received no treatment. Terminal ileal samples were collected for histopathological examination. The expression level of nuclear factor-κB (NF-κB) p65 in ileal tissue was evaluated by immunohistochemistry. The gene and protein expression levels of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in ileal tissues were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Additionally, plasma endotoxin level was determined. In comparison to the blank group, a significant alteration in the morphology of intestinal mucosal villi in the non-treatment group was observed. The intestinal mucosal villi were atrophic, shorter, and fractured, and inflammatory cells were infiltrated into the lamina propria and muscular layer. Besides, serious swell of villi and loose structure of mucous membrane were observed. Oxymatrine reversed the CCl4-induced histological changes and restored intestinal barrier integrity. Moreover, oxymatrine reduced the protein expression level of NF-κB p65, TNF-α, and IL-6, which were elevated in the vehicle-treated group. In addition, the serum endotoxin level was significantly decreased after oxymatrine treatment in CCl4-induced cirrhotic rats. The results indicate that oxymatrine improves intestinal barrier function via NF-κB-mediated signaling pathway and may be used as a new protecting agent for cirrhosis-associated intestinal mucosal damage.


Redistribution of cellular and herpes simplex virus proteins from the trans-golgi network to cell junctions without enveloped capsids.
Herpes simplex virus (HSV) and other alphaherpesviruses assemble enveloped virions in the trans-Golgi network (TGN) or endosomes. Enveloped particles are formed when capsids bud into TGN/endosomes and virus particles are subsequently ferried to the plasma membrane in TGN-derived vesicles. Little is known about the last stages of virus egress from the TGN/endosomes to cell surfaces except that the HSV directs transport of nascent virions to specific cell surface domains, i.e., epithelial cell junctions. Previously, we showed that HSV glycoprotein gE/gI accumulates extensively in the TGN at early times after infection and also when expressed without other viral proteins. At late times of infection, gE/gI and a cellular membrane protein, TGN46, were redistributed from the TGN to epithelial cell junctions. We show here that gE/gI and a second glycoprotein, gB, TGN46, and another cellular protein, carboxypeptidase D, all moved to cell junctions after infection with an HSV mutant unable to produce cytoplasmic capsids. This redistribution did not involve L particles. In contrast to TGN membrane proteins, several cellular proteins that normally adhere to the cytoplasmic face of TGN, Golgi, and endosomal membranes remained primarily dispersed throughout the cytoplasm. Therefore, cellular and viral membrane TGN proteins move to cell junctions at late times of HSV infection when the production of enveloped particles is blocked. This is consistent with the hypothesis that there are late HSV proteins that reorganize or redistribute TGN/endosomal compartments to promote virus egress and cell-to-cell spread.


Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice.
Many atypical antipsychotic drugs cause weight gain, but the mechanism of this weight gain is unclear. To dissect the role of the dopamine D2 receptor (D2R), an important receptor in the pharmacology of antipsychotic drugs, we analyzed the effect of olanzapine, risperidone, and ziprasidone on changes in body weight and food intake in male wild-type (WT) and D2R knockout (D2R(-/-)) mice. The oral delivery of atypical antipsychotics, olanzapine (5 and 10mg/kg), risperidone (0.1 and 1.0mg/kg) and ziprasidone (10 and 20mg/kg) in both strains mice for 2 weeks suppressed body weight gain, except for olanzapine treatment in D2R(-/-) mice. Olanzapine treatment suppressed body weight gain and decreased food intake in WT mice, but also reduced fat body mass and locomotor activity, whereas D2R(-/-) mice did not show these changes. Ziprasidone and risperidone treatment produced similar responses in WT and D2R(-/-) mice. These data suggest the involvement of D2R in the effect of olanzapine on metabolic regulation. Further studies are required to explore the implications of D2R activity in antipsychotic-mediated metabolic complications.


The state of professionalisation of midwifery in Belgium: A discussion paper.
To describe the state of the professionalisation of midwifery in Belgium, and to formulate recommendations for advancing the midwifery profession. A descriptive overview of maternity care in Belgium and the professionalisation of midwifery through an analysis of relevant policy and academic texts, underpinned by Greenwood's sociological criteria for a profession: (1) own body of knowledge, (2) recognised authority, (3) broader community sanctions, (4) own code of ethics and (5) professional culture sustained by formal professional associations. From these insights, recommendations for advancing the midwifery profession in Belgium are formulated. Current strengths of the professionalisation of midwifery in Belgium included unified midwifery education programmes, progress in midwifery research and overarching national documents for guiding midwifery education, practice and regulation. In contrast however challenges, such as the limited recognition of midwives' roles by its clientele, limitations of midwives' competencies and autonomy, lacking development of advanced roles in maternity care practice and a lack of unity of the organisation and its members, were also identified. Based on these, recommendations are made to strengthen Belgian midwifery. Recommendations for advancing the midwifery profession in Belgium includes in particular increasing public awareness of midwives' roles and competencies, implementing the full scope of midwifery practice and monitoring and advancing this practice. Thus, professional autonomy over both midwifery practice and working conditions should be enhanced. United midwifery organisations, together with women's groups, other maternity care professionals and policy-makers as equal partners are key to bring about changes in the Belgian maternity care landscape.


[Historical compendium of physical activity and sport].
The Historical Compendium of Physical Activity and Sport analyses, from a scientific perspective, past events in the array of tasks or manoeuvres comprising body movement, in a setting of human liberty and creative capacity. Sport is examined as a result of the evolution of games and in a context of these games. This book contemplates sports, whose selection criteria have included specific features of their individual or team qualities, or combat or opposition characteristics, or those related to their artistic features or to instrumentation or adaptation, or other connotations. 1st authors are 36 professors, from the universities of Barcelona, (Central), Granada, Jaen, Las Palmas de Gran Canaria, León, Madrid (Complutense), Málaga, Murcia, Oviedo, País Vasco, Salamanca, Valencia and Zaragoza.


[The role of apoptosis in the thymic involution during growth of the syngeneic transplanted tumor in mice].
Thymic involution accompanies the growth of many human and animals tumors but the precise mechanism of this phenomenon is unknown. We tried to elucidate the role of apoptosis as a possible mechanism of thymic involution during tumor growth. The mice were inoculated subcutaneously with syngeneic hepatoma 22a cells. Starting from the 3rd week after tumor inoculation, progressive thymic involution was observed. Histological studies revealed distinct delymphatization of the thymic cortex, reduced numbers of big lymphocytes in the subcapsular zone and of mitoses in the cortex, and an increased amount of mast cells. This was followed by decreased DNA synthesis in vitro as measured from 3H-thymidine incorporation. The number of pycnoses in the cortex was two to three times that in the thymus of control animals. DNA gel electrophoresis did not reveal any signs of apoptosis in the thymocytes without preincubation. Within 2 h of in vitro incubation of the thymocytes taken on the 7th day after the tumor inoculation, spontaneous apoptosis was more expressed than in the thymocytes from intact mice. This may reflect different induction mechanisms of apoptosis in the thymocytes from the tumor bearing and control mice. We propose that the mechanism of thymic involution during tumor growth is related to inhibition of thymocytes' proliferation, impaired differentiation and enhanced intrathymic death caused by cytokine release from the nonlymphoid thymic population.


Toward robust information: data quality and inter-rater reliability in the American College of Surgeons National Surgical Quality Improvement Program.
Data used for evaluating quality of medical care need to be of high reliability to ensure valid quality assessment and benchmarking. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) has continually emphasized the collection of highly reliable clinical data through its program infrastructure. We provide a detailed description of the various mechanisms used in ACS NSQIP to assure collection of high quality data, including training of data collectors (surgical clinical reviewers) and ongoing audits of data reliability. For the 2005 through 2008 calendar years, inter-rater reliability was calculated overall and for individual variables using percentages of agreement between the data collector and the auditor. Variables with > 5% disagreement are flagged for educational efforts to improve accurate collection. Cohen's kappa was estimated for selected variables from the 2007 audit year. Inter-rater reliability audits show that overall disagreement rates on variables have fallen from 3.15% in 2005 (the first year of public enrollment in ACS NSQIP) to 1.56% in 2008. In addition, disagreement levels for individual variables have continually improved, with 26 individual variables demonstrating > 5% disagreement in 2005, to only 2 such variables in 2008. Estimated kappa values suggest substantial or almost perfect agreement for most variables. The ACS NSQIP has implemented training and audit procedures for its hospital participants that are highly effective in collecting robust data. Audit results show that data have been reliable since the program's inception and that reliability has improved every year.


Homocysteine and Hyperhomocysteinaemia.
Homocysteine (Hcy) is a thiol group containing the amino acid, which naturally occurs in all humans. Hcy is degraded in the body through two metabolic pathways, while a minor part is excreted through kidneys. The chemical reactions that are necessary for degradation of Hcy require the presence of folic acid, vitamins B6 and B12. Consequently, the level of the total Hcy in the serum is influenced by the presence or absence of these vitamins. An elevated level of the Hcy, hyperhomocysteinemia (HHcy) and homocystinuria is connected with occlusive artery disease, especially in the brain, the heart, and the kidney, in addition to venous thrombosis, chronic renal failure, megaloblastic anemia, osteoporosis, depression, Alzheimer's disease, pregnancy problems, and others. Elevated Hcy levels are connected with various pathologies both in adult and child population. Causes of HHcy include genetic mutations and enzyme deficiencies in 5, 10-methylenetetrahydrofolate reductase (MTHFR) methionine synthase (MS), and cystathionine β-synthase (CβS). HHcy can be caused by deficiencies in the folate, vitamin B12 and to a lesser extent, deficiency in B6 vitamin what influences methionine metabolism. Additionally, HHcy can be caused by the rich diet and renal impairment. This review presents literature data from recent research related to Hcy metabolism and the etiology of the Hcy blood level disorder. In addition, we also described various pathological mechanisms induced by hereditary disturbances or nutritional influences and their association with HHcy induced pathology in adults and children and treatment of these metabolic disorders.


Neuroradiological features of vertigo.
The diagnostic pathway in a patient with vertigo starts with the accurate evaluation of medical history followed by a general physical and neurological examination. This step can often lead to the identification of the correct cause of the disease or, at least, to a distinction between peripheral and central vertigo. Neuroradiological investigations have to be considered as elective diagnostic procedures and include: computed tomography (CT), magnetic resonance (MR), MR angiography (MRA), angiography. For the diagnosis of peripheral vertigo, benign paroxysmal positional vertigo, labyrinthitis, Meniere disease, perilymphatic fistula, local trauma, toxic labyrinthitis, acute otitis media and chronic middle ear effusion,the role of imaging techniques is controversial. CT and MR are performed to rule out other pathologies and to confirm the diagnosis. Increased resolution and application of special MR sequences enhancing the intralabyrinthine fluids have enabled more detailed analysis of labyrinthine structures and pathology. Both T2 and T1 contrast sequences are necessary. A high resolution CT study is required when otitis media is suspected and in the follow-up of post-traumatic vertigo. The causes of central vertigo are numerous and include: vertebro-basilar circulation vascular events, multiple sclerosis (MS), migraine-associated vertigo, cerebellar and brainstem tumors, CNS infections. Among them cerebrovascular ischemia and multiple sclerosis are the most frequent. In these situations imaging studies become mandatory. CT can diagnose most cerebellar hemorrhages and some cerebellar and brainstem acute ischemia, enhanced MR has proved to be the most sensitive tool to detect posterior fossa lesion. Diffusion-weighted MR can reveal acute ischemic changes before routine MR. There has been evidence that MR angiography, providing angiogram-like images of the intracranial vessels may sometimes avoid invasive angiography. MRA resolution is not as good as traditional angiography and may also be compromised by movements and other artifacts. Selective angiography of the posterior circulation is often indicated for therapeutic decisions.


Total neoadjuvant therapy approach for the treatment of locally advanced rectal cancer. Where do we stand?
for the management of locally advanced rectal cancer (LARC), initial treatment with neoadjuvant chemoradiotherapy followed by surgery and chemotherapy in selected patients is considered one of the recommended options by the main international clinical guidelines. Nonetheless, the administration of all chemotherapy before definitive treatment (total neoadjuvant therapy or TNT) is an optimal alternative with a growing level of evidence that must be evaluated in multidisciplinary boards. This review summarizes the available data and controversies in this scenario. we have analyzed the characteristics of the main published studies that assess the use of TNT in patients with LARC, evaluating their inclusion criteria and distinguishing between the employed radiotherapy fractionations, systemic agents, timing, and the implications of these treatments in regard to surgery and long-term oncological results. Our aim is to describe the evidence that supports the use of a specific regime in everyday clinical practice. there is solid evidence for the use of TNT in patients with LARC. There is no data indicating the superiority of one specific TNT scheme among all the existing options. International clinical guidelines leave the door open to choose the most adequate treatment based on the clinical and pathological characteristics of each patient. This review shows the different approaches to TNT and assesses the best options based on clinical evidence.


Ciprofloxacin therapy of infections caused by Pseudomonas aeruginosa and other resistant bacteria.
Ciprofloxacin was administered orally to 48 patients with 24 Pseudomonas aeruginosa infections and 13 other infections caused by cephalothin-resistant gram-negative bacilli. The types of infections treated included those of skin or skin structure, bone, urinary tract, and respiratory tract. In 83% of P. aeruginosa infections, a favorable clinical outcome occurred, compared with 85% for all infections. Failure to achieve a cure correlated with the emergence of resistant P. aeruginosa and Acinetobacter calcoaceticus strains in four instances and superinfection with Candida (two cases) and Streptococcus (two cases) species. Therapy was discontinued in three patients because of the development of nausea. Ciprofloxacin appears to be safe and effective in the therapy of infections caused by resistant gram-negative bacilli.


Expression of anionic sites at the dermoepibolic junction.
The emergence of anionic sites during basement membrane zone formation was studied using migrating epidermis in organ culture as a model system. Ultrastructural investigations using a strongly cationized probe revealed that the heparitinase-sensitive, anionic sites were formed synchronously with the newly built basal lamina after 7 days in culture.


Anti-idiotypic antibodies in antisera against human C3 and factor H and their application in the enrichment of antibodies specific for H-binding domains of C3.
Antisera separately raised against C3 and factor H should contain antibodies against the binding domains by which these factors interact. Because these interacting domains are likely to be sterically complementary to each other, antibodies specific for these domains should also be sterically complementary or of anti-idiotypic specificity. To test this hypothesis, rabbit anti-human C3 IgG antibodies which bound to Sepharose-coupled rabbit anti-factor H IgG (anti-H-binding anti-C3) were separated by affinity chromatography. In a control experiment, the anti-human factor H column was found to bind 10 times more anti-C3 antibodies than a Sepharose column coupled with nonimmune rabbit IgG. The binding specificity of the control eluate was indistinguishable from the original anti-C3 preparation, whereas the anti-H-binding anti-C3 was shown to be enriched in regard to antibodies directed against the 42 kd fragment of the C3 alpha-chain of C3c, as demonstrated by immunoblotting of electrophoretically separated polypeptides of C3c and C3d in polyacrylamide gels. In competition binding studies, factor H was 25 times more potent as inhibitor of the anti-H-binding anti-C3 than of the original anti-C3 preparation. This similarity in binding specificity also paralleled a functional similarity in that anti-H-binding anti-C3 in the presence of factor I effected a 20% degradation of the alpha'-chain of C3b into fragments of 65, 45, and 42 kd which are the normal degradation products in the presence of factors I and H. These results suggest that the affinity procedure described resulted in the enrichment of anti-C3 antibodies with selective specificities for factor H-binding domains of C3, from a polyclonal antibody source.


Genomic and metabolomic profile associated to microalbuminuria.
To identify factors related with the risk to develop microalbuminuria using combined genomic and metabolomic values from a general population study. One thousand five hundred and two subjects, Caucasian, more than 18 years, representative of the general population, were included. Blood pressure measurement and albumin/creatinine ratio were measured in a urine sample. Using SNPlex, 1251 SNPs potentially associated to urinary albumin excretion (UAE) were analyzed. Serum metabolomic profile was assessed by 1H NMR spectra using a Brucker Advance DRX 600 spectrometer. From the total population, 1217 (mean age 54 ± 19, 50.6% men, ACR>30 mg/g in 81 subjects) with high genotyping call rate were analysed. A characteristic metabolomic profile, which included products from mitochondrial and extra mitochondrial metabolism as well as branched amino acids and their derivative signals, were observed in microalbuminuric as compare to normoalbuminuric subjects. The comparison of the metabolomic profile between subjects with different UAE status for each of the genotypes associated to microalbuminuria revealed two SNPs, the rs10492025_TT of RPH3A gene and the rs4359_CC of ACE gene, with minimal or no statistically significant differences. Subjects with and without microalbuminuria, who shared the same genotype and metabolomic profile, differed in age. Microalbuminurics with the CC genotype of the rs4359 polymorphism and with the TT genotype of the rs10492025 polymorphism were seven years older and seventeen years younger, respectively as compared to the whole microalbuminuric subjects. With the same metabolomic environment, characteristic of subjects with microalbuminuria, the TT genotype of the rs10492025 polymorphism seems to increase and the CC genotype of the rs4359 polymorphism seems to reduce risk to develop microalbuminuria.


The expression of CD154 by Kaposi's sarcoma cells mediates the anti-apoptotic and migratory effects of HIV-1-TAT protein.
Kaposi's sarcoma (KS) is a malignancy associated to conditions of immune system impairment such as HIV-1 infection and post-transplantation therapy. Here we report that HIV-1-Tat protein, at concentrations well below those detected in AIDS patients, up-regulates the expression of both CD40 and CD154 on KS cells. This occurred also in the presence of vincristine, that at doses shown to induce apoptosis decreased the expression of both CD40 and CD154 on KS cells. The treatment with a soluble CD40-muIg fusion protein (CD40 fp) that prevents the binding of CD154 with cell surface CD40, as well as the transfection with a vector for soluble CD40 (KS sCD40), decreased the anti-apoptotic effect of Tat. Moreover, Tat-induced motility of KS cells was inhibited by soluble CD40 fp. Tat also enhanced the expression of intracellular proteins known to transduce signals triggered by CD40 engagement, in particular TRAF-3. Tat as well as soluble CD154 (sCD154) prevented vincristine-induced reduction of TRAF-3 in KS cells transfected with a vector for neomycin resistance (KS psv-neo), but not in KS sCD40. Immunoprecipitation studies showed that Tat induced CD40 / TRAF-3 association and that this binding was abrogated upon the incubation with the soluble CD40 fp. These data suggest that Tat activates the CD40-CD154 pathway by enhancing the membrane expression of CD40 and in particular of CD154, and by activating the TRAF-3-dependent signaling pathway of CD40. These findings indicate that the CD40-CD154 pathway mediates the anti-apoptotic and migratory effects of HIV-1- Tat, suggesting the potential therapeutic benefits of blocking CD40 activation in HIV-1-associated KS.


The distribution of 5-HT(6) receptors in rat brain: an autoradiographic binding study using the radiolabelled 5-HT(6) receptor antagonist [(125)I]SB-258585.
We used the highly selective 5-HT(6) receptor radioligand [(125)I]SB-258585 (4-iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide) to perform autoradiographic binding studies on the rat brain. High levels of specific binding occurred in the corpus striatum, nucleus accumbens, Islands of Calleja and the olfactory tubercle. A high level of binding also appeared in the choroid plexus. Moderate levels occurred in several regions of the hippocampal formation and in certain regions of the cerebral cortex, thalamus, hypothalamus, and substantia nigra; and very low levels in the globus pallidus, cerebellum, other mesencephalic regions, and the rhombencephalon. Displacement of total binding with 10 microM unlabelled SB-214111 (4-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), another selective 5-HT(6) receptor antagonist, or 10 microM unlabelled methiothepin, reduced binding to barely discernible levels. Some animals received unilateral injections of 6-hydroxydopamine (6-OHDA) into the median forebrain bundle to lesion the nigro-striatal pathway before autoradiographic examination. Effectiveness of the 6-OHDA lesions in the substantia nigra and striatum was confirmed with tyrosine hydroxylase immunohistochemistry. Such lesions resulted in no significant changes in [(125)I]SB-SB258585 binding in any brain region examined, suggesting that 5-HT(6) receptors in the striatum are not located on dendritic, somatic or terminal elements of dopaminergic neurones. Thus, the striatal binding sites seen in this study may be on intrinsic GABAergic or cholinergic neurones, or on terminals of projection neurones from the thalamus or cerebral cortex. The 5-HT(6) receptor ligand binding seen here in the striatum, accumbens, olfactory tubercle, Islands of Calleja, cerebral cortex and hippocampus are in concordance with previous immunohistochemical studies, and suggest a possible involvement of 5-HT(6) receptors in locomotor control, cognition, memory, and control of affect. The high levels of binding observed in the choroid plexus in this study have not been reported before. This finding suggests that 5-HT(6) receptors could play a role in the control of cerebrospinal fluid dynamics.


Shigella gastroenteritis: clinical and epidemiological aspects, and antibiotic susceptibility.
The epidemiology and antibiotic sensitivity of Shigella species is changing worldwide. The present study surveyed the changing clinical and epidemiological characteristics and antibiotic susceptibility of Shigella gastroenteritis in Hacettepe University Ihsan Dogramaci Children's Hospital Diarrhoea Training and Treatment Unit between 1987 and 1994. Among 19,812 diarrheal admissions, 618 (3.2%) patient files with Shigella gastroenteritis were reviewed retrospectively. Shigella soneii has been the commonest isolate (64%) since 1987 followed by S. flexineri (30%), S. boydii (5%) and S. dysenteriae (1%), the latter having not been isolated since 1990. The isolate rate of S. sonnei has increased whereas the isolation rate of S. flexineri has decreased concomitantly since 1987 (r = -0.94; P < 0.001). The majority of cases (365/618, 59%) were between 1 and 5 years of age. On admission bloody diarrhea was present in 36%, seizures in 3% and mild-moderate dehydration in 11% of cases. No case had severe dehydration. Only six patients (1%) were hospitalized. No deaths were recorded. The resistance rate for trimethoprim-sulfamethoxazole has increased from 27% in 1990 to 66% in 1994 (P < 0.05) while the resistance rate for ampicillin has decreased from 81% in 1987 to 32% in 1993 (P < 0.001). Shigella flexineri was found to have higher resistance rates to ampicillin, sulbactam-ampicillin, chloramphenicol and gentamicin than S. sonnei. Changing Shigella sp. over the years may be the reason for the mild course of Shigella gastroenteritis. Further regional epidemiological studies are necessary to develop more appropriate management guidelines, especially in developing countries.


Four children with colchicine poisoning.
Colchicine poisoning is a rare event. It is characterized by multiorgan involvement and by poor prognosis associated with overdose. In this article we present four children with colchicine poisoning to emphasize that colchicine poisoning has a large spectrum in childhood. The children's ages ranged between 1 year and 3.5 years. The ingested dosage of colchicine was between 0.37 and 1.72 mg/kg. Most of the findings of colchicine poisoning such as gastrointestinal symptoms, hepatotoxicity, cardiotoxicity, bone marrow suppression, hypocalcaemia and hair loss were diagnosed in our patients. Two children receiving 0.37 mg/kg and 1 mg/kg colchicine and admitted 13 and 19 hours after poisoning, respectively, died. Our findings suggest that in addition to amounts of the drug, mortality was also related to the duration between drug ingestion and admission to hospital.


Hamartomas of the internal auditory canal: report of two cases.
To highlight the clinical, radiological, and surgical findings and therapeutic options for this rare entity, which may mimic a purely intrameatal vestibular schwannoma, and to define the particular aspects of preoperative differential diagnosis and surgical management. Two patients presented with clinical findings typical of vestibular schwannomas, i.e., tinnitus, hearing loss of 30 dB, and an intrameatal contrast-enhancing lesion on magnetic resonance imaging studies. The lesions were exposed via a suboccipital transmeatal approach, and tumor infiltration of the cochlear and/or facial cranial nerves was identified. In view of the unclear intraoperative histology, surgical management was based on criteria of cranial nerve function. In Patient 1, after nerve decompression by subtotal tumor removal, preserved auditory brainstem responses and facial nerve electromyography indicated functional nerve preservation and facilitated the decision for partial resection. In Patient 2, minimal tumor dissection resulted in complete loss of auditory brainstem response without reversibility. Therefore, a radical tumor removal was performed that sacrificed the cochlear but preserved the facial nerve. Symptoms and signs of internal auditory canal hamartomas are congruent with other typical pathological lesions of the internal auditory canal and cerebellopontine angle. Accurate preoperative diagnosis by radiological means is not possible, but careful evaluation of the different signal intensities on magnetic resonance imaging studies may indicate this rare pathological condition. Intraoperative surgical findings of tumor infiltration of the faciocochlear cranial nerve complex may support simple observation. In view of the nonneoplastic characteristic of these lesions, a more conservative approach is justified. The decision should be based on the functional status of the cranial nerves, for which reliable electrophysiological monitoring is indispensable.


[The effect of various multimodal analgesia regimens during surgical treatment of patients with spinal stenosis on the rate of failed back surgery syndrome].
To determine the effect of various methods of perioperative analgesia on the rate of failed back surgery syndrome in patients operated on for spinal stenosis. A total of 122 patients were operated on for spinal stenosis in 2010-2016. The patients were assigned to groups according to the type of received analgesia: Group K (n=19) underwent analgesia on-demand. Patients in the PMA group (n=21) received preventive multimodal analgesia (PMA) with ketoprofen, paracetamol and morphine. Patients in the PMA+PG (n=20) and PMA+N (n=20) groups additionally received pregabalin and nefopam, respectively. Patients in the PMA+E group (n=22) received continuous epidural analgesia with a combination of ropivacaine and morphine. In patients in the PMA+I group (n=20), the wound was infiltrated with ropivacaine and ketorolac. In Group K, analgesia was not adequate during five postoperative days. Analgesia with PMA resulted in significant pain reduction during three postoperative days compared to Group K. Wound infiltration in addition to PMA was followed by more significant pain relief during six postoperative hours (compared to the PMA group). Administration of pregabalin or nefopam, as well as epidural analgesia, did not improve quality of postoperative analgesia. Five to seven months after the surgery, 66% (57; 75%) of patients had low back and/or leg pain; 41% (32; 50%) of patients had leg pain. Among patients suffering from pain, 32-41% patients had the severe chronic pain syndrome that resulted in sleep disorder, disability and significant deterioration of quality of life. The rate of failed back surgery syndrome did not depend on the perioperative analgesia regimen.


Combating an invisible enemy: the American military response to global pandemics.
The present moment is not the first time that America has found itself at war with a pathogen during a time of international conflict. Between crowded barracks at home and trenches abroad, wartime conditions helped enable the spread of influenza in the fall of 1918 during World War I such that an estimated 20-40% of U.S. military members were infected. While the coronavirus disease 2019 (COVID-19) pandemic is unparalleled for most of today's population, it is essential to not view it as unprecedented lest the lessons of past pandemics and their effect on the American military be forgotten. This article provides a historical perspective on the effect of the most notable antecedent pandemic, the Spanish Influenza epidemic, on American forces with the goal of understanding the interrelationship of global pandemics and the military, highlighting the unique challenges of the current pandemic, and examining how the American military has fought back against pandemics both at home and abroad, both 100 years ago and today.


Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump.
Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERβ chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR.


Outlier removal, sum scores, and the inflation of the Type I error rate in independent samples t tests: the power of alternatives and recommendations.
In psychology, outliers are often excluded before running an independent samples t test, and data are often nonnormal because of the use of sum scores based on tests and questionnaires. This article concerns the handling of outliers in the context of independent samples t tests applied to nonnormal sum scores. After reviewing common practice, we present results of simulations of artificial and actual psychological data, which show that the removal of outliers based on commonly used Z value thresholds severely increases the Type I error rate. We found Type I error rates of above 20% after removing outliers with a threshold value of Z = 2 in a short and difficult test. Inflations of Type I error rates are particularly severe when researchers are given the freedom to alter threshold values of Z after having seen the effects thereof on outcomes. We recommend the use of nonparametric Mann-Whitney-Wilcoxon tests or robust Yuen-Welch tests without removing outliers. These alternatives to independent samples t tests are found to have nominal Type I error rates with a minimal loss of power when no outliers are present in the data and to have nominal Type I error rates and good power when outliers are present.


Cases of XY female, single-birth freemartin and trisomy (61, XX, +20) observed in cytogenetical studies on 18 sterile heifers.
A total of 18 sterile heifers, their mother cows, their half-sib cows and a bull which may or may not be a full-sib were cytogenetically investigated. Three cases out of the 18 sterile heifers showed different types of chromosomal abnormalities respectively; 60, XY; 60, XX/60, XY; 61, XX, +20. The remainder showed normal karyotype.


Switching strategies for antipsychotic monotherapy in schizophrenia: a multi-center cohort study of aripiprazole.
Changing antipsychotics of patients with chronic schizophrenia involves several risks. Switching to aripiprazole is especially difficult. We investigated switching methods and related factors for successful switching patients with chronic schizophrenia to aripiprazole. This study was a multi-center historical cohort study and approved by the research ethics committee of Okayama University Hospital and Okayama Psychiatric Medical Center. We compared survival proportions of 178 chronic schizophrenia patients who continued aripiprazole monotherapy for 6 months after non-direct switching (add-on switching (n = 45), cross switching (n = 62)) or direct switching (n = 71). We adjusted possible confounders using a Cox proportional hazards model. Of patients with chronic schizophrenia, 56.7% (101/178) were switched to aripiprazole monotherapy, and 55.0% (98/178) showed improvement in symptoms as demonstrated by the Clinical Global Impression Severity score. Kaplan-Meier survival curves showed that non-direct switching had a higher survival proportion than direct switching (log-rank test, p = 0.012). Even after adjusting for several variables using a Cox proportional hazards model, add-on switching had a significantly lower hazard at 6 months than direct switching (hazard ratio 0.42, 95% confidence interval 0.21-0.82, P = 0.01). In cases of switching to aripiprazole for psychiatric symptoms, non-direct switching had a lower hazard than direct switching (hazard ratio 0.41, 95% confidence interval 0.21-0.81, P = 0.01) but was not significant for adverse reaction. When aripiprazole was switched from olanzapine, add-on switch showed the lowest hazard ratio for continuation (hazard ratio 0.29, 95% confidence interval 0.07-1.11, P = 0.07). Flexibility in strategies when switching to aripiprazole may induce a better outcome for patients with chronic schizophrenia.


Rhinos and risk assessments: Adjusting risk assessment methodologies to account for 'unforeseeable' events.
It is wrong to describe the COVID-19 pandemic as a 'black swan' (ie a catastrophic event that no one saw coming). Far more apt would be to call it a 'grey rhino' - something that has long been predicted but overlooked by leadership the world over. This paper argues that it is time to stop relying on outdated risk formulas and adjust risk assessment methodologies to account for these grey rhinos. Simply put, it is time to accept that the potential impact of an event is more important than its likelihood.


Promiscuous CTL recognition of viral epitopes on multiple human leukocyte antigens: biological validation of the proposed HLA A24 supertype.
Multiple HLA class I alleles can bind peptides with common sequence motifs due to structural similarities in the peptide binding cleft, and these groups of alleles have been classified into supertypes. Nine major HLA supertypes have been proposed, including an A24 supertype that includes A*2301, A*2402, and A*3001. Evidence for this A24 supertype is limited to HLA sequence homology and/or similarity in peptide binding motifs for the alleles. To investigate the immunological relevance of this proposed supertype, we have examined two viral epitopes (from EBV and CMV) initially defined as HLA-A*2301-binding peptides. The data clearly demonstrate that each peptide could be recognized by CTL clones in the context of A*2301 or A*2402; thus validating the inclusion of these three alleles within an A24 supertype. Furthermore, CTL responses to the EBV epitope were detectable in both A*2301(+) and A*2402(+) individuals who had been previously exposed to this virus. These data substantiate the biological relevance of the A24 supertype, and the identification of viral epitopes with the capacity to bind promiscuously across this supertype could aid efforts to develop CTL-based vaccines or immunotherapy. The degeneracy in HLA restriction displayed by some T cells in this study also suggests that the dogma of self-MHC restriction needs some refinement to accommodate foreign peptide recognition in the context of multiple supertype alleles.


Peripheral nerves and nerve function in highland Ethiopians.
In Ethiopia, where leprosy has been one of the commonest causes of peripheral nerve enlargement and dysfunction, nerve functions are assessed by a battery of "physical" tests. Voluntary Muscle Test (VMT) and Graded Sensory Skin Test (STG) are standard tests used for persons with leprosy. Normal values for nerve function tests (NFT) in Highland Ethiopians have not previously been determined, but have been taken from standard textbooks. In this study, normal values for NFT were determined by VMT, STG, 2-Point Discrimination Tests both static and moving, and Thermal Threshold Test. Physiological enlargement of right ulnar and radial-cutaneous nerves has been recognised by some leprologists, but we were unable to find written records in the available medical literature. We assessed 236 students and adults aged 10-75 years from Chencha Woreda, an area with low endemicity of leprosy for 25-30 years. Two affected by leprosy were excluded from the analysis. NFT thresholds were affected variously by age, exercise and skin factors, domicile and exposure to organo-phosphates. Nerve size was affected by age, gender, exercise, skin fold thickness, body mass index. Exercise related physiological nerve enlargement has been documented. These data provide a usefull baseline for investigation of peripheral nerve function in highland Ethiopians.


Willingness of Saudi dental professionals to treat Hepatitis B virus-infected patients.
Hepatitis B virus (HBV) is considered the most important cross-infection hazard in developing countries. Patients infected with hepatitis virus could encounter difficulties in obtaining dental care. The aim of this study was to investigate the willingness of Saudi dental professionals to treat hepatitis B virus infected patients. This cross-sectional survey was carried out by distributing 300 questionnaires to Saudi dentists working in 40 government and private dental centers in Riyadh, Saudi Arabia. The questionnaire included questions related to age, sex, vaccination against HBV, screening for HBV antibody levels, willingness to treat hepatitis B infected patients, and the reasons behind any refusal. A t-test was used to compare the results and a P < 0.05 was considered significant. Of the 300 distributed questionnaires, 274 were collected giving a response rate of 91%. The respondents were 212 males (77.4%) and 62 (22.6%) females. Only 10.2% of the Saudi dentists were willing to treat HB infected patients. The other dentists (89.8%) were unwilling to provide dental care for HB infected patients. Although 94.5% of the surveyed dentists were vaccinated against HBV, the main reason behind the refusal to treat HB infected patients (92.3%) was the risk of cross infection. High percentages of Saudi dentists are unwilling to treat HBV-infected patients due to their apprehension about risk of cross infection. Many of the Saudi dentists do not screen for HBV antibody levels. All vaccinated dentists should carefully monitor their antibody levels to evaluate the need for booster doses. There is a need for educational programs to change the attitude of dentists toward treating HBV-infected patients. The strict adoption of cross infection preventive protocols by dentists will reduce the risk of transmitting infectious diseases in dental clinics as identification of blood-borne infections is not always possible.


Does horse temperament influence horse-rider cooperation?
Cooperation between rider and horse is of major importance in equitation. A balanced team of horse and rider improves (sport) performances and welfare aspects by decreasing stress, frustration, risks of injuries, and accidents. Important features affecting the cooperation are the physical skills, knowledge, and personality of the rider on one hand and the temperament, experience, and physical abilities of the horse on the other. A study with 16 riders and 16 warm-blood riding horses tested the effect of personality of riders and temperament of horses on cooperation between riders and horses. More emotionally reactive horses showed more evasive behavior during riding. Riders preferred to ride those horses who were assessed by the riders as being attentive to the rider's aid. The frequency of evasive behaviors during riding--as assessed by riders, in contrast to the assessments made by an external judge--influenced the cooperation between rider and horse. On average, a rider's personality did not affect the cooperation between rider and horse; however, it is suggested that a rider's personality does affect the cooperation with more emotionally reactive horses.


[Continuous predetermined insulin infusion in insulin-dependent diabetes mellitus (author's transl)].
At the present, prognosis of insulin-dependent diabetes depends on it's degenerative complications. Many studies have confirmed that the incidence of severe degenerative complications of early onset parallels the degree of metabolic unbalance. Unfortunately, in many diabetic patients satisfactory metabolic control is difficult to ensure because of the irregular absorption of insulin injected discontinuously in subcutaneous tissues. This is true even under strict diet conditions. Continuous insulin infusion at a predetermined dosage was therefore suggested. Data on basic requirements is provided by an artificial pancreas. Satisfactory results have already been reported with intravenous and subcutaneous routes. Intramuscular and intraperitoneal routes are at present under trial. The use of portable pumps facilitates these techniques. The insulin dosage must be correctly determined and adjusted to the patient's diet and activity. In brittle diabetes, these methods can provide, at least temporarily, a satisfactory metabolic balance, and useful data for adjusting further therapy.


Liver AMP-Activated Protein Kinase Is Unnecessary for Gluconeogenesis but Protects Energy State during Nutrient Deprivation.
AMPK is an energy sensor that protects cellular energy state by attenuating anabolic and promoting catabolic processes. AMPK signaling is purported to regulate hepatic gluconeogenesis and substrate oxidation; coordination of these processes is vital during nutrient deprivation or pathogenic during overnutrition. Here we directly test hepatic AMPK function in regulating metabolic fluxes that converge to produce glucose and energy in vivo. Flux analysis was applied in mice with a liver-specific deletion of AMPK (L-KO) or floxed control littermates to assess rates of hepatic glucose producing and citric acid cycle (CAC) fluxes. Fluxes were assessed in short and long term fasted mice; the latter condition is a nutrient stressor that increases liver AMP/ATP. The flux circuit connecting anaplerosis with gluconeogenesis from the CAC was unaffected by hepatic AMPK deletion in short and long term fasting. Nevertheless, depletion of hepatic ATP was exacerbated in L-KO mice, corresponding to a relative elevation in citrate synthase flux and accumulation of branched-chain amino acid-related metabolites. L-KO mice also had a physiological reduction in flux from glycogen to G6P. These results demonstrate AMPK is unnecessary for maintaining gluconeogenic flux from the CAC yet is critical for stabilizing liver energy state during nutrient deprivation.


The burden of rabies in Tanzania and its impact on local communities.
Rabies remains a major public health threat in many parts of the world and is responsible for an estimated 55,000 human deaths annually. The burden of rabies is estimated to be around US$20 million in Africa, with the highest financial expenditure being the cost of post-exposure prophylaxis (PEP). However, these calculations may be substantial underestimates because the costs to households of coping with endemic rabies have not been investigated. We therefore aimed to estimate the household costs, health-seeking behaviour, coping strategies, and outcomes of exposure to rabies in rural and urban communities in Tanzania. Extensive investigative interviews were used to estimate the incidence of human deaths and bite exposures. Questionnaires with bite victims and their families were used to investigate health-seeking behaviour and costs (medical and non-medical costs) associated with exposure to rabies. We calculated that an average patient in rural Tanzania, where most people live on less than US$1 per day, would need to spend over US$100 to complete WHO recommended PEP schedules. High costs and frequent shortages of PEP led to poor compliance with PEP regimens, delays in presentation to health facilities, and increased risk of death. The true costs of obtaining PEP were twice as high as those previously reported from Africa and should be considered in re-evaluations of the burden of rabies.


Sulindac inhibits beta-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients.
Sulindac reduces colorectal cancer risk in genetically susceptible humans and animals. The molecular mechanisms underlying these effects are incompletely understood. Many studies suggest an important role for induction of apoptosis involving the mitochondrial pathway and the death receptor pathway. Alternatively, mechanisms involving the APC-beta-catenin-Wnt pathway have been suggested, possibly mediated by p21. We determined the effects of sulindac on apoptosis and expression of death receptor (DR)-4 and DR5, beta-catenin, and p21 in normal-appearing colorectal epithelium. Biopsies were obtained before and after sulindac treatment during two chemoprevention studies. Patients (n = 18) with hereditary nonpolyposis colorectal cancer (HNPCC) received 150 mg sulindac bd for 4 weeks in a placebo-controlled crossover design. Patients (n = 6) with familial adenomatous polyposis (FAP) received 150 mg sulindac bd for 6 months. Apoptosis was assessed by M30 staining and expression patterns of DR4, DR5, beta-catenin, and p21 were studied immunohistochemically. In HNPCC patients, apoptotic indices were similar following placebo and sulindac. Also in FAP patients, apoptotic indices were not different after sulindac compared with pretreatment values. Expression of DR4 and DR5 was observed in all samples with no consistent differences between placebo/baseline and sulindac. Intensity of membranous beta-catenin staining was lower in HNPCC samples following sulindac compared with placebo (P < 0.001). Similar results were obtained in FAP samples (P < 0.01). p21 expressions before and after sulindac treatment were similar in both patient groups. In conclusion, sulindac inhibits beta-catenin expression in normal colorectal epithelium from HNPCC and FAP patients without affecting apoptotic indices and DR4, DR5, and p21 expression.


Prophage induction, but not production of phage particles, is required for lethal disease in a microbiome-replete murine model of enterohemorrhagic E. coli infection.
Enterohemorrhagic Escherichia coli (EHEC) colonize intestinal epithelium by generating characteristic attaching and effacing (AE) lesions. They are lysogenized by prophage that encode Shiga toxin 2 (Stx2), which is responsible for severe clinical manifestations. As a lysogen, prophage genes leading to lytic growth and stx2 expression are repressed, whereas induction of the bacterial SOS response in response to DNA damage leads to lytic phage growth and Stx2 production both in vitro and in germ-free or streptomycin-treated mice. Some commensal bacteria diminish prophage induction and concomitant Stx2 production in vitro, whereas it has been proposed that phage-susceptible commensals may amplify Stx2 production by facilitating successive cycles of infection in vivo. We tested the role of phage induction in both Stx production and lethal disease in microbiome-replete mice, using our mouse model encompassing the murine pathogen Citrobacter rodentium lysogenized with the Stx2-encoding phage Φstx2dact. This strain generates EHEC-like AE lesions on the murine intestine and causes lethal Stx-mediated disease. We found that lethal mouse infection did not require that Φstx2dact infect or lysogenize commensal bacteria. In addition, we detected circularized phage genomes, potentially in the early stage of replication, in feces of infected mice, confirming that prophage induction occurs during infection of microbiota-replete mice. Further, C. rodentium (Φstx2dact) mutants that do not respond to DNA damage or express stx produced neither high levels of Stx2 in vitro or lethal infection in vivo, confirming that SOS induction and concomitant expression of phage-encoded stx genes are required for disease. In contrast, C. rodentium (Φstx2dact) mutants incapable of prophage genome excision or of packaging phage genomes retained the ability to produce Stx in vitro, as well as to cause lethal disease in mice. Thus, in a microbiome-replete EHEC infection model, lytic induction of Stx-encoding prophage is essential for lethal disease, but actual phage production is not.


Preventive effects of Pueraria mirifica on bone loss in ovariectomized rats.
Effects of Pueraria mirifica on bone loss in fully mature ovariectomized rats are examined. Two series of experiments were performed. In the first series, rats were kept with their ovaries intact and divided into two groups; initial control (IC) and sham control (SH). The IC rats were sacrificed on day 1 and their data were kept as baseline control. The SH rats were subjected to sham operation on day 0 and gavaged daily with distilled water for 90 days. In the second series, rats were subjected to ovariectomy, divided into five groups and gavaged daily with 0.1mg/kg B.W./day of 17-alpha-ethinylestradiol (EE), 0, 10, 100 and 1000mg/kg B.W./day of P. mirifica (P0, P10, P100 and P1000, respectively) for 90 days. Changes of bone mineral density and bone mineral content were measured using peripheral Quantitative Computerized Tomography. Bone loss was significantly induced by ovariectomy and it was dose-dependently prevented by P. mirifica treatment for 90 days. The preventive effects of P. mirifica on bone loss depended on bone types (axial or long bone), bone sites (metaphysis or diaphysis), and bone compartments (trabecular and cortical). At P100 and P1000, bone loss was completely prevented both in trabecular bone mineral density and content. The effects of P. mirifica were, as expected, comparable to that in the EE group. These results suggest that P. mirifica may be applicable to treat the osteoporosis in menopausal women; however, an undesirable side effect on stimulating reproductive organs should be concerned.


Estimating improvement in prediction with matched case-control designs.
When an existing risk prediction model is not sufficiently predictive, additional variables are sought for inclusion in the model. This paper addresses study designs to evaluate the improvement in prediction performance that is gained by adding a new predictor to a risk prediction model. We consider studies that measure the new predictor in a case-control subset of the study cohort, a practice that is common in biomarker research. We ask if matching controls to cases in regards to baseline predictors improves efficiency. A variety of measures of prediction performance are studied. We find through simulation studies that matching improves the efficiency with which most measures are estimated, but can reduce efficiency for some. Efficiency gains are less when more controls per case are included in the study. A method that models the distribution of the new predictor in controls appears to improve estimation efficiency considerably.


Major phytochemicals in apple cultivars: contribution to peroxyl radical trapping efficiency.
Forty-one samples of apples (peel plus pulp), obtained from eight cultivars, were examined for concentration of some important phytochemicals and for antioxidant activity expressed as peroxyl radical trapping efficiency. Five major polyphenolic groups plus ascorbate were identified and quantified by HPLC in the apple varieties. Oligomeric and polymeric proanthocyanidins were found to be about two-thirds of total polyphenols. The antioxidant efficiency of the apple extracts and of representative pure compounds for each group of phytochemicals was measured in a micellar system mimicking lipid peroxidation in human plasma. Although the amount of polyphenols measured by HPLC is similar to that measured by standard methods, the antioxidant efficiency calculated on the basis of the contribution of the pure compounds was lower than the antioxidant efficiency of the apple extracts. The higher efficiency of apples appears to be strictly related to the overwhelming presence of oligomeric proanthocyanidins.


[Treatment of gastroduodenal ulcer hemorrhages].
The results of treatment of 901 patients with acute ulcerogenic gastroduodenal bleedings in 1986 to 1997 are analysed. The tactics of the treatment, developed in the clinic, combines active diagnostic and curative measures with differentiated determination of the indications for urgent operative treatment. Improvements of the method for urgent operative treatment, wide implementation of the organ-saving and mini-invasive surgical procedures, usage of new methods for nonoperative (endoscopical) hemostasis, as well as an improvement of the complex for intensive and anti-ulcerogenic therapy enabled in the last group of patients (1994-1997 years) to decrease the postoperative lethality up to 5.9%, and general lethality--to 6.4%.


Experiences with a training DSW knowledge model for early-stage researchers.
Background: Data management is fast becoming an essential part of scientific practice, driven by open science and FAIR (findable, accessible, interoperable, and reusable) data sharing requirements. Whilst data management plans (DMPs) are clear to data management experts and data stewards, understandings of their purpose and creation are often obscure to the producers of the data, which in academic environments are often PhD students. Methods: Within the RNAct EU Horizon 2020 ITN project, we engaged the 10 RNAct early-stage researchers (ESRs) in a training project aimed at formulating a DMP. To do so, we used the Data Stewardship Wizard (DSW) framework and modified the existing Life Sciences Knowledge Model into a simplified version aimed at training young scientists, with computational or experimental backgrounds, in core data management principles. We collected feedback from the ESRs during this exercise. Results: Here, we introduce our new life-sciences training DMP template for young scientists. We report and discuss our experiences as principal investigators (PIs) and ESRs during this project and address the typical difficulties that are encountered in developing and understanding a DMP. Conclusions: We found that the DS-wizard can also be an appropriate tool for DMP training, to get terminology and concepts across to researchers. A full training in addition requires an upstream step to present basic DMP concepts and a downstream step to publish a dataset in a (public) repository. Overall, the DS-Wizard tool was essential for our DMP training and we hope our efforts can be used in other projects.


Immunomodulatory effect of plasmids co-expressing cytokines in classical swine fever virus subunit gp55/E2-DNA vaccination.
The aim of this study was to determine the immunomodulatory effects of IL-12, IL-18 and CD154 (CD40 ligand, CD40L) in DNA-vaccination against the classical swine fever virus. Four recombinant plasmids were constructed including the CSFV coding region for the glycoprotein gp55/E2 alone or together with porcine IL-12, IL-18 or CD154 genes. Five groups of four pigs each were immunized intramuscularly (i.m.) three times with the respective constructs. The control group was inoculated with empty plasmid DNA. Eighteen days after the final immunization, the pigs were challenged with a lethal dose of CSFV strain Eystrup and monitored for a further 16 days. This study showed that co-delivery of IL-18 and CD154 induced an earlier appearance of serum antibodies, reduced B-cell deficiency after infection and protected pigs against a lethal CSFV infection. In contrast, co-delivery of IL-12 led to a reduced titer of neutralizing antibodies and protection against a lethal CSFV challenge in comparison to the other pigs and to pigs that were immunized with a gp55/E2 plasmid alone.


"Protected Means Armed": Perspectives on Pre-Exposure Prophylaxis (PrEP) Among Women Who Engage in Sex Work and Use Drugs in Kazakhstan.
Pre-exposure prophylaxis (PrEP) for HIV prevention has recently become available in Kazakhstan, but women engaged in sex work who use drugs (WESW-UD) could benefit from tailored approaches to support uptake and adherence. To better understand how best to support WESW-UD at each stage of the PrEP continuum (awareness, acceptability, uptake, and adherence), we analyzed data from 30 in-depth interviews and four focus groups with 48 WESW-UD from two cities in Kazakhstan. We conducted thematic analysis to characterize perceptions, barriers, and motivators within each step of the PrEP continuum. Participants reported low awareness, but high interest in PrEP. Motivating factors included optimizing health and increased confidence. Participants expressed many preferences and concerns regarding PrEP modality and delivery. Participants also described how organizational mistrust and social support can prevent or facilitate PrEP uptake or adherence. Kazakhstan's scale-up of PrEP should consider the needs and preferences of WESW-UD to ensure equitable access.


Nanoscale light-matter interactions in metal-organic frameworks cladding optical fibers.
The utilization of refractive index (RI) change due to guest-host interactions between the guest volatile organic compound vapor and porous metal-organic frameworks (vapor-MOF interactions) is promising in photonic vapor sensors. Therefore, the study of light-matter interactions in nanoporous metal-organic frameworks (MOFs) is fundamental and essential for MOF-based photonic devices. In this work, the manipulation of light in MOFs to investigate the vapor-MOF interactions by using optical fiber devices is demonstrated. The vapor-MOF interactions and the light-vapor interactions (light in MOFs to sense the RI changes resulting from the vapor-MOF interactions) are investigated. The cladding mode is excited by a long-period fiber grating (LPFG) for evanescent field sensing in a ZIF-8 sensitive coating. The experimental results combining quantum chemical calculations and optical simulations reveal the relationships between the microscopic energy of vapor desorption, RI changes and evanescent field enhancement in ZIF-8 during the vapor-MOF interactions. With exceptionally large RI changes, the evanescent field of cladding mode in ZIF-8 is greatly enhanced to sense the vapor-MOF interactions. As a proof-of-concept, a LPFG sensor with ZIF-8 coating showed a high sensitivity of 1.33 pm ppm-1 in the linear range from 9.8 ppm to 540 ppm for the sensing of ethanol vapor. The investigation of light-matter interactions in ZIF-8 provides a useful guideline for the design and fabrication of MOF-based optical waveguide/fiber sensors.


Reflections on sex research among young Bedouin in Jordan: risks and limitations.
Research about sexuality is characterised by silences and invisibilities. This is particularly evident in some Islamic Arab societies where discussion of sexuality in general is not encouraged and practices such as homosexuality or pre-marital sex are not acknowledged. This creates a barrier to carrying out sex research and also means that much of the research-based knowledge and methodologies developed in a Western setting may have limited applicability. This paper uses research recently carried out among Bedouin young women in Jordan to examine these limitations and the extent to which research approaches and findings from relatively liberal Western cultures are appropriate and relevant. Following a description of the cultural context in which the study took place, the paper identifies potential risks of conducting sex research in this setting and the research limitations related to this risk. Finally, it addresses the question of whether doing sex research has any value given these restrictions.


Bayesian mixture models for partially verified data: age- and stage-specific discriminatory power of an antibody ELISA for paratuberculosis.
Bayesian mixture models can be used to discriminate between the distributions of continuous test responses for different infection stages. These models are particularly useful in case of chronic infections with a long latent period, like Mycobacterium avium subsp. paratuberculosis (MAP) infection, where a perfect reference test does not exist. However, their discriminatory ability diminishes with increasing overlap of the distributions and with increasing number of latent infection stages to be discriminated. We provide a method that uses partially verified data, with known infection status for some individuals, in order to minimize this loss in the discriminatory power. The distribution of the continuous antibody response against MAP has been obtained for healthy, MAP-infected and MAP-infectious cows of different age groups. The overall power of the milk-ELISA to discriminate between healthy and MAP-infected cows was extremely poor but was high between healthy and MAP-infectious. The discriminatory ability increased with increasing age. The great overlap between the distributions of the different infection stages would have hampered our ability to discriminate between the different infection stages. Thus, the proposed method, which uses partially verified data on the true status for some individuals, is an intuitive extension to the standard non-gold standard methods, especially in the case of infections with a long latent period.


The effect of diets on milk production and composition, and on lactation curves in pastured dairy goats.
A 2-yr study investigated effects of different levels of concentrate supplementation on milk production, composition, and lactation curves in pastured dairy goats. For both years, 44 Alpine goats (Capra hircus; 55 +/- 11 kg body weight) were randomly allocated to 4 groups. Animals were supplemented with 0.66 (treatments A and B), 0.33 (treatment C), or 0 kg of concentrate (treatment D) per kg of milk over 1.5 kg/d. Mixed vegetative forages were rotationally grazed by the goats (treatments B, C, and D), except that treatment A was confined and fed alfalfa hay. Individual milk production was recorded daily, and milk samples were collected once every 2 wk for the 7-mo period (March to September) and analyzed for fat, protein, lactose, urea-N, nonesterified fatty acids, and allantoin (second year only). Milk yield and composition varied among dietary treatments, with some measures affected by year. Average daily milk yield was lowest for treatment D. The increased level of concentrate supplementation in treatment A led to 22% greater milk yield compared with treatment D. Milk production increased by 1.7 and 0.9 kg for each additional kilogram of concentrate fed per day during the first and second years, respectively. Average peak yield, time of peak yield, and persistency were lower for treatment D than for other treatments. The percentage of milk fat was lower for treatment D than for other treatments. Concentration of milk protein was greater for treatments A and B during the first year, and was higher for treatment C than for other treatments during the second year. Average milk lactose concentration was higher for treatments B and C than for other treatments. However, milk urea-N concentration in treatment A was higher than other treatments. Milk allantoin, used to estimate microbial proteins synthesis, was 20 to 25% greater for treatment A than for other treatments. Averaged across year, plasma urea-N and nonesterified fatty acids concentration were lowest for treatment B. Average organic matter intake was similar among treatments during both years. Ratios of acetate and propionate concentrations for treatment A were lowest among treatments. In conclusion, milk production and composition were affected by the feeding treatment and year. Increased level of nutrition lead to an increase in daily milk yield, peak yield, time of peak yield, and persistency compared with treatment D. Alpine dairy goats grazing on fresh forages without concentrate supplementation can produce milk inexpensively, and response to concentrate supplementation is greater for low quality pasture.


Review of cyclosporine immunosuppressive safety data in dermatology patients after two decades of use.
Cyclosporine is an immunosuppressive agent that has been shown to be effective in the treatment of psoriasis. However, its serious side effects in transplant patients have hindered many dermatologists from exploiting its therapeutic capabilities. The literature contains reports of lymphomas, internal malignancies, skin cancers, and serious infections in psoriasis patients on cyclosporine therapy. However, no study has evaluated the relative risk of these side effects in relation to the general population, nor monitored the patients for years after cyclosporine was discontinued. The recently published 5-year cohort study is the most rigorous data to date on the long-term safety of cyclosporine and shows no increased risk of lymphoma or internal malignancies. The study, however, illustrates increased risk of non-melanoma skin cancers, especially squamous cell carcinoma. Review of the literature does not suggest any increased risk of opportunistic infections or tuberculosis reactivation. These data suggest that cyclosporine in dermatologic dosage (3-5 mg/kg/d) is safe and dermatologists may consider using it.


Inflammation-dependent changes in alpha2,3-, alpha2,6-, and alpha2,8-sialic acid glycotopes on serum glycoproteins in mice.
The expression of acute-phase serum proteins increases in response to inflammatory stimuli. Most of these proteins are glycoproteins that often contain sialic acids (Sia). It is unknown, however, how the expression of Sia in these glycoproteins changes during inflammation. This study demonstrates changes in the alpha2,3-, alpha2,6-, and alpha2,8-Sia glycotopes on serum glycoproteins in response to turpentine oil-induced inflammation, based on lectin- and immunoblot analyses by using sialyl linkage-specific lectins, Maackia amurensis for the alpha2,3-Sia glycotope and Sambucus sieboldiana for the alpha2,6-Sia glycotopes, and monoclonal antibody 2-4B (mAb.2-4B) recognizing the di- and oligomers of the alpha2,8-Neu5Gc residue. There was an increase in a limited number of sialoglycoproteins containing the alpha2,3-, alpha2,6-, or alpha2,8-Sia glycotopes. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression profiles of mRNAs for the known sialyltransferases in mouse liver during inflammation indicated the up-regulated expression of beta-galactoside alpha2,3-sialyltransferases (ST3Gal I and ST3Gal III) and beta-N-acetylgalactosaminide alpha2,6-sialyltransferase (ST6GalNAc VI) as well as beta-galactoside alpha2,6-sialyltransferase (ST6Gal I) mRNAs. Notably, ST3Gal I and III and ST6GalNAc VI are involved in the synthesis of the alpha2,3- and alpha2,6-Sia glycotopes on O-glycan chains and possibly on gangliosides, whereas ST6Gal I is specific for N-glycan chains. These results provide evidence for the inflammation-induced expression of sialyl glycotopes in serum glycoproteins. We demonstrated that inflammation significantly increased the expression of an unknown 32-kDa glycoprotein containing the alpha2,8-Sia glycotope. The mechanism for the increase in glycoprotein in inflamed mouse serum remains to be examined, as mRNA expression for all of the alpha2,8-sialyltransferases (ST8Sia I-VI) was unchanged during inflammation.


A conceptual model using CliftonStrengths® to support dental hygiene students' professional development.
Professional development is instrumental in the ongoing success of healthcare professionals and students. The purpose of the second year of this 2-year study was to continue to apply the results from the CliftonStrengths® assessment to support entry-level dental hygiene students' professional development and to create a conceptual model for professional development in dental hygiene education. CliftonStrengths® was incorporated into didactic and community learning experiences throughout year two of the dental hygiene curriculum. At the end of year two, focus group interviews assessed student perceptions of professional strengths based on these learning experiences. Co-investigators used a qualitative analysis software program to identify codes and themes. Investigator triangulation and member checks were used to validate responses. All second-year dental hygiene students (n = 32) participated in year two of the study. Two themes were identified: relevance of CliftonStrengths® and professional development. Within the theme of relevance, the subthemes of adaptability, making connections and teamwork emerged. The theme of professional development yielded three subthemes: appreciation, personal and professional identity and insight. This study demonstrated CliftonStrengths® can be used to promote professional development among dental hygiene students. As a result, a conceptual model was developed for professional development in dental hygiene education. This model can be used as a framework for teaching and to improve student learning experiences.


β-Catenin serves as a clutch between low and high intercellular E-cadherin bond strengths.
A wide range of invasive pathological outcomes originate from the loss of epithelial phenotype and involve either loss of function or downregulation of transmembrane adhesive receptor complexes, including Ecadherin (Ecad) and binding partners β-catenin and α-catenin at adherens junctions. Cellular pathways regulating wild-type β-catenin level, or direct mutations in β-catenin that affect the turnover of the protein have been shown to contribute to cancer development, through induction of uncontrolled proliferation of transformed tumor cells, particularly in colon cancer. Using single-molecule force spectroscopy, we show that depletion of β-catenin or the prominent cancer-related S45 deletion mutation in β-catenin present in human colon cancers both weaken tumor intercellular Ecad/Ecad bond strength and diminishes the capacity of specific extracellular matrix proteins-including collagen I, collagen IV, and laminin V-to modulate intercellular Ecad/Ecad bond strength through α-catenin and the kinase activity of glycogen synthase kinase 3 (GSK-3β). Thus, in addition to regulating tumor cell proliferation, cancer-related mutations in β-catenin can influence tumor progression by weakening the adhesion of tumor cells to one another through reduced individual Ecad/Ecad bond strength and cellular adhesion to specific components of the extracellular matrix and the basement membrane.


Hitchhiking women's hair color.
To test the effect of women's hair color on the frequency of offering help, male (n = 1,508) and female (n = 892) French motorists were tested in a hitchhiking situation. Five 20- to 22- yr.-old female confederates wore a wig with blonde, brown, or black hair. Each confederate was instructed to stand by the side of a road frequented by hitchhikers and hold out her thumb to catch a ride. Blonde hair, compared with brown hair or black hair, was associated with a small but significantly larger number of male drivers who stopped to offer a ride (18 vs 14%). No difference was found for those with brown and black hair (14 and 13%, respectively). No effect of hair color was found for female drivers who stopped. The greater attractiveness associated with blonde hair for women appears to explain these data.


Effectiveness of percutaneous adhesiolysis with hypertonic saline neurolysis in refractory spinal stenosis.
The increasing proportion of elderly patients, coupled with increasing longevity, causes the problem of lumbosacral pain secondary to spinal stenosis of the lumbar spine to be an important issue. Symptoms of spinal stenosis are caused by entrapment and compression of intraspinal vascular and nervous structures; which may lead to inactivity, loss of productivity, and potential loss of independence, particularly in the elderly. Surgical decompression is considered as the natural treatment. However, the results of surgical treatments have been mixed. Results of conservative treatment are also not encouraging. While the effectiveness of caudal epidural blocks for lumbar canal stenosis was positive, the effectiveness of interlaminar epidural steroid injections showed no beneficial effects on symptomatology of spinal stenosis. Percutaneous epidural adhesiolysis with hypertonic saline neurolysis has been studied in patients with refractory low back pain secondary to post lumbar laminectomy syndrome, as well as spinal stenosis. The specific role of adhesiolysis and hypertonic saline neurolysis in the management of refractory low back and lower extremity pain secondary to spinal stenosis has not been studied. This retrospective evaluation included 18 patients derived from a total sample of 239 patients undergoing adhesiolysis and hypertonic saline neurolysis over a period of 3 years. The results showed significant improvement with reduction of pain; with improvement of physical health, mental health, and functional status. Improvement in psychological status was also noted, with decrease in narcotic intake. Epidural adhesiolysis with hypertonic saline neurolysis is a safe and probably effective modality of treatment in managing symptomatic moderate to severe lumbar spinal canal stenosis.


First insights into the structural features of Ebola virus methyltransferase activities.
The Ebola virus is a deadly human pathogen responsible for several outbreaks in Africa. Its genome encodes the 'large' L protein, an essential enzyme that has polymerase, capping and methyltransferase activities. The methyltransferase activity leads to RNA co-transcriptional modifications at the N7 position of the cap structure and at the 2'-O position of the first transcribed nucleotide. Unlike other Mononegavirales viruses, the Ebola virus methyltransferase also catalyses 2'-O-methylation of adenosines located within the RNA sequences. Herein, we report the crystal structure at 1.8 Å resolution of the Ebola virus methyltransferase domain bound to a fragment of a camelid single-chain antibody. We identified structural determinants and key amino acids specifically involved in the internal adenosine-2'-O-methylation from cap-related methylations. These results provide the first high resolution structure of an ebolavirus L protein domain, and the framework to investigate the effects of epitranscriptomic modifications and to design possible antiviral drugs against the Filoviridae family.


Differentiation in additive and multiplicative inputs to motoneuron pool as origins of spasticity - a neuromorphic modeling study.
Spasticity is characterized by a velocity-dependent increase in the tonic stretch reflex. Evidence suggests that spasticity originates from hyperactivity in the descending tract or reflex loop. To pinpoint the source of hyperactivity, however, is difficult due to lack of human data in-vivo. Thus, we implemented a neuromorphic model to revive the neurodynamics with spiking neuronal activity. Two types of input were modeled: (1) the additive condition (ADD) to apply tonic synaptic inputs directly into the reflex loop; (2) the multiplicative (MUL) condition to adjust the loop gains within the reflex loop. Results show that both conditions produced antagonist EMG responses resembling patient data. The timing of spasticity is more sensitive to the ADD condition, whereas the amplitude of spastic EMG is more sensitive to the MUL condition. In conclusion, our model shows that both additive and multiplicative hyperactivities suffice to elicit velocity-dependent spastic electromyographic signals (EMG), but with different sensitivities. This simulation study suggests that spasticity caused by different origins may be discernable by the progression of severity, which may help individualized goalsetting and parameter-selection in rehabilitation.Clinical Relevance-Potential application of neuromorphic modeling on spasticity includes selection of parameters for therapeutic plans, such as movement range, repetition, and load.


Mechanism of "hypoglycemic" cataract formation in the rat lens. II. Further studies on the role of hexokinase instability.
In Part I1 of this study, the thermolability of lens hexokinase was implicated in the development of an experimental "hypoglycemic" cataract. After eight hours of glucose deprivation, there is a precipitous loss of lens hexokinase. This occurs approximately nine hours prior to the disorganization of the other enzymatic steps in glycolysis. Epithelial hexokinase, as an immediate response to glucose deficiency, shifts from the soluble to the insoluble phase. There is no such shift in the cortex-nucleus where only soluble hexokinase is found. After eight hours of glucose deprivation, both soluble and insoluble hexokinases throughout the lens undergo rapid deactivations. During the first eight hours of glucose deprivation the loss of lenticular ATP and K+ and the gain in wet weight can be reversed by restoring normal glucose levels; beyond eight hours the changes are irreversible. During the period of reversibility, hexokinase activity levels are normal; during the period of irreversibility hexokinase activity is 10 to 20 per cent of normal. Of the substances tested (mannose, galactose, fructose, glutamine, adenosine) only mannose could sustain the lens in the absnece of glucose. Neither endogenous free glucose nor glycogen could sustain the lens in the face of glucose deprivation. There appear to be no alternative exogenous or endogenous energy yielding substrates. The younger the animal, the more susceptible is its lens to glucose deprivation. This most certainly is a reflection of the increased susceptibility of younger lenses to osmotic stress, since lenses in each age group manifested similar changes in hexokinase activity, ATP, Na+, and K+ level.


Overexpression of HMGB1 in hepatocytes accelerates PTEN inactivation-induced liver cancer.
Liver cancer is increasing due to the rise in metabolic dysfunction-associated steatohepatitis (MASH). High-mobility group box-1 (HMGB1) is involved in the pathogenesis of chronic liver disease, but its role in MASH-associated liver cancer is unknown. We hypothesized that an increase in hepatocyte-derived HMGB1 in a mouse model of inactivation of PTEN that causes MASH could promote MASH-induced tumorigenesis. We analyzed publicly available transcriptomics datasets, and to explore the effect of overexpressing HMGB1 in cancer progression, we injected 1.5-month-old Pten∆Hep mice with adeno-associated virus serotype-8 (AAV8) vectors to overexpress HMGB1-EGFP or EGFP, and sacrificed them at 3, 9 and 11 months of age. We found that HMGB1 mRNA increases in human MASH and MASH-induced hepatocellular carcinoma (MASH-HCC) compared to healthy livers. Male and female Pten∆Hep mice overexpressing HMGB1 showed accelerated liver tumor development at 9 and 11 months, respectively, with increased tumor size and volume, compared to control Pten∆Hep mice. Moreover, Pten∆Hep mice overexpressing HMGB1, had increased incidence of mixed HCC-intrahepatic cholangiocarcinoma (iCCA). All iCCAs were positive for nuclear YAP and SOX9. Male Pten∆Hep mice overexpressing HMGB1 showed increased cell proliferation and F4/80+ cells at 3 and 9 months. Overexpression of HMGB1 in hepatocytes accelerates liver tumorigenesis in Pten∆Hep mice, enhancing cell proliferation and F4/80+ cells to drive MASH-induced liver cancer.


[Features of the organization of occupational therapy in the complex treatment of patients with severe degrees of mental retardation].
A clinical and experimental study of two groups of patients with idiopathic oligophrenia in the stages of idiocy and deep imbecility bordering on idiocy (48 adults aged 23-35 years and 14 boys aged 12-16 years with different terms of total hospitalization) has shown the possibility of changing behavioural reactions of the patients. Stable occupational skills for performing two kinds of elementary work (preparation of half-finished cardboard boxes and assembling of panels) have been cultivated in the patients. The methods for the organization of labor therapy for patients suffering from erectile and torpid forms of this disease have been elaborated. The data suggest that it is possible to develop purposeful forms of behaviour in patients of this group. Comparison of two different age groups shows the necessity of the earliest possible employment of labor therapy in the combined treatment aimed at correcting the psychomotor defects.