Upregulation of p75 tumor necrosis factor alpha receptor in Mycobacterium avium-infected mice: evidence for a functional role.
The bacterial growth and the production of tumor necrosis factor alpha (TNF-alpha) and TNF receptors (TNF-Rs) in the spleen and blood of BALB/c mice challenged with Mycobacterium avium complex (MAC) were monitored. Infection developed in two phases: the first, up to day 21, was associated with rapid MAC multiplication in the spleen and a drop in the mycobacteremia, and the second was associated with control of the infection in both compartments. In the spleen, TNF-alpha and TNF-RII mRNA levels peaked on day 21 and then slowly decreased; however, no increase in the level of TNF-RI mRNA was observed throughout these experiments. The level of circulating soluble TNF-RII (sTNF-RII) was transiently increased after day 21. In a model in which overproduction of bioactive TNF-alpha was triggered in response to a second infection with MAC, an increased production of sTNF-RII by cultured splenocytes was also observed. Administration of an antagonist anti-TNF-RII monoclonal antibody (MAb 6G1) to infected mice inhibited the bacterial growth in the spleen, suggesting that the TNF-RII and/or sTNF-RII was functionally involved in the mechanisms that control the infection. Overall, these observations suggest that upregulation of TNF-RII or sTNF-RII contributes to modulation of the TNF-alpha antibacterial activity in MAC infections.


Influence of apparently negative personality characteristics on the long-term outcome of health anxiety: Secondary analysis of a randomized controlled trial.
It is known that personality has an influence on the outcome of mental state disorders, but detailed studies on its long-term impact are few. We examined the influence of personality status on the 8-year outcome of health anxiety and its relationship to the effects of cognitive behaviour therapy in a randomized controlled trial. This study aims to examine both the usefulness of the diagnosis of personality disorder and an additional measure of pathological dependence, in predicting the outcome of medical patients with health anxiety treated with cognitive behaviour therapy. Because the influence of personality is often shown in the long term, these assessments covered the period of 8 years after randomization. An additional aim is to examine the costs of different levels of personality dysfunction in each treatment group. Personality dysfunction, using both ICD-10 and ICD-11 classifications of severity, was assessed at baseline by interview in a randomized controlled trial. Patients were also assessed for pathological dependence using the Dependent Personality Questionnaire, also scored along a severity dimension. Four hundred forty-four patients from medical clinics with pathological health anxiety were treated with a modified form of cognitive behaviour therapy for health anxiety (CBT-HA) or standard care. Total costs over follow-up were calculated from hospital data and compared by personality group. At baseline, 381 (86%) had some personality dysfunction, mainly at the lower level of personality difficulty (not formally a disorder). One hundred eighty four (41%) had a personality disorder. A similar proportion was found with regard to dependent personality. Using the ICD-10 classification, 153 patients (34.6%) had a personality disorder, with 83 (54.2%) having anxious or dependent personality disorder, 20 (13.1%) having an anankastic disorder, but also with 66 (43.1%) having mixed disorder. During initial treatment, those with personality disorder adhered more closely to CBT-HA, and after 8 years, they had a significantly better outcome than those with personality difficulty and no personality disorder (p < 0.002). Similar results were found in those scoring high on the Dependent Personality Questionnaire. All these differences increased over the follow-up period. Costs were similar in all groups but were somewhat higher in the CBT-HA one; this finding is hypothesised to be due to fuller hospital treatment once health anxiety is discounted. Personality disorder in people with health anxiety, particularly in those who have anxious and dependent traits, reinforces the benefits of cognitive behaviour therapy, particularly in the longer term. © 2020 The Authors Personality and Mental Health Published by John Wiley & Sons Ltd.


Tandem repeats finder: a program to analyze DNA sequences.
A tandem repeat in DNA is two or more contiguous, approximate copies of a pattern of nucleotides. Tandem repeats have been shown to cause human disease, may play a variety of regulatory and evolutionary roles and are important laboratory and analytic tools. Extensive knowledge about pattern size, copy number, mutational history, etc. for tandem repeats has been limited by the inability to easily detect them in genomic sequence data. In this paper, we present a new algorithm for finding tandem repeats which works without the need to specify either the pattern or pattern size. We model tandem repeats by percent identity and frequency of indels between adjacent pattern copies and use statistically based recognition criteria. We demonstrate the algorithm's speed and its ability to detect tandem repeats that have undergone extensive mutational change by analyzing four sequences: the human frataxin gene, the human beta T cellreceptor locus sequence and two yeast chromosomes. These sequences range in size from 3 kb up to 700 kb. A World Wide Web server interface atc3.biomath.mssm.edu/trf.html has been established for automated use of the program.


Conditional risk factors for atherosclerosis.
Although most patients who experience a coronary heart disease (CHD) event have one or more of the conventional risk factors for atherosclerosis, so do many people who have not yet experienced such an event. Therefore, predictive models based on conventional risk factors have a lower than desired accuracy, providing a stimulus to search for new tools to refine CHD risk prediction. In particular, there is intense interest in evaluating circulating biomarkers related to the atherosclerotic process that might add to our ability to better predict CHD risk. One such group of biomarkers was termed conditional risk factors in an American Heart Association/American College of Cardiology statement in 1999. The conditional risk factors include homocysteine, fibrinogen, lipoprotein(a), low-density lipoprotein particle size, and C-reactive protein. This review updates the conditional risk factors. The main focus is on the potential utility of these risk factors, which are currently available to clinicians, in the prediction of CHD risk in asymptomatic persons. The putative mechanisms of risk, available assays, evidence for association with CHD, and the clinical implications thereof are discussed for each of the risk factors.


Loss of interaction between plectin and type XVII collagen results in epidermolysis bullosa simplex.
Plectin is a linker protein that interacts with intermediate filaments and β4 integrin in hemidesmosomes of the epidermal basement membrane zone (BMZ). Type XVII collagen (COL17) has been suggested as another candidate plectin binding partner in hemidesmosomes. Here, we demonstrate that plectin-COL17 binding helps to maintain epidermal BMZ organization. We identified an epidermolysis bullosa (EB) simplex patient as having markedly diminished expression of plectin and COL17 in skin. The patient is compound heterozygous for sequence variants in the plectin gene (PLEC); one is a truncation and the other is a small in-frame deletion sequence variant. The in-frame deletion is located in the putative COL17-binding domain of plectin and abolishes the plectin-COL17 interaction in vitro. These results imply that disrupted interaction between plectin and COL17 is involved in the development of EB. Our study suggests that protein-protein binding defects may underlie EB in patients with unidentified disease-causing sequence variants.


The effect of combined calcium and vitamin D3 supplementation on serum intact parathyroid hormone in moderate CKD.
Studies addressing the effects of vitamin D(3) supplementation on secondary hyperparathyroidism in patients with moderate chronic kidney disease are scarce. Post hoc analysis of the randomized clinical trial Vitamin D, Calcium, Lyon Study II (DECALYOS II) to assess effects according to baseline estimated glomerular filtration rate (eGFR). Multicenter, randomized, double-blinded, placebo-controlled study of 639 elderly women randomly assigned to calcium-vitamin D(3) fixed combination; calcium plus vitamin D(3) separate combination, or placebo. Placebo or calcium (1,200 mg) and vitamin D(3) (800 IU) in fixed or separate combination. Proportion of participants with a mean decrease in intact parathyroid hormone (iPTH) level of 30% or greater. eGFR was calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation and categorized as 60 or greater, 45 to 59, and less than 45 mL/min/1.73 m(2). 610 participants had an eGFR at baseline: 288 (47.2%), 222 (36.4%), and 100 (16.4%) were in each decreasing eGFR category. Across decreasing eGFR groups, 88%, 86%, and 89% had 25-hydroxyvitamin D (25[OH]D) levels less than 15 ng/mL at baseline. On treatment, similar improvements in the proportion of participants achieving 25(OH)D levels greater than 30 ng/mL at 6 months were seen in all kidney function groups (43%, 49%, and 41%, respectively). Active regimens versus placebo increased mean 25(OH)D levels from baseline in all eGFR groups at all times (P < 0.001 for all). The proportion with a 30% or greater decrease in iPTH level at 6 months was 50% in all eGFR groups on treatment versus 6% to 9% for placebo (P < 0.001 for all). The effects of the intervention on iPTH levels did not differ according to baseline eGFR (interaction P > 0.1 for all times). This study included only elderly white women. Vitamin D(3) was effective in increasing 25(OH)D and decreasing iPTH levels in patients with moderate chronic kidney disease.


Binding of ouabain and human ouabainlike substance to different Na+, K+-ATPase isoforms.
There is very little on the affinity of the human immunoreactive ouabainlike substance (OLS) to individual alpha-isoforms of Na+,K+-ATPase. The present study addresses this issue by comparing ouabain and OLS binding to dog kidney alpha1, rabbit kidney alpha1 and porcine cerebral cortex alpha3 Na+,K+-ATPase. OLS was initially isolated by solid phase extraction from human serum using C18 columns. The extract was further purified by reverse phase HPLC in an acetonitrile/water (containing 0.1% TFA) step-up gradient (16-80%). In this system, two distinct ouabain immunoreactive peaks were resolved. Peak I demonstrated a polarity identical with that of authentic ouabain. In contrast, peak II was relatively non-polar and eluted later in the run. The final step in the purification of OLS involved immuno-affinity chromatography of peak I using a specific sepharose immobilized mouse monoclonal anti-ouabain antiserum. Dose response curves (range 0-100 nmol/l) for ouabain with canine alpha1 and porcine alpha3 Na+,K+-ATPase showed similar inhibitory profiles (IC50=15 nmol/l), whilst rabbit alpha1 Na+,K+-ATPase was relatively insensitive to ouabain and purified peak I OLS. Two fold serial dilution of Peak I OLS, with subsequent analysis by canine and porcine Na+,K+-ATPase inhibition assays and RIA, demonstrated strong positive correlations between OLS determined by RIA and both canine (y=0.945x-2.532, r2=0.977) and porcine (y=0.428x-1.685; r2=0.993) Na+,K+-ATPase assays. The difference in the respective slopes suggests, however, that peak I OLS has a greater affinity for the canine derived enzyme compared to the porcine. In conclusion, these data suggest that like authentic ouabain, peak I OLS is a-isoform and species selective.


Home or away? Choosing a setting for a falls-prevention program for people with multiple sclerosis.
Evidence suggests that choice of setting may be important in influencing the outcomes of rehabilitation programs, as well as optimizing participant satisfaction and adherence. This article aims to examine the factors that may inform the choice of setting for a falls-prevention program tailored to the needs of people with multiple sclerosis, including the influence of setting on program effectiveness, participant engagement, cost, and sustainability. Any new program should ensure that the choice of setting is informed by the intended program outcomes as well as an awareness of the opportunities and challenges presented by each type of setting. Evaluations of falls programs for older people suggest that immediate outcomes are similar regardless of setting; however, long-term outcomes may differ by setting, possibly owing to differential effects on adherence. Programs based away from home may offer benefits in terms of maintaining motivation, providing peer-support opportunities, and allowing regular access to facilitator input, while home-based programs offer unique opportunities for context-based practice and the integration of falls-prevention activities into real life. Additionally, home-based programs may address some of the long-term feasibility issues associated with programs away from home. A "mixed" program incorporating elements of home- and community-based activity may be the most sustainable and effective choice to achieve both long- and short-term goals within a falls-prevention program. However, currently there are significant gaps in knowledge relating to comparative program outcomes, cost, and long-term sustainability.


Vocalizations of toddlers with cleft lip and palate.
This study examined the early vocalizations of toddlers with cleft lip and palate. Ten toddlers, ranging in age from 12 to 14 months, served as subjects: five toddlers with cleft lip and palate and five noncleft toddlers. Samples of the toddler's spontaneous vocalizations were obtained while they interacted with their mothers during an unstructured play session. All speech-like vocalizations were transcribed, and comparisons were made between the cleft and noncleft groups for (1) size of consonant inventory, (2) type and frequency of occurrence of consonants, and (3) frequency and type of multisyllabic productions. Results indicated differences in the consonant inventories and multisyllabic productions of the two groups of toddlers.


Wear-Time Compliance with a Dual-Accelerometer System for Capturing 24-h Behavioural Profiles in Children and Adults.
To advance the field of time-use epidemiology, a tool capable of monitoring 24 h movement behaviours including sleep, physical activity, and sedentary behaviour is needed. This study explores compliance with a novel dual-accelerometer system for capturing 24 h movement patterns in two free-living samples of children and adults. A total of 103 children aged 8 years and 83 adults aged 20-60 years were recruited. Using a combination of medical dressing and purpose-built foam pouches, participants were fitted with two Axivity AX3 accelerometers—one to the thigh and the other to the lower back—for seven 24 h periods. AX3 accelerometers contain an inbuilt skin temperature sensor that facilitates wear time estimation. The median (IQR) wear time in children was 160 (67) h and 165 (79) h (out of a maximum of 168 h) for back and thigh placement, respectively. Wear time was significantly higher and less variable in adults, with a median (IQR) for back and thigh placement of 168 (1) and 168 (0) h. A greater proportion of adults (71.6%) achieved the maximum number of complete days when compared to children (41.7%). We conclude that a dual-accelerometer protocol using skin attachment methods holds considerable promise for monitoring 24-h movement behaviours in both children and adults.


Humanized anti-Trop-2 IgG-SN-38 conjugate for effective treatment of diverse epithelial cancers: preclinical studies in human cancer xenograft models and monkeys.
Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans. Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2-humanized antibody, hRS7. The immunoconjugates were characterized in vitro for stability, binding, and cytotoxicity. Efficacy was tested in five different human solid tumor-xenograft models that expressed Trop-2 antigen. Toxicity was assessed in mice and in Cynomolgus monkeys. The hRS7 conjugates of the two SN-38 derivatives were equivalent in drug substitution (∼ 6), cell binding (K(d) ∼ 1.2 nmol/L), cytotoxicity (IC(50) ∼ 2.2 nmol/L), and serum stability in vitro (t/(½) ∼ 20 hours). Exposure of cells to the ADC demonstrated signaling pathways leading to PARP cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted. Significant antitumor effects were produced by hRS7-SN-38 at nontoxic doses in mice bearing Calu-3 (P ≤ 0.05), Capan-1 (P < 0.018), BxPC-3 (P < 0.005), and COLO 205 tumors (P < 0.033) when compared to nontargeting control ADCs. Mice tolerated a dose of 2 × 12 mg/kg (SN-38 equivalents) with only short-lived elevations in ALT and AST liver enzyme levels. Cynomolgus monkeys infused with 2 × 0.96 mg/kg exhibited only transient decreases in blood counts, although, importantly, the values did not fall below normal ranges. The anti-Trop-2 hRS7-CL2A-SN-38 ADC provides significant and specific antitumor effects against a range of human solid tumor types. It is well tolerated in monkeys, with tissue Trop-2 expression similar to humans, at clinically relevant doses, and warrants clinical investigation.


Current and Emerging Trends in the Management of Fall Risk in People with Lower Limb Amputation.
People living with lower limb amputation are at an increased risk of falling compared with the healthy geriatric population. Factors of increased age and increased number of comorbidities could compound the already increased risk. The purpose of this article is to highlight recent research associated with fall risk in amputees and provide the reader with evidence to help guide clinical interventions. Though research on the topic of falls in people with amputation is becoming more common, there is still a dearth of evidence regarding what contributes to increased fall risk and how to address it in this population. There are recent studies that have examined therapy and prosthetic interventions that could mitigate fall risk in people with amputation, yet there is not enough evidence to develop a consensus on the topic. More research is required to determine what contributes to increased fall rates in people with amputation, and what detriments to an amputee's function or psyche may result after incurring a fall. Borrowing from what is known about geriatric fall risk and combining the information with novel and existing approaches to fall mitigation in amputees can offer clinicians the opportunity to develop evidence-based programs to address fall risk in their patients with lower limb amputation.


Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention.
Peroxynitrite is formed in biological systems when superoxide and nitric oxide are produced at near equimolar ratio. Although not a free radical by chemical nature (as it has no unpaired electron), peroxynitrite is a powerful oxidant exhibiting a wide array of tissue damaging effects ranging from lipid peroxidation, inactivation of enzymes and ion channels via protein oxidation and nitration to inhibition of mitochondrial respiration. Low concentrations of peroxynitrite trigger apoptotic death, whereas higher concentrations induce necrosis with cellular energetics (ATP and NAD) serving as switch between the two modes of cell death. Peroxynitrite also damages DNA and thus triggers the activation of DNA repair systems. A DNA nick sensor enzyme, poly(ADP-ribose) polymerase-1 (PARP-1) also becomes activated upon sensing DNA breakage. Activated PARP-1 cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins. Peroxynitrite-induced overactivation of PARP consumes NAD(+) and consequently ATP culminating in cell dysfunction, apoptosis or necrosis. This cellular suicide mechanism has been implicated among others in the pathomechanism of stroke, myocardial ischemia, diabetes and diabetes-associated cardiovascular dysfunction. Here, we review the cytotoxic effects (apoptosis and necrosis) of peroxynitrite focusing on the role of accelerated ADP-ribose turnover. Regulatory mechanisms of peroxynitrite-induced cytotoxicity such as antioxidant status, calcium signalling, NFkappaB activation, protein phosphorylation, cellular adaptation are also discussed.


Pathways from teacher depression and child-care quality to child behavioral problems.
The purpose of this study was to examine the associations among teacher depression, global child-care quality, and child internalizing and externalizing behavioral problems in early child-care settings. We analyzed data from 3-year-old children (N = 761) and their mothers, primarily of disadvantaged socioeconomic status in urban areas, in the late 1990s using the Fragile Families and Child Wellbeing Study. We also had data from the children's teachers, who reported their own depressed moods. Child behavioral problems were reported by both teachers and parents, and global environmental quality of child care was observed. Path analysis tested direct and indirect effects of teacher depression on children's behavioral problems via global child-care quality. Teacher depression was directly and indirectly linked to teacher-reported externalizing and internalizing problems through observed global child-care quality, whereas for parent-reported outcomes, teacher depression was only directly related to children's internalizing problems. Results of this study suggest that teachers' depressive symptoms can be a contributor to global environmental child-care quality and to child externalizing and internalizing behavioral problems. Practical implications are that programs and policies must take into account effects of teacher depression on child-care quality and young children's school readiness regarding behavioral problems. Future research should further explore these relationships.


Fryns syndrome with Hirschsprung disease: support for possible neural crest involvement.
Fryns syndrome is an autosomal recessive multiple congenital anomaly/mental retardation syndrome characterized by coarse face, distal limb hypoplasia, and diaphragmatic anomalies. We describe a newborn girl with Fryns syndrome and Hirschsprung disease, an association that has been reported in five previous cases. These patients support the hypothesis that the neural crest plays a role in the pathogenesis of Fryns syndrome. Clinically asymptomatic or subtle anomalies that are in the spectrum of neural crest maldevelopment should be sought in all patients with Fryns syndrome including stillbirths, neonatal deaths, as well as long-term survivors. We suspect that the clinical observation about Hirschsprung disease and Fryns syndrome may provide insight into its molecular mechanisms and candidate genes.


[Results of endonasal intubation of the nasolacrimal duct in children with congenital dacryocystitis].
Results of endonasal catheterization of the naso-lacrimal canal of 74 children with congenital dacryocystitis (bilateral problem in 10 of them) are presented. Prior to this manipulation, the patients were exposed to contrast X-ray study of the lacrimal sac for diagnostic purposes. Retrograde catheterization as a method for treating congenital dacryocystitis was very good in 97.3% children of up to 2 years old, 50% children of up to 3 years old, and 33.3% children between 3-4 years old. The patency of the naso-lacrimal canal also recovered in an 8-year-old child. All this gives evidence that, irrespective of children's age, retrograde catheterization should be applied to treat congenital dacryocystitis. After the patency of the naso-lacrimal canal was restored, the external fistula of the lacrimal sac was cauterized with 7% solution of trichloroacetic acid.


Highlight Commentary on "Influence of lung oxidant and antioxidant status on alveolarization: Role of light-exposed total parenteral nutrition".
Bronchopulmonary dysplasia (BPD) is a frequent complication of premature newborns, particularly very low birth-weight babies (<1500 g). Undoubtedly multiple mechanisms contribute to the adverse outcomes associated with BPD but oxidative stress is one causative factor. In this issue of Free Radical Biology and Medicine, Lavoie et al. describe the increased peroxide generation when the multivitamin solution used for nutritional support, total parenteral nutrition (TPN), is exposed to ambient light. Because the premature newborn has limited antioxidant capacity, this increased oxidative burden from the TPN becomes increasingly significant. Infusion of this light-exposed solution in a newborn guinea pig decreased lung tissue vitamin C but not vitamin E. When the multivitamin and lipid solutions were mixed and then exposed to light, alveolarization of the developing lung was decreased. This study by Lavoie et al. highlights simple measures that can potentially decrease the oxidant burden delivered to this vulnerable population and improve alveolarization.


The solution structures of Escherichia coli trp repressor and trp aporepressor at an intermediate resolution.
We have determined the solution structures and examined the dynamics of the Escherichia coli trp repressor (a 25-kDa dimer), with and without the co-repressor L-tryptophan, from NMR data. This is the largest protein structure thus far determined by NMR. To obtain a set of data sufficient for a structure determination it was essential to resort to isotopic spectral editing. Line broadening observed in this molecular mass range precludes for the most part the measurement of coupling constants and stereospecific assignments, with the inevitable result that the attainable resolution of the final structure will be somewhat lower than the resolution reported for smaller proteins and peptides. Nevertheless the general topology of the protein can be deduced from the subsets of NOEs defining the secondary and tertiary structure, providing a basis for further refinement using the full set of NOEs and energy minimization. We report here (a) an intermediate resolution structure that can be deduced from NMR data, covalent, angular and van-der-Waals constraints only, without resort to detailed energy calculations, and (b) the limits of uncertainty within which this structure is valid. An examination of these structures combined with backbone amide exchange data shows that even at this resolution three important conclusions can be drawn: (a) the protein structure changes upon binding tryptophan; (b) the putative DNA binding region is much more flexible than the core of the molecule, with backbone amide proton exchange rates 1000 times faster than in the core; (c) the binding of tryptophan stabilizes the repressor molecule, which is reflected in both the appearance of additional NOEs, and in the slowing of backbone proton exchange rates by factors of 3-10. Sequence-specific 1H-NMR assignments and the secondary structure of the holopressor (L-tryptophan-bound form) have been reported previously [C. H. Arrowsmith, R. Pachter, R. B. Altman, S. B. Iyer & O. Jardetzky (1990) Biochemistry 29, 6332-6341]. Those for the trp aporepressor (L-tryptophan-free form), made using the same methods and conditions as described in the cited paper, are reported here. The secondary structure of the aporepressor was calculated from sequential and medium-range NOEs and is the same as reported for the holorepressor except that helix E is shorter. The tertiary solution structures for both forms of the repressor were calculated from long-range NOE data.(ABSTRACT TRUNCATED AT 400 WORDS)


Modelling the early detection of breast cancer.
A mathematical model was developed to predict the outcome of early detection clinical trials or programs targeted at evaluating mortality benefit from earlier diagnosis of breast cancer. The model was applied to eight randomized breast cancer trials, which were carried out to evaluate the benefits of mammography, physical examination or their combination. The model assumes that breast cancer is a progressive disease and any mortality benefit from earlier diagnosis is generated from a favorable shift in the stage at diagnosis relative to usual care. The model predicted the reduction in mortality for seven of the eight trials within the reported confidence intervals. Input data required by the models are: stage shift distribution, examination schedules, population age distribution, follow up time, and survival conditional on stage at diagnosis. Survival distributions were obtained from the 1973-82 SEER database whereas the remaining data was obtained for each of the trials. Information on sensitivity and stage was ordinarily available during the early phase of the trials. The theoretical model has the promise of being able to predict the long-term outcome of early detection trials or programs during the initial examination phase. The theoretical model is general and may be applied to other chronic diseases, which satisfy the basic assumptions.


Tropical and temperate wastewater treatment plants assemble different and diverse microbiomes.
The diversity and assembly of activated sludge microbiomes play a key role in the performances of municipal wastewater treatment plants (WWTPs), which are the most widely applied biotechnological process systems. In this study, we investigated the microbiomes of municipal WWTPs in Bangkok, Wuhan, and Beijing that respectively represent tropical, subtropical, and temperate climate regions, and also explored how microbiomes assembled in these municipal WWTPs. Our results showed that the microbiomes from these municipal WWTPs were significantly different. The assembly of microbiomes in municipal WWTPs followed deterministic and stochastic processes governed by geographical location, temperature, and nutrients. We found that both taxonomic and phylogenetic α-diversities of tropical Bangkok municipal WWTPs were the highest and were rich in yet-to-be-identified microbial taxa. Nitrospirae and β-Proteobacteria were more abundant in tropical municipal WWTPs, but did not result in better removal efficiencies of ammonium and total nitrogen. Overall, these results suggest that tropical and temperate municipal WWTPs harbored diverse and unique microbial resources, and the municipal WWTP microbiomes were assembled with different processes. Implications of these findings for designing and running tropical municipal WWTPs were discussed. KEY POINTS: • Six WWTPs of tropical Thailand and subtropical and temperate China were investigated. • Tropical Bangkok WWTPs had more diverse and yet-to-be-identified microbial taxa. • Microbiome assembly processes were associated with geographical location.


Evaluation of Dolutegravir- and Bictegravir-Based Antiretroviral Regimen Utilization in Patients who Cannot Take Medications by Mouth.
A retrospective review of patients unable to take medications by mouth showed short interruptions of therapy for most patients. In a secondary analysis, our data showed maintenance and/or achievement of viral suppression for most patients. A retrospective review of intensive care patients unable to take antiretrovirals by mouth showed 56.6% of patients experiencing a transient interruption in therapy. Additionally, our case series further supports previous literature on crushing dolutegravir and bictegravir regimens to maintain and achieve viral suppression.


[Cost-effectiveness of initial adherence to antiretroviral therapy among HIV infected patients in Belo Horizonte, Brazil].
In Brazil, there is free antiretroviral (ARV) distribution to patients with HIV disease by the National Health System. Adherence to the treatment is one of the main factors that health services can manage to increase the effectiveness of the ARV medication. The aim of this study is to evaluate the cost-effectiveness of initial adherence to the ARV therapy and to identify factors that influence patient's costs and global evolution. Prospective study of HIV infected patients receiving their first ARV prescription in two public referral centers to HIV/Aids, Brazil. The non-adherence was defined as the intake of <95% of the prescribed doses for 3 days prior to the first follow-up visit. A cost-effectiveness ratio was calculated for either groups, the adherent and the non-adherent. Univariate and multivariate analysis were performed using multiple linear and binary logistic regression models. 79.7% of the 197 participants was adherent to the ARV treatment and the ratio cost-effectiveness obtained for this group (2667.67 Eros) was smaller than the ratio observed among the non-adherent group. Multivariate analysis (p < 0.05) showed that adherence to ARV therapy and use of protease inhibitors in the treatment were associated with higher direct cost of care. The favorable global evolution was associated with being asymptomatic, TCD4+ linphocyte count >200 cels/mm3 and be adherent to the ARV treatment. The observed results supported the ARV therapy as a cost-effective intervention. However, low adherence increases the risk of therapeutic failure and illness progression that results in a negative impact on the cost-efectiveness of the ARV therapy.


Association of Amyloid and Tau With Cognition in Preclinical Alzheimer Disease: A Longitudinal Study.
Positron emission tomography (PET) imaging now allows in vivo visualization of both neuropathologic hallmarks of Alzheimer disease (AD): amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Observing their progressive accumulation in the brains of clinically normal older adults is critically important to understand the pathophysiologic cascade leading to AD and to inform the choice of outcome measures in prevention trials. To assess the associations among Aβ, tau, and cognition, measured during different observation periods for 7 years. Prospective cohort study conducted between 2010 and 2017 at the Harvard Aging Brain Study, Boston, Massachusetts. The study enrolled 279 clinically normal participants. An additional 90 individuals were approached but declined the study or did not meet the inclusion criteria. In this report, we analyzed data from 60 participants who had multiple Aβ and tau PET observations available on October 31, 2017. A median of 3 Pittsburgh compound B-PET (Aβ, 2010-2017) and 2 flortaucipir-PET (tau, 2013-2017) images were collected. We used initial PET and slope data, assessing the rates of change in Aβ and tau, to measure cognitive changes. Cognition was evaluated annually using the Preclinical Alzheimer Cognitive Composite (2010-2017). Annual consensus meetings evaluated progression to mild cognitive impairment. Of the 60 participants, 35 were women (58%) and 25 were men (42%); median age at inclusion was 73 years (range, 65-85 years). Seventeen participants (28%) exhibited an initial high Aβ burden. An antecedent rise in Aβ was associated with subsequent changes in tau (1.07 flortaucipir standardized uptake value ratios [SUVr]/PiB-SUVr; 95% CI, 0.13-3.46; P = .02). Tau changes were associated with cognitive changes (-3.28 z scores/SUVR; 95% CI, -6.67 to -0.91; P = .001), covarying baseline Aβ and tau. Tau changes were greater in the participants who progressed to mild cognitive impairment (n = 6) than in those who did not (n = 11; 0.05 SUVr per year; 95% CI, 0.03-0.07; P = .001). A serial mediation model demonstrated that the association between initial Aβ and final cognition, measured 7 years later, was mediated by successive changes in Aβ and tau. We identified sequential changes in normal older adults, from Aβ to tau to cognition, after which the participants with high Aβ with greater tau increase met clinical criteria for mild cognitive impairment. These findings highlight the importance of repeated tau-PET observations to track disease progression and the importance of repeated amyloid-PET observations to detect the earliest AD pathologic changes.


Evaluating ivosidenib for the treatment of acute myeloid leukemia.
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, but the results for patients with AML are still unsatisfactory. The discovery of new mutations in AML, including IDH mutations, has opened the door for treatment with targeted agents. Ivosidenib is a selective, potent inhibitor of the IDH1 mutant protein. This review summarizes the mechanism of action, safety profile and efficacy of ivosidenib for patients with IDH1-mutated AML. The authors then provide their expert perspectives on the use of the drug including their future perspectives. Ivosidenib is a promising, most probably practice changing, new drug for the treatment of IDH1-mutated AML. Current phase III trials are ongoing to evaluate the addition of ivosidenib to the current standards-of-care. In the near future, more drug combinations are awaited. Challenges for the future include the development of resistance and establishing the duration of maintenance therapy.


Megalencephalic leukoencephalopathy with subcortical cysts.
Megalencephalic leukoencephalopathy with subcortical cysts is one of the newly described white-matter disorders for which recognition has been brought about by advances in imaging technology. The essential diagnostic features include megalencephaly noted in infancy, motor disability in the form of spasticity, ataxia, occasional seizures, mild cognitive decline, and slow progression. Magnetic resonance imaging (MRI) shows bilateral extensive white-matter changes with cysts in the temporal regions. Based on the clinical and MRI features, megalencephalic leukoencephalopathy with subcortical cysts can be distinguished from other conditions (ie, Alexander's disease, Canavan's disease, glutaricaciduria type I) that present in infancy with megalencephaly. Megalencephalic leukoencephalopathy with subcortical cysts is an autosomal recessive disorder, and mutations in the MLC1 gene have now been shown to cause this condition. Several genotypic and phenotypic variations have been described. In India, megalencephalic leukoencephalopathy with subcortical cysts occurs predominantly in the Agarwal community. A common mutation in the MLC1 gene has been seen in 31 Agarwal patients, which suggests a founder effect.


Possible Virus-Induced Genetic Abnormalities in Tree Fruits.
Seedlings of Prunus avium and P. cerasus, grown from seed of infected trees, showed symptoms of cherry necrotic rusty mottle and sour cherry yellows diseases. No virus could be detected in the P. avium seedlings showing virus-like symptoms and only 10 percent of the 30 percent of P. cerasus seedlings showing symptoms contained virus. These results suggest that viruses may induce certain genetic abnormalities.


[Experimental verification of several assumptions and methods of statistical genetics. II].
The applicability of A. S. Serebrovsky's formulas and N. A. Sobolev's methods was investigated for a dihybrid cross. It was shown that Serebrovsky's formulas do not always lead to a correct estimation of the minimal number of genes by which the parents are distinguished. In the case of gene interaction this estimation sometimes proved to be exaggerated 2-4 times. A test of Sobolev's method demonstrated that this method cannot be considered as reliable for work. Most of his estimations are not correct. Various estimations of the same phenomenon are often contradictory.


Association between breakfast skipping and metabolic outcomes by sex, age, and work status stratification.
The association between breakfast skipping and abnormal metabolic outcomes remains controversial. A comprehensive study with various stratified data is required. The aim of this study was to investigate the relationship between abnormal metabolic outcomes and breakfast skipping by sex, age, and work status stratification. We used data from the Korea National Health and Nutrition Examination Surveys from 2013 to 2018. A total of 21,193 (9022 men and 12,171 women) participants were included in the final analysis. The risk of metabolic outcomes linked to breakfast skipping was estimated using the negative binomial regression analysis by sex, work status, and age stratification. A total of 11,952 (56.4%) participants consumed breakfast regularly. The prevalence of abnormal metabolic outcomes was higher among those with irregular breakfast consumption habits. Among young male workers, negative binomial regression analysis showed that irregular breakfast eaters had a higher risk of abnormal metabolic outcomes, after adjusting for covariates (odds ratio, 1.15; 95% confidence interval, 1.03-1.27). The risk of abnormal metabolic outcomes was significant in young men in the working population. Further studies are required to understand the association of specific working conditions (working hours or shift work) with breakfast intake status and the risk of metabolic diseases.


Intravenous immunoglobulin reduces tau pathology and preserves neuroplastic gene expression in the 3xTg mouse model of Alzheimer's disease.
Despite recent negative results of the Gammaglobulin Alzheimer's Partnership (GAP) trial, the good tolerability to intravenous immunoglobulin (IVIG) and its potential benefit for patient subpopulations have highlighted the importance of understanding IVIG's mechanism of action. IVIG contains antibodies to amyloid suggesting an amyloid clearance mechanism. However, the suboptimal results of the amyloid immunotherapy trials suggest an additional mechanism. Therefore, we tested whether IVIG alters the expression of tau neurofibrillary tangle (NFT)-like deposits within hippocampal CA1 neurons of the 3xTg mouse model of AD. Three-month-old mice were treated intravenously with IVIG (10%, 400 mg/kg) or placebo (10% BSA/saline) every two weeks for either three or six months. At sacrifice, plasma was isolated for gene expression profiling and brains were processed for immunohistochemistry using the AT-180 antibody, which recognizes hyperphosphorylated tau in NFTs. Stereologic analysis of CA1 neurons following three months of treatment revealed no difference in AT-180+ neuron number but a significant 15-20% decrease in AT-180 intraneuronal optical density with IVIG compared to placebo. By contrast, the number of AT-180+ CA1 neurons was reduced by 25-30% following six months of IVIG treatment compared to placebo. Expression profiling studies showed that IVIG treatment resulted in a significant 40-50% increase in plasma levels of genes regulating neuronal cytoskeletal plasticity function and calcium-mediated signaling compared to placebo. Moreover, several transcripts encoding protein phosphatase subunits were 40-50% higher in IVIG-treated mice. Hence, IVIG reduces hippocampal NFT pathology in the 3xTg mouse through a mechanism that may involve preservation of neuronal plasticity and tau phosphorylation homeostasis.


Comparative genomics in the grass family: molecular characterization of grass genome structure and evolution.
The genomes of grasses are very different in terms of size, ploidy level and chromosome number. Despite these significant differences, it was found by comparative mapping that the linear order (colinearity) of genetic markers and genes is very well conserved between different grass genomes. The potential of such conservation has been exploited in several directions, e.g. in defining rice as a model genome for grasses and in designing better strategies for positional cloning in large genomes. Recently, the development of large insert libraries in species such as maize, rice, barley and diploid wheat has allowed the study of large stretches of DNA sequence and has provided insight into gene organization in grasses. It was found that genes are not distributed randomly along the chromosomes and that there are clusters of high gene density in species with large genomes. Comparative analysis performed at the DNA sequence level has demonstrated that colinearity between the grass genomes is retained at the molecular level (microcolinearity) in most cases. However, detailed analysis has also revealed a number of exceptions to microcolinearity, which have given insight into mechanisms that are involved in grass-genome evolution. In some cases, the use of rice as a model to support gene isolation from other grass genomes will be complicated by local rearrangements. In this Botanical Briefing, we present recent progress and future prospects of comparative genomics in grasses.


Mycobacterium tuberculosis growth at the cavity surface: a microenvironment with failed immunity.
Protective immunity against pulmonary tuberculosis (TB) is characterized by the formation in the lungs of granulomas consisting of macrophages and activated T cells producing tumor necrosis factor alpha and gamma interferon, both required for the activation of the phagocytes. In 90% of immunocompetent humans, this response controls the infection. To understand why immunity fails in the other 10%, we studied the lungs of six patients who underwent surgery for incurable TB. Histologic examination of different lung lesions revealed heterogeneous morphology and distribution of acid-fast bacilli; only at the surface of cavities, i.e., in granulomas with a patent connection to the airways, were there numerous bacilli. The mutation profile of the isolates suggested that a single founder strain of Mycobacterium tuberculosis may undergo genetic changes during treatment, leading to acquisition of additional drug resistance independently in discrete physical locales. Additional drug resistance was preferentially observed at the cavity surface. Cytokine gene expression revealed that failure to control the bacilli was not associated with a generalized suppression of cellular immunity, since cytokine mRNA was up regulated in all lesions tested. Rather, a selective absence of CD4(+) and CD8(+) T cells was noted at the luminal surface of the cavity, preventing direct T-cell-macrophage interactions at this site, probably allowing luminal phagocytes to remain permissive for bacillary growth. In contrast, in the perinecrotic zone of the granulomas, the two cell types colocalized and bacillary numbers were substantially lower, suggesting that in this microenvironment an efficient bacteriostatic or bactericidal phagocyte population was generated.


[Development of a Dan Jeon Breathing Model for health promotion in middle-aged women].
The purpose of this study was to develop a Dan Jeon Breathing Model and to identify effects of the developed Dan Jeon Breathing Model for maintenance and promotion of health and improvement of health problems in middle-aged women. This study was constructed with two procedures. The first procedure was to develop appropriate movements for middle-aged women, performing a focus group discussion and developing a Dan Jeon Breathing Model in qualitative research. The collected data from focus group discussions was categorized for fitting movements. The second procedure was to verify and conclude a Hypothetic Dan Jeon Breathing Model through a quasi-experimental nonequivalent control group pre-post test design. The developed Dan Jeon Breathing Model was composed of 28 preparation movements to accept Ki comfortably, 10 breathing movements to accumulate Ki for activation of metabolic function in organs and 14 finishing movements to transmit activated Ki to organs. It took 40 minutes to do them. In the Second procedure, the score of physical health (t=4.205, p=.000), psycho-social health (t=3.292, p=.002) and physical strength of the experimental group (t=5.905, p=.000) was higher than that of the control group. The Dan Jeon Breathing Model developed in this study is the correct health promotion model for middle-aged women, their demand, developmental traits and health problems.


Predictors of postoperative cardiovascular complications up to 3 months after kidney transplantation.
Renal transplant patients have a high peri-operative risk for cardiovascular events. Pre-operative screening for cardiac ischaemia might lower this risk, but there are no specific guidelines. We conducted a chart review for all renal transplants performed between January 2010 and December 2013. We collected data about patient characteristics, pre-operative cardiac evaluation before referral, diagnostic tests and interventions. Logistic regression analyses were then applied to relate these factors to the composite endpoint of cardiac death, myocardial infarction, coronary revascularisation or admission for heart failure within 3 months after transplantation. A total of 770 kidney transplants were performed in 751 patients. In 750 cases (97%) a referral to the cardiologist was made. Non-invasive ischaemia detection by myocardial perfusion scintigraphy, exercise stress test or dobutamine stress echocardiography was carried out in 631 cases (82%). Coronary angiography was performed in 85 cases, which revealed significant coronary artery disease in 19 cases. Prophylactic revascularisation was done in 7 cases. The incidence of the study endpoint was 8.6%. In multivariable regression analysis, age at transplantation, pre-transplant myocardial infarction or heart failure, post-operative decrease in haemoglobin and positive non-invasive ischaemia testing were significantly associated with the study endpoint. However, when analysed separately, none of the different non-invasive ischaemia detection modalities were related to the study endpoint. Especially those renal transplant candidates with a cardiac history carry a high risk for a cardiovascular event post-transplantation. Uniformity in cardiac screening of renal transplant candidates and better pre-operative preparation might lower this post-operative risk. Besides, post-transplant anaemia should be prevented.


[Dynamics of various integral indices of individual changes of heat-resistance of isolated frog muscles kept in Ringer solution].
A study was made of the dynamics of the heat resistance (HR) mean level, of the correlation between the initial individual HR level and the value and direction of this level shifting, and of the pattern of correlation between HR levels of pair sartoria muscles and variability of HR level in muscles kept at 5-6 degrees C in the Ringer for 12 days. A two-phase changes in the mean HR level of muscles was revealed that involved its increase by 48% within one day of maintenance in the Ringer solution followed by its decrease by 14% in 6 days. On the first steps of muscle maintenance in the Ringer solution, a negative correlation was noticed between the initial HR level and the value and direction of its shifting, in addition to narrowing the range of variability of muscle HR level. All these events were accompanied by phase fluctuations in the correlation coefficient between HR levels of pair muscles. By the end of experiment the range of variability of the HR level was seen to increase, and the earlier positive correlation between pair muscle HR levels appeared either to change or to be a negative one. The increase in the range of variability preceded the decrease in the mean level of muscle HR.


The role of the renin-angiotensin system in the renal response to moderate hypoxia in the rat.
1. In two groups of Saffan-anaesthetized rats, we studied the role of the renin-angiotensin system in mediating the antidiuresis and antinatriuresis induced by moderate systemic hypoxia. 2. In both groups, a first period of hypoxia (breathing 12% O2 for 20 min) induced a fall in arterial partial pressure of O2 (Pa,O2; to 42 mmHg), a fall in mean arterial pressure (MABP), no change in renal blood flow (RBF) due to an increase in renal vascular conductance (RVC = RBF/MABP) and falls in urine flow and absolute sodium excretion (UNaV). Concomitantly, plasma renin activity increased from 3.08 +/- 0.68 (mean +/- S.E.M.) to 8.36 +/- 1.8 ng ml-1 hr-1. 3. In group 1 (n = 11), Losartan (10 mg kg-1, I.V.), the angiotensin (AII) AT1 receptor antagonist, induced a fall in MABP (115 +/- 3 to 90 +/- 3 mmHg), an increase in RVC such that RBF was unchanged, and falls in glomerular filtration rate (GFR), urine flow and UNaV. However, hypoxia induced qualitatively similar changes to those seen before Losartan treatment. 4. In group 2 (n = 9), we occluded the aorta distal to the renal artery to prevent basal MABP and renal perfusion pressure (RPP) from falling after addition of Losartan and to keep the hypoxia-induced fall in MABP the same as before Losartan treatment. Nevertheless, Losartan induced an increase in basal RVC, RBF, urine flow and UNaV whilst hypoxia induced falls in urine flow and UNaV that were proportionately similar to those seen prior to addition of Losartan. 5. These results indicate that in the Saffan-anaesthetized rat, AII exerts tonic, renal vasoconstrictor and consequent antidiuretic and antinatriuretic influences in normoxia, but does not contribute to the hypoxia-induced antidiuresis and antinatriuresis. We propose that renin secretion is increased by the hypoxia-induced fall in RPP rather than by an increase in renal sympathetic activity. Thus, the AII generated cannot produce antidiuresis and antinatriuresis by its known facilitatory influence on the actions of an increase in sympathetic activity on the renal tubules and is insufficient to produce these effects by direct actions. Rather, these results support the view that the antidiuresis and antinatriuresis of moderate hypoxia is predominantly due to the fall in RPP.


With or Without You? Contextualizing the Impact of Romantic Relationship Breakup on Crime Among Serious Adolescent Offenders.
The decline and delay of marriage has prolonged adolescence and the transition to adulthood, and consequently fostered greater romantic relationship fluidity during a stage of the life course that is pivotal for both development and offending. Yet, despite a growing literature of the consequences of romantic relationships breakup, little is known about its connection with crime, especially among youth enmeshed in the criminal justice system. This article addresses this gap by examining the effects of relationship breakup on crime among justice-involved youth-a key policy-relevant group. We refer to data from the Pathways to Desistance Study, a longitudinal study of 1354 (14% female) adjudicated youth from the juvenile and adult court systems in Phoenix and Philadelphia, to assess the nature and complexity of this association. In general, our results support prior evidence of breakup's criminogenic influence. Specifically, they suggest that relationship breakup's effect on crime is particularly acute among this at-risk sample, contingent upon post-breakup relationship transitions, and more pronounced for relationships that involve cohabitation. Our results also extend prior work by demonstrating that breakup is attenuated by changes in psychosocial characteristics and peer associations/exposure. We close with a discussion of our findings, their policy implications, and what they mean for research on relationships and crime among serious adolescent offenders moving forward.


Prevention of in vitro lipolysis by tetrahydrolipstatin.
Metabolic effects of free fatty acids (FFAs) frequently are tested using combined infusion of triglycerides and heparin, which stimulates lipolysis in vivo. Ongoing in vitro lipolysis, however, probably produces falsely high plasma FFA concentrations under these conditions. Therefore, this study aims to assess the efficacy of tetrahydrolipstatin (THL) in inhibiting plasma lipolytic activity and to improve plasma FFA determination. Plasma concentrations of FFAs and glycerol were measured in five healthy subjects in the presence and absence of THL. Blood was drawn at baseline, during infusion of a triglyceride emulsion (1.5 mL/min), and during infusion of triglycerides plus heparin (0.2 IU. kg(-1). min(-1)). In addition, the effects of storage temperature of the samples were analyzed. In samples frozen immediately after collection, plasma FFAs were 28% lower in the presence of THL than in its absence (P = 0.008). When THL-free plasma was incubated for 3 h on ice or at room temperature, plasma FFAs were 22% (P = 0.02) and 91% (P = 0.0004) higher, respectively, than in samples frozen immediately. The addition of THL blunted temperature-dependent in vitro lipolysis by 88% (P<0.01) and 89% (P <0.001) after incubation on ice and at room temperature, respectively. Changes in plasma glycerol concentrations exhibited similar behavior. THL, which is safe and easy to handle, is a potent inhibitor of in vitro lipolysis and could, therefore, be added to blood samples drawn during triglyceride/heparin infusions to allow more accurate determination of plasma FFA concentrations.


Cerebral thromboembolic risk in atrial fibrillation ablation: a direct comparison of vitamin K antagonists versus non-vitamin K-dependent oral anticoagulants.
Cerebral thromboembolic events are well-known complications of pulmonary vein isolation (PVI) and can manifest as stroke or silent cerebral embolic lesions. The aim of this study was to compare the incidence of cerebral embolic lesions (including silent cerebral embolism and stroke) after AF ablation in patients on vitamin K antagonists versus patients on non-vitamin K-dependent oral anticoagulants, and to identify corresponding clinical and procedural risk factors. A total of 421 patients undergoing PVI were prospectively included into the study. Of these, 43.7% were on VKA and 56.3% on NOAC treatment (dabigatran, rivaroxaban, apixaban, and edoxaban). In the NOAC group, 38% of patients had an interruption of anticoagulation for 24-36 h. All patients underwent pre- and postprocedural cerebral magnetic resonance imaging. Periprocedural cerebral lesions occurred in 13.1% overall. Of these, three (0.7%) resulted in symptomatic cerebrovascular accidents and 52 (12.4%) in silent cerebral embolic lesions. Incidence of cerebral lesions was significantly higher in patients on NOAC compared with VKA (16% vs. 9.2%, respectively, p = 0.04), and in patients who had intraprocedural cardioversions compared with no cardivoersions (19.5% vs. 10.4%, respectively, p = 0.03). In multivariate analysis, both parameters were found to be independent risk factors for cerebral embolism. No significant difference between interrupted and uninterrupted NOAC administration could be detected. In patients undergoing AF ablation, we identified the use of NOAC and intraprocedural cardioversion as independent risk factors for the occurrence of periprocedural cerebral embolic lesions.


Clinical efficacy of lumbar interbody fusion using a channel system combined with ozone therapy for the treatment of central-type L3-L4 lumbar disc herniation.
The clinical efficacy of minimally invasive lumbar interbody fusion via the intervertebral foramen combined with ozone (O3) therapy for the treatment of L3-L4 central-type lumbar disc herniation was explored. We recruited patients with sciatica who attended our hospital between July 2013 and October 2015 and underwent lumbar X-ray (anteroposterior and lateral view), lumbar flexion-extension radiographs, computed tomography, and magnetic resonance imaging after admission. Seventy-four patients with central-type lumbar disc herniation but no other complications were randomly selected and divided into the observation and control groups. The observation group comprised 37 patients treated with lumbar fusion using a channel system combined with O3 therapy, whereas the control group comprised 37 patients treated with lumbar fusion alone. The effects of the two therapies were evaluated using visual analog scale, Japanese Orthopaedic Association, and MacNab scores. There was no significant difference in scores between the two groups before surgery (P>0.05). The scores of the observation group after treatment were significantly lower than those before surgery and those of the control group (P<0.05). One patient in the observation group experienced no obvious improvement in symptoms after surgery, and two patients in the control group experienced postoperative recurrence; these three patients subsequently underwent laminectomy combined with planted bone fusion and internal fixation. There was no significant difference in total efficacy rates between the two groups (P>0.05). Lumbar fusion using a channel system combined with O3 therapy for the treatment of L3-L4 central-type lumbar disc herniation is safe and effective. It has the advantages of reduced trauma, fewer complications, and rapid pain relief, and it promotes the recovery of lumbar function. Strict mastery of the surgical indications is key to the success of the procedure; however, it is worth expanding its use in the clinical setting.


M335, a novel small-molecule STING agonist activates the immune response and exerts antitumor effects.
In the context of antitumor immune responses, the activation of the stimulator of interferon genes (STING) assumes a critical role and imparts enhanced immunogenicity. An effective strategy for exogenously activating the immune system involves the utilization of STING agonists, and prior investigations primarily concentrated on modifying endogenous cyclic dinucleotides (CDNs) to achieve this. Nevertheless, the practical utility of CDNs was restricted due to limitations associated with their physicochemical attributes and administration protocols. In this article, we present the discovery of a novel small-molecule agonist denoted as M335, identified through high-throughput screening using surface plasmon resonance (SPR). M335 demonstrates the ability to activate the TBK1-IRF3-IFN axis in a STING-dependent manner in vitro. Through experimentation on mouse models bearing tumors, we observed that the administration of M335 resulted in the activation of immune cells. Notably, significant antitumor effects were achieved with both intratumoral and intraperitoneal administration of M335. These findings suggest the potential of M335 as a promising agent for cancer immunotherapy, which will promote the development of STING agonists in anti-tumor applications.


Hydroxychloroquine decreases Th17-related cytokines in systemic lupus erythematosus and rheumatoid arthritis patients.
Hydroxychloroquine is an antimalarial agent that has been used in systemic lupus erythematosus and rheumatoid arthritis treatment for many years. Recently, novel mechanisms of action have been proposed, thereby broadening the therapeutic perspective of this medication. The purpose of this study was to evaluate the immunomodulatory activity of hydroxychloroquine in T helper 17 (Th17) cytokines in healthy individuals and patients. Eighteen female patients with systemic lupus erythematosus (mean age 39.0±12.9 years) and 13 female patients with rheumatoid arthritis (mean age 51.5±7.7 years) were recruited from Universidade Federal de Pernambuco-Brazil. The patients were included after fulfilling four classification criteria for systemic lupus erythematosus or rheumatoid arthritis from the American College of Rheumatology. After being stimulated with phorbol 12-myristate 13-acetate and ionomycin in the absence or presence of different concentrations of hydroxychloroquine, the interleukin 6, 17 and 22 levels were quantified with an enzyme-linked immunosorbent assay in culture supernatants of peripheral blood mononuclear cells from healthy individuals and patients. We demonstrated that in peripheral blood mononuclear cells from healthy volunteers and in systemic lupus erythematosus and rheumatoid arthritis patients, there was a significant reduction in the IL-6, IL-17 and IL-22 supernatant levels after adding hydroxychloroquine. CONCLUSIONS Our in vitro results demonstrated that hydroxychloroquine inhibits IL-6, IL-17 and IL-22 production and contributes to a better understanding of the mechanism of action of this medication.


An analysis of differential item functioning by gender in the Learning Disability Screening Questionnaire (LDSQ).
The Learning Disability Screening Questionnaire (LDSQ; McKenzie & Paxton, 2006) was developed as a brief screen for intellectual disability. Although several previous studies have evaluated the LDSQ with respect to its utility as a clinical and research tool, no studies have considered the fairness of the test across males and females. In the current study we, therefore, used a multi-group item response theory approach to assess differential item functioning across gender in a sample of 211 males and 132 females assessed in clinical and forensic settings. Although the test did not show evidence of differential item functioning by gender, it was necessary to exclude one item due to estimation problems and to combine two very highly related items (concerning reading and writing ability) into a single literacy item Thus, in addition to being generally supportive of the utility of the LDSQ, our results also highlight possible areas of weakness in the tool and suggest possible amendments that could be made to test content to improve the test in future revisions.


Temperature and intraspecific variation affect host-parasite interactions.
Parasites play key roles in regulating aquatic ecosystems, yet the impact of climate warming on their ecology and disease transmission remains poorly understood. Isolating the effect of warming is challenging as transmission involves multiple interacting species and potential intraspecific variation in temperature responses of one or more of these species. Here, we leverage a wide-ranging mosquito species and its facultative parasite as a model system to investigate the impact of temperature on host-parasite interactions and disease transmission. We conducted a common garden experiment measuring parasite growth and infection rates at seven temperatures using 12 field-collected parasite populations and a single mosquito population. We find that both free-living growth rates and infection rates varied with temperature, which were highest at 18-24.5 °C and 13 °C, respectively. Further, we find intraspecific variation in peak performance temperature reflecting patterns of local thermal adaptation-parasite populations from warmer source environments typically had higher thermal optima for free-living growth rates. For infection rates, we found a significant interaction between parasite population and nonlinear effects of temperature. These findings underscore the need to consider both host and parasite thermal responses, as well as intraspecific variation in thermal responses, when predicting the impacts of climate change on disease in aquatic ecosystems.


Impact of Brain Fatty Acid Signaling on Peripheral Insulin Action in Mice.
Glucose homeostasis and energy balance are under control by peripheral and brain processes. Especially insulin signaling in the brain seems to impact whole body glucose homeostasis and interacts with fatty acid signaling. In humans circulating saturated fatty acids are negatively associated with brain insulin action while animal studies suggest both positive and negative interactions of fatty acids and insulin brain action. This apparent discrepancy might reflect a difference between acute and chronic fatty acid signaling. To address this question we investigated the acute effect of an intracerebroventricular palmitic acid administration on peripheral glucose homeostasis. We developed and implemented a method for simultaneous monitoring of brain activity and peripheral insulin action in freely moving mice by combining radiotelemetry electrocorticography (ECoG) and euglycemic-hyperinsulinemic clamps. This method allowed gaining insight in the early kinetics of brain fatty acid signaling and its contemporaneous effect on liver function in vivo, which, to our knowledge, has not been assessed so far in mice. Insulin-induced brain activity in the theta and beta band was decreased by acute intracerebroventricular application of palmitic acid. Peripherally it amplified insulin action as demonstrated by a significant inhibition of endogenous glucose production and increased glucose infusion rate. Moreover, our results further revealed that the brain effect of peripheral insulin is modulated by palmitic acid load in the brain. These findings suggest that insulin action is amplified in the periphery and attenuated in the brain by acute palmitic acid application. Thus, our results indicate that acute palmitic acid signaling in the brain may be different from chronic effects.


Gene Set Enrichment Analysis Reveals Individual Variability in Host Responses in Tuberculosis Patients.
Group-aggregated responses to tuberculosis (TB) have been well characterized on a molecular level. However, human beings differ and individual responses to infection vary. We have combined a novel approach to individual gene set analysis (GSA) with the clustering of transcriptomic profiles of TB patients from seven datasets in order to identify individual molecular endotypes of transcriptomic responses to TB. We found that TB patients differ with respect to the intensity of their hallmark interferon (IFN) responses, but they also show variability in their complement system, metabolic responses and multiple other pathways. This variability cannot be sufficiently explained with covariates such as gender or age, and the molecular endotypes are found across studies and populations. Using datasets from a Cynomolgus macaque model of TB, we revealed that transcriptional signatures of different molecular TB endotypes did not depend on TB progression post-infection. Moreover, we provide evidence that patients with molecular endotypes characterized by high levels of IFN responses (IFN-rich), suffered from more severe lung pathology than those with lower levels of IFN responses (IFN-low). Harnessing machine learning (ML) models, we derived gene signatures classifying IFN-rich and IFN-low TB endotypes and revealed that the IFN-low signature allowed slightly more reliable overall classification of TB patients from non-TB patients than the IFN-rich one. Using the paradigm of molecular endotypes and the ML-based predictions allows more precisely tailored treatment regimens, predicting treatment-outcome with higher accuracy and therefore bridging the gap between conventional treatment and precision medicine.


Sex hormone-binding protein, hyperinsulinemia, insulin resistance and noninsulin-dependent diabetes.
Possible data complicating sex hormones, especially testosterone, in the etiology of cardiovascular disease and noninsulin-dependent diabetes mellitus (NIDDM) comes from the much higher rates of cardiovascular disease in men than in women. Pharmacological administration of anabolic steroids to both men and women increases glucose and insulin concentrations and also insulin resistance. In vivo assessment of sex hormones and binding proteins in both premenopausal and postmenopausal women has suggested that increased free testosterone and decreased sex hormone-binding globulin (SHBG) is associated with higher glucose and insulin concentrations. In a few studies, increased insulin resistance has been associated with decreased SHBG levels. Some data suggests that visceral fat mediated the associates of sex hormones with insulin in women. Little prospective data is available on the association of sex hormones to the development of NIDDM in women but in two studies, low SHBG concentrations predicted NIDDM in Gothenburg and San Antonio. Recently, attention has focused on the role of sex hormones in relation to insulin in men. Surprisingly, higher levels of testosterone have been associated with improved cardiovascular risk factors (such as high-density lipoprotein cholesterol) and lower glucose and insulin levels. Total testosterone and SHBG have been associated with defects in nonoxidative glucose disposal and upper body adiposity in normoglycemic Finnish men. The latter observation is of interest since specific defects in nonoxidative glucose disposal are observed in normoglycemic relatives of subjects with NIDDM. The temporal relationship between sex hormones and insulin has been controversial. The traditional view of sex hormones increasing insulin resistance has been challenged in women by studies showing that insulin stimulates androgen production in the ovary. Recent data [JCEM 1995;80:654-658] suggests that insulin stimulates testosterone production and suppresses SHBG production in normal and obese men. On the other hand, administration of testosterone to centrally obese hypogonadal middle-aged men has improved insulin sensitivity.


MICROPERIMETRY AS A SCREENING TEST FOR HYDROXYCHLOROQUINE RETINOPATHY: The Hard-Risk-1 Study.
To assess the sensitivity and specificity of microperimetry as a screening test to detecting hydroxychloroquine retinopathy. Retrospective cohort study. Patients with history of hydroxychloroquine use for more than 5 years and with concomitant microperimetry and multifocal electroretinogram testing were retrospectively reviewed. Microperimetry was considered positive if there were three or more contiguous scotoma points in the parafoveal region. Multifocal electroretinogram was used as gold standard and was considered positive if there was an increased R1/R2 ring ratio (>2.5) or reduced R1 absolute amplitude (<9.0). Sensitivity, specificity, positive predictive value, and negative predictive value of microperimetry were calculated. A total of 197 patients were reviewed. Hydroxychloroquine retinopathy was present in 22 (11%) patients. Their mean (SD) age was 54 (14) years, and 96% were women. Their mean (SD) daily dose was 5.7 (1.3) mg/kg, cumulative dose was 2041 (1,548) g, and duration of use was 15 (10) years. Sensitivity, specificity, positive predictive value, and negative predictive value of microperimetry were 73%, 93%, 53%, and 96%, respectively. Microperimetry has inferior sensitivity but good specificity in detecting hydroxychloroquine retinopathy (compared with multifocal electroretinogram). As such, it may be a useful ancillary test to exclude retinopathy, especially in high-risk patients or those with conflicting results on different modalities.


The 120-kDa soluble ectodomain of type XVII collagen is recognized by autoantibodies in patients with pemphigoid and linear IgA dermatosis.
Type XVII collagen promotes adhesion of basal keratinocytes to epidermal basement membrane, and is the target of disease in patients with certain inherited or acquired blistering diseases. Two forms of type XVII collagen are produced by cultured human keratinocytes: a 180-kDa full-length, transmembrane protein, and a recently identified 120-kDa soluble fragment that corresponds to its collagenous ectodomain. We aimed to determine the incidence and pattern of reactivity of autoantibodies against the 180- and 120-kDa forms of type XVII collagen in sera from 40 patients with bullous pemphigoid (BP), pemphigoid gestationis or cicatricial pemphigoid (CP), as well as six patients with linear IgA dermatosis (LAD). Various immunochemical techniques were used. These studies found that the 120-kDa fragment of type XVII collagen was bound by circulating autoantibodies in 13 of 38 patients with BP or CP and all six patients with LAD. While many pemphigoid sera had specific reactivity against one but not both forms of this protein, autoantibodies from patients with LAD bound only the soluble ectodomain. These findings are consistent with the presence of both neoepitopes and cross-reactive epitopes on the ectodomain of type XVII collagen. The finding that sera from patients with LAD showed specific reactivity to epidermal basement membrane suggests that such neoepitopes are present in human skin and that their targeting by autoantibodies may contribute to disease pathogenesis.


Associations Between Physical Fitness and Brain Structure in Young Adulthood.
A comprehensive analysis of associations between physical fitness and brain structure in young adulthood is lacking, and further, it is unclear the degree to which associations between physical fitness and brain health can be attributed to a common genetic pathway or to environmental factors that jointly influences physical fitness and brain health. This study examined genotype-confirmed monozygotic and dizygotic twins, along with non-twin full-siblings to estimate the contribution of genetic and environmental factors to variation within, and covariation between, physical fitness and brain structure. Participants were 1,065 young adults between the ages of 22 and 36 from open-access Young Adult Human Connectome Project (YA-HCP). Physical fitness was assessed by submaximal endurance (2-min walk test), grip strength, and body mass index. Brain structure was assessed using magnetic resonance imaging on a Siemens 3T customized 'Connectome Skyra' at Washington University in St. Louis, using a 32-channel Siemens head coil. Acquired T1-weighted images provided measures of cortical surface area and thickness, and subcortical volume following processing by the YA-HCP structural FreeSurfer pipeline. Diffusion weighted imaging was acquired to assess white matter tract integrity, as measured by fractional anisotropy, following processing by the YA-HCP diffusion pipeline and tensor fit. Following correction for multiple testing, body mass index was negatively associated with fractional anisotropy in various white matter regions of interest (all | z| statistics > 3.9) and positively associated with cortical thickness within the right superior parietal lobe (z statistic = 4.6). Performance-based measures of fitness (i.e., endurance and grip strength) were not associated with any structural neuroimaging markers. Behavioral genetic analysis suggested that heritability of white matter integrity varied by region, but consistently explained >50% of the phenotypic variation. Heritability of right superior parietal thickness was large (∼75% variation). Heritability of body mass index was also fairly large (∼60% variation). Generally, 1 2 to 2 3 of the correlation between brain structure and body mass index could be attributed to heritability effects. Overall, this study suggests that greater body mass index is associated with lower white matter integrity, which may be due to common genetic effects that impact body composition and white matter integrity.


Ecosystem services provided by birds.
Ecosystem services are natural processes that benefit humans. Birds contribute the four types of services recognized by the UN Millennium Ecosystem Assessment-provisioning, regulating, cultural, and supporting services. In this review, we concentrate primarily on supporting services, and to a lesser extent, provisioning and regulating services. As members of ecosystems, birds play many roles, including as predators, pollinators, scavengers, seed dispersers, seed predators, and ecosystem engineers. These ecosystem services fall into two subcategories: those that arise via behavior (like consumption of agricultural pests) and those that arise via bird products (like nests and guano). Characteristics of most birds make them quite special from the perspective of ecosystem services. Because most birds fly, they can respond to irruptive or pulsed resources in ways generally not possible for other vertebrates. Migratory species link ecosystem processes and fluxes that are separated by great distances and times. Although the economic value to humans contributed by most, if not all, of the supporting services has yet to be quantified, we believe they are important to humans. Our goals for this review are 1) to lay the groundwork on these services to facilitate future efforts to estimate their economic value, 2) to highlight gaps in our knowledge, and 3) to point to future directions for additional research.


Formulation and in vitro-in vivo evaluation of piribedil solid lipid micro- and nanoparticles.
Modification of the dissolution rate and, thus, the enhancement of the bioavailability of a dopaminergic drug, piribedil, which has a low aqueous solubility and short elimination half-life have been the aim in this study. Preparations of micron and submicron particles using solid lipid carriers have been performed for this purpose. For the avoidance of solvent residues resulting from the preparation technique, cold and hot homogenization methods have been used to prepare solid lipid particles. After obtaining an appropriate particle size, piribedil loading and preparation yield by the use of those two methods, various formulations have been prepared with different lipid, drug and surfactant materials. The factors mentioned were found to affect properties of the particles, and the release rate was found to be the fastest in acidic medium. Suspensions of pure piribedil and a formulation, selected according to the results obtained from in vitro dissolution and particle size experiments, were compared using tremor tests in mice. The same suspensions were applied perorally to rabbits and bioavailability of the solid lipid particle was found to be higher than the pure piribedil. After an in vitro-in vivo evaluation of piribedil solid lipid particles developed for Parkinson's disease therapy, it has been determined that release rate could be controlled and piribedil bioavailability could be improved.


Listeriosis, a model infection to study host-pathogen interactions in vivo.
Listeria monocytogenes (Lm) is a foodborne pathogen and the etiological agent of listeriosis. This facultative intracellular Gram-positive bacterium has the ability to colonize the intestinal lumen, cross the intestinal, blood-brain and placental barriers, leading to bacteremia, neurolisteriosis and maternal-fetal listeriosis. Lm is a model microorganism for the study of the interplay between a pathogenic microbe, host tissues and microbiota in vivo. Here we review how animal models permissive to Lm-host interactions allow deciphering some of the key steps of the infectious process, from the intestinal lumen to the crossing of host barriers and dissemination within the host. We also highlight recent investigations using tagged Lm and clinically relevant strains that have shed light on within-host dynamics and the purifying selection of Lm virulence factors. Studying Lm infection in vivo is a way forward to explore host biology and unveil the mechanisms that have selected its capacity to closely associate with its vertebrate hosts.


Genetic and phenotypic parameters for test day milk yield of Sahiwal cattle in the semi-arid tropics.
A total of 19 376 test day (TD) milk yield records from the first three lactations of 1618 cows daughters of 162 sires were used to estimate genetic and phenotypic parameters and determine the relationship between daily milk yield and lactation milk yield in the Sahiwal cattle in Kenya. Variance components were estimated using animal models based on a derivative free restricted maximum likelihood procedure. Variance components were estimated using various univariate and multi-trait fixed regression test day models (TDM) that defined contemporary groups either based on the year-season of calving (YSCV) or on the year-season of TD milk sampling (YSTD). Variance components were influenced by CG which resulted in differences in heritability and repeatability estimates between TDM. Models considering YSTD resulted in higher additive genetic variances and lower residual variances compared with models in which YSCV was considered. Heritability estimates for daily yield ranged from 0.28 to 0.46, 0.38 to 0.52 and 0.33 to 0.52 in the first, second and third lactation, respectively. In the first and second lactation, the heritability estimates were highest between TD 2 and TD 4. Genetic correlations among daily milk yields ranged from 0.41 to 0.93, 0.50 to 0.83 and 0.43 to 86 in the first, second and third lactation, respectively. The phenotypic correlations were correspondingly lower. Genetic correlations were different from unit when fitting multi-trait TDM. Therefore, a multiple trait model would be more ideal in determining the genetic merit of dairy sires and bulls based on daily yield records. Genetic and phenotypic correlations between daily yield and lactation yields were high and positive. Genetic correlations ranged from 0.84 to 0.99, 0.94 to 1.00 and 0.94 to 0.97 in the first, second and third lactations, respectively. The corresponding phenotypic correlation estimates ranged from 0.50 to 0.85, 0.50 to 0.83 and 0.53 to 0.87. The high genetic correlation between daily yield and lactation yield imply that both traits are influenced by similar genes. Therefore daily yields records could be used in genetic evaluation in the Sahiwal cattle breeding programme.


Susceptibilities of medaka (Oryzias latipes) cell lines to a betanodavirus.
Betanodaviruses, members of the family Nodaviridae, have bipartite, positive-sense RNA genomes and are the causal agents of viral nervous necrosis in many marine fish species. Recently, the viruses were shown to infect a few freshwater fish species including a model fish medaka (Oryzias latipes). Although virological study using cultured medaka cells would provide a lot of insight into virus-fish interactions in molecular aspects, no such cells have yet been tested for virus susceptibility. We tested ten medaka cell lines for susceptibilities to redspotted grouper nervous necrosis virus (RGNNV). Although the viral coat protein was detected in all the cell lines inoculated, the levels of cytopathic effect development and viral propagation were quite different among the cell lines. Those levels were especially high in OLHNI-1 and OLHNI-2 cells, but were extremely low in OLME-104 cells. Some cell lines entered into antiviral state after RGNNV infections probably because of inducing an antiviral system. This is the first report to examine the susceptibilities of cultured medaka cells against a virus. OLHNI-1 and OLHNI-2 cells are candidates of new standard cells for betanodavirus study because of their high susceptibilities to the virus and their several advantages as model fish cells.


HLA polymorphisms as incidence factor in the progression to end-stage renal disease in Brazilian patients awaiting kidney transplant.
Chronic renal failure (CRF) leads in the majority of instances to end-stage renal disease (ESRD) requiring renal replacement therapy. Age, gender, genetics, race, hypertension, and smoking among others are factors associated with ESRD. Our interest was to evaluate the possible associations of class I and II HLA antigens with ESRD renal disease independent of other factors, among patients with CRF, having various diagnoses in the Brazilian population of the São Paulo state. So 21 HLA-A, 31 HLA-B, and 13 HLA-DR were detected in 105 patients who were compared with 160 healthy controls of both sexes who were not related to the patients evaluated until 2005. We calculated allelic frequencies, haplotypes frequencies, etiological fractions (EF), preventive fractions, and relative risks (RR). We compared demographic data of patients and controls. The antigens positively associated with ESRD were: HLA-A78 (RR = 30.31 and EF = 0.96) and HLA-DR11 (RR = 18.87 and EF = 0.65). The antigens HLAB14 (RR = 29.90 and EF = 0.75) was present at a significantly lower frequency among patients compared with controls. In contrast, no haplotype frequency showed statically significant associations. Further molecular studies may clarify types and subtypes of alleles involved with ESRD progression.


Geographical distribution-based differentiation of cultivated Angelica dahurica, exploring the relationship between the secretory tract and the quality.
Based on geographical distribution, cultivated Chinese Angelica dahurica has been divided into Angelica dahurica cv. 'Hangbaizhi' (HBZ) and Angelica dahurica cv. 'Qibaizhi' (QBZ). Long-term geographical isolation has led to significant quality differences between them. The secretory structure in medicinal plants, as a place for accumulating effective constituents and information transmission to the environment, links the environment with the quality of medicinal materials. However, the secretory tract differences between HBZ and QBZ has not been revealed. This study aimed to explore the relationship between the secretory tract and the quality of two kinds of A. dahurica. Root samples were collected at seven development phases. High-Performance Liquid Chromatography (HPLC) and Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI-MSI) were used for the content determination and spatial location of coumarins. Paraffin section was used to observe and localize the root secretory tract. Origin, CaseViewer, and HDI software were used for data analysis and image processing. The results showed that compared to QBZ, HBZ, with better quality, has a larger area of root secretory tracts. Hence, the root secretory tract can be included in the quality evaluation indicators of A. dahurica. Additionally, DESI-MSI technology was used for the first time to elucidate the temporal and spatial distribution of coumarin components in A. dahurica root tissues. This study provides a theoretical basis for the quality evaluation and breeding of improved varieties of A. dahurica and references the DESI-MSI technology used to analyze the metabolic differences of various compounds, including coumarin and volatile oil, in different tissue parts of A. dahurica.


Influence of pressure on the lengths of chemical bonds.
An expression to describe the force that a chemical bond exerts on its terminal atoms is proposed, and is used to derive expressions for the bond force constant and bond compressibility. The unknown parameter in this model, the effective charge on the atoms that form the bond, is determined by comparing the derived force constants with those obtained spectroscopically. The resultant bond compressibilities are shown to generally agree well with those determined from high-pressure structure determinations and from the bulk moduli of high-symmetry structures. Bond valences can be corrected for pressure by recognizing that the bond-valence parameter, R(0), changes with pressure according to the equation dR(0)/dP = 10(-4) R(04)/(1/B-2/R(0) AA GPa (-1).


[FLIGHT CERTIFICATION OF CIVILIAN PILOTS FOLLOWING SURGERY OF BRACHIOCEPHALIC ATHEROSCLEROTIC STENOSES].
The paper presents cases of surgery of brachiocephalic atherosclerotic lesions with asymptomatic stenosis in civilian pilots reviewed by a Flight Certification Board. Cerebrovascular diseases varying in their clinical presentation (syncopes, transitory ischemic attacks or strokes) may culminate in acute conditions and, consequently, threaten flight safety. There is an exigent need of law-guided regulations for flight certification boards on how to manage cases of pilots with a history of cerebrovascular disease.


[Deliberate termination of life in newborns in The Netherlands; review of all 22 reported cases between 1997 and 2004].
To gain insight into the reporting and assessment of active termination of life in newborns in The Netherlands. DESIGN; Retrospective. Data on all cases of deliberate termination of life in newborns up to the age of 6 months, reported to the public prosecutor as from 1997 onward, were collected and compared. In January 1997-June 2004, 22 cases of deliberate termination of life in newborns were reported. All cases concerned newborns with spina bifida and hydrocephalus. Deliberate termination of life was acceptable to the physicians because of the presence of hopeless suffering, with no means of alleviating the suffering. In all cases, at least 2 doctors were consulted outside the medical team. In 17 of 22 cases, a multidisciplinary spina bifida team was consulted. All parents consented to the termination of life; in 4 cases they explicitly requested it. In 14 cases a combination of analgesics, sedatives and paralyzing drugs were used, in 8 cases only analgesics and sedatives were administered. For the public prosecutor the termination of life was acceptable if 4 requirements were properly fulfilled: the presence of hopeless and unbearable suffering, consent of the parents to termination of life, consultation having taken place and a careful execution ofthe termination. The mean time between reporting of the case and the decision concerning prosecution was 5.3 months. None of the cases led to prosecution. Three cases of deliberate termination of life in newborns were reported in The Netherlands annually. The public prosecutor used fixed criteria to assess the case and all cases of active termination of life reported were found to be in accordance with good practice.


Septic monoarthritis and osteomyelitis in an elderly man following Klebsiella pneumoniae genitourinary infection: case report.
Klebsiella pneumoniae septic arthritis and osteomyelitis, albeit uncommon in adults, are important sites of disseminated infection. Many case reports have shown K. pneumoniae as a cause of nosocomial transmitted septic arthritis in neonates and children. We report a rare case of an elderly patient with K. pneumoniae genitourinary infection spreading to the liver and other extra hepatic sites like the prostate and peripheral joint. The patient presented with a short history of general malaise, fever and urinary symptoms, associated with an acute monoarthritis of the ankle. On admission, he was in septic shock. Investigations suggested an infective cause, as evidenced by raised total white cell count and pyuria. K. pneumoniae was cultured from both urine and ankle synovial fluid. Imaging confirmed multiple liver and prostatic abscesses, as well as osteomyelitis of the foot bones adjacent to the ankle. Treatment in this case included surgical drainage of the affected joint and surrounding soft tissue structures, in addition to a 6-week course of systemic antibiotics. The patient had good clinical response following treatment. In addition, we noted a normalisation of his laboratory parameters and resolution of the intraabdominal and pelvic abscesses. This case emphasises the importance of timely and accurate diagnosis followed by appropriate treatment in disseminated K. pneumoniae infection to prevent significant morbidity and mortality.


In vitro neurogenesis: development and functional implications of iPSC technology.
Neurogenesis is the developmental process regulating cell proliferation of neural stem cells, determining their differentiation into glial and neuronal cells, and orchestrating their organization into finely regulated functional networks. Can this complex process be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology? Can neurodevelopmental and neurodegenerative diseases be modeled using iPSCs? What is the potential of iPSC technology in neurobiology? What are the recent advances in the field of neurological diseases? Since the applications of iPSCs in neurobiology are based on the capacity to regulate in vitro differentiation of human iPSCs into different neuronal subtypes and glial cells, and the possibility of obtaining iPSC-derived neurons and glial cells is based on and hindered by our poor understanding of human embryonic development, we reviewed current knowledge on in vitro neural differentiation from a developmental and cellular biology perspective. We highlight the importance to further advance our understanding on the mechanisms controlling in vivo neurogenesis in order to efficiently guide neurogenesis in vitro for cell modeling and therapeutical applications of iPSCs technology.


[Metastatic cancer of the prostate in a young 40 year-old HIV-infected male patient].
Cancer of the prostate in HIV-infected patients has rarely been reported in the literature. A 40 year-old man presented with an adenocarcinoma of the prostate and bone and glandular metastases. The patient exhibited HIV seropositivity stage B1, the immune-virology of which was well controlled by antiretroviral tritherapy. The relationship between cancer and HIV has been established for certain cancers such as Hodgkin's disease, non-Hodgkin malignant lymphoma, Kaposi's sarcoma and invasive cancers of the uterine neck in women. The significant increase in some cancers in patients infected by HIV (lung, penis, soft tissue, lips, seminoma) suggests the potential association with immunodepression unless it corresponds to a risk induced by antiretroviral treatments in the long term.


Tonic contraction and the control of relaxation in a chemically skinned molluscan smooth muscle.
The same functional states that characterize the living anterior byssus retractor muscle (ABRM) from Mytilus edulis can be initiated in the saponin-treated (chemically skinned) muscle preparation under controlled biochemical conditions. A tonic contraction was induced if the concentration of free Ca2+ was above approximately 10(7) M in the presence of Mg2+ and ATP. Maximum tension development was achieved at a Ca2+ concentration of approximately 10(4) M. Within these Ca2+ concentrations tension was always associated with the presence of 'active state," as indicated by a high recovery of tension after a quick release in muscle length. Tonic tension, and the associated active state was maintained for hours during these conditions irrespective of variations in both ionic strength and pH. Reduction of the Ca2+ concentration to below threshold for tension initiation during a tonic contraction immediately switched off the active state and relaxation of the muscle preparation resulted. However, the rate of relaxation was extremely low, leaving a substantial fraction of tension in the absence of active state. Both 5-hydroxytryptamine (5-HT) and cAMP accelerated this slow relaxation in the absence of Ca2+. Thus, this state was considered equivalent to the 'catch state" in the living ABRM. In the presence of Ca2+ concentrations above 10(7) M, cAMP did not affect either the maximum tension developed or the Ca2+ sensitivity of the chemically skinned muscle preparation.


Presence of CXCR3-positive cells and IFN-gamma-producing cells in human periapical granulomas.
In an attempt to understand further the balance between the types of helper T (Th) cells in human apical periodontitis, we examined the difference in the expression of the chemokine receptor and cytokine in samples obtained from human subjects by means of immunohistochemical methods. Chemokine receptor CXCR3-positive cells and IFN-gamma-producing cells were found to be present in human periapical granulomas, whereas chemokine receptor CCR3-positive cells and IL-4-producing cells could not be detected. By contrast, no factor expression was observed in a clinically healthy periodontal ligament serving as a negative control. Our findings suggest that Th1 cells may play an important role in the pathological process of local inflammation such as apical periodontitis.