GridLoc: An automatic and unsupervised localization method for high-density ECoG grids.
Precise localization of electrodes is essential in the field of high-density (HD) electrocorticography (ECoG) brain signal analysis in order to accurately interpret the recorded activity in relation to functional anatomy. Current localization methods for subchronically implanted HD electrode grids involve post-operative imaging. However, for situations where post-operative imaging is not available, such as during acute measurements in awake surgery, electrode localization is complicated. Intra-operative photographs may be informative, but not for electrode grids positioned partially or fully under the skull. Here we present an automatic and unsupervised method to localize HD electrode grids that does not require post-operative imaging. The localization method, named GridLoc, is based on the hypothesis that the anatomical and vascular brain structures under the ECoG electrodes have an effect on the amplitude of the recorded ECoG signal. More specifically, we hypothesize that the spatial match between resting-state high-frequency band power (45-120 Hz) patterns over the grid and the anatomical features of the brain under the electrodes, such as the presence of sulci and larger blood vessels, can be used for adequate HD grid localization. We validate this hypothesis and compare the GridLoc results with electrode locations determined with post-operative imaging and/or photographs in 8 patients implanted with HD-ECoG grids. Locations agreed with an average difference of 1.94 ± 0.11 mm, which is comparable to differences reported earlier between post-operative imaging and photograph methods. The results suggest that resting-state high-frequency band activity can be used for accurate localization of HD grid electrodes on a pre-operative MRI scan and that GridLoc provides a convenient alternative to methods that rely on post-operative imaging or intra-operative photographs.


Effectiveness of various irrigation activation protocols and the self-adjusting file system on smear layer and debris removal.
The purpose of the present study is to evaluate smear layer generation and residual debris after using self-adjusting file (SAF) or rotary instrumentation and to compare the debris and smear layer removal efficacy of the SAF cleaning/shaping irrigation system against final agitation techniques. One hundred and eight maxillary lateral incisor teeth were randomly divided into nine experimental groups (n = 12), and root canals were prepared using ProTaper Universal rotary files, with the exception of the SAF instrumentation group. During instrumentation, root canals were irrigated with a total of 16 mL of 5% NaOCl. For final irrigation, rotary-instrumented groups were irrigated with 10 mL of 17% EDTA and 10 mL of 5% NaOCl using different irrigation agitation regimens (syringe irrigation with needles, NaviTip FX, manual dynamic irrigation, CanalBrush, EndoActivator, EndoVac, passive ultrasonic irrigation (PUI), and SAF irrigation). In the SAF instrumentation group, root canals were instrumented for 4 min at a rate of 4 mL/min with 5% NaOCl and received a final flush with same as syringe irrigation with needles. The surface of the root dentin was observed using a scanning electron microscope. The SAF instrumentation group generated less smear layer and yielded cleaner canals compared to rotary instrumentation. The EndoActivator, EndoVac, PUI, and SAF irrigation groups increased the efficacy of irrigating solutions on the smear layer and debris removal. The SAF instrumentation yielded cleaner canal walls when compared to rotary instrumentation. None of the techniques completely removed the smear layer from the root canal walls.


Sudden onset of temporomandibular joint swelling and limited mouth opening: a rare case of ganglion cyst.
Preauricular swelling followed by limited mouth opening can be a challenging diagnosis. All anatomical structures and related pathologies should be examined. A 41-year-old woman presented to the Emergency Room complaining of limited mouth opening, severe pain that was worse on chewing, and swelling over her right temporomandibular joint (TMJ) that had started 3 days previously. Physical examination revealed localized swelling and redness over her right TMJ. Her right masticatory muscles were very painful and tender on palpation. Mouth opening was slightly limited. A computed tomography (CT) scan demonstrated a collection adjacent to her right TMJ, and reactive arthritis was diagnosed. Aspiration and arthrocentesis were performed, leading to immediate improvement. When symptoms returned 6 months later, magnetic resonance imaging (MRI) demonstrated a cystic lesion adjacent to the TMJ. Under general anesthesia an excisional biopsy was performed, and the pathologic examination revealed fibrous connective tissue with pseudocyst-like formation compatible with ganglion cyst. This case report demonstrates that a CT scan might lead to an incorrect diagnosis, whereas MRI scanning led to the correct diagnosis, thereby emphasizing the importance of choosing the right imaging modality. When a pathologic process of the TMJ is suspected, MRI is the gold standard imaging modality to diagnose the exact TMJ pathology. Complete surgical excision of ganglion cyst is recommended to determine a definite diagnosis. The final diagnosis should eventually be made by combining standard histology and MRI findings.


The impact of structured plaque control for patients with gingival manifestations of oral lichen planus: a randomized controlled study.
To evaluate the impact of a structured plaque control intervention on clinical and patient-centred outcomes for patients with gingival manifestations of oral lichen planus. Eighty-two patients were recruited into a 20-week randomized controlled trial. The intervention was structured plaque control comprising powered tooth brushing and inter-dental cleaning advice. Control subjects continued with their normal dental plaque control regimen. The primary outcome measure was the oral health impact profile (OHIP) with secondary outcomes of pain, plaque index, mucosal disease score and cost-effectiveness. Overall, the intervention patients showed statistically significant improvements in OHIP sum ordinal and OHIP dichotomous scores compared with control. There were improvements in the functional limitation, psychological discomfort and physical disability domains at 4- and 20-weeks and in the psychological disability domain at 20-weeks. The intervention was successful in reducing plaque compared to control (p < 0.001) and improvements were observed using the mucosal disease indices at the 4- and 20-week follow-ups (p < 0.001). A structured plaque control intervention was effective in improving the oral health-related quality of life and clinically observed gingival lesions. This study provides evidence to include intensive plaque control within patients' initial and on-going management.


Integration of high-volume molecular and imaging data for composite biomarker discovery in the study of melanoma.
In this work the effects of simple imputations are studied, regarding the integration of multimodal data originating from different patients. Two separate datasets of cutaneous melanoma are used, an image analysis (dermoscopy) dataset together with a transcriptomic one, specifically DNA microarrays. Each modality is related to a different set of patients, and four imputation methods are employed to the formation of a unified, integrative dataset. The application of backward selection together with ensemble classifiers (random forests), followed by principal components analysis and linear discriminant analysis, illustrates the implication of the imputations on feature selection and dimensionality reduction methods. The results suggest that the expansion of the feature space through the data integration, achieved by the exploitation of imputation schemes in general, aids the classification task, imparting stability as regards the derivation of putative classifiers. In particular, although the biased imputation methods increase significantly the predictive performance and the class discrimination of the datasets, they still contribute to the study of prominent features and their relations. The fusion of separate datasets, which provide a multimodal description of the same pathology, represents an innovative, promising avenue, enhancing robust composite biomarker derivation and promoting the interpretation of the biomedical problem studied.


Inhibition of the insulin-like growth factor-1 receptor potentiates acute effects of castration in a rat model for prostate cancer growth in bone.
Prostate cancer (PCa) patients with bone metastases are primarily treated with androgen deprivation therapy (ADT). Less pronounced ADT effects are seen in metastases than in primary tumors. To test if acute effects of ADT was enhanced by concurrent inhibition of pro-survival insulin-like growth factor 1 (IGF-1), rats were inoculated with Dunning R3327-G tumor cells into the tibial bone marrow cavity and established tumors were treated with castration in combination with IGF-1 receptor (IGF-1R) inhibitor NVP-AEW541, or by each treatment alone. Dunning R3327-G cells were stimulated by androgens and IGF-1 in vitro. In rat tibia, Dunning R3327-G cells induced bone remodeling, identified through increased immunoreactivity of osteoblast and osteoclast markers. Tumor cells occasionally grew outside the tibia, and proliferation and apoptotic rates a few days after treatment were evaluated by scoring BrdU- and caspase-3-positive tumor cells inside and outside the bone marrow cavity, separately. Apoptosis was significantly induced outside, but unaffected inside, the tibial bone by either castration or NVP-AEW541, and the maximum increase (2.7-fold) was obtained by the combined treatment. Proliferation was significantly reduced by NVP-AEW541, independently of growth site, although the maximum decrease (24%) was observed when NVP-AEW541 was combined with castration. Tumor cell IGF-1R immunoreactivity was evaluated in clinical PCa bone metastases (n = 61), and positive staining was observed in most cases (74%). In conclusion, IGF-1R inhibition may be evaluated in combination with ADT in patients with metastatic PCa, or in combination with therapies for the subsequent development of castration-resistant disease, although diverse responses could be anticipated depending on metastasis site.


Possible functions of alkaline phosphatase in dental mineralization: cadmium effects.
In mineralizing dental tissues the non-specific alkaline phosphatase, using paranitrophenylphosphate (p-NPP) as substrate, is also capable of splitting inorganic pyrophosphate (PPi). In contrast to the p-NPP-ase part of the enzyme, the PPi-ase part requires Zn2+ as a cofactor for its hydrolytic activity. The PPi-ase activity of the enzyme can be inhibited by cadmium ions (Cd2+), perhaps by replacing Zn2+ from the active site of the enzyme molecule. In addition to splitting PPi, the PPi-ase part of the enzyme may also be involved in the phosphorylation process of yet undetermined organic macromolecules. Cd2+ inhibits this phosphorylation process. Inhibition of the PPi-ase activity can also be accomplished by ascorbic acid known for its capacity to complex bivalent cations. Ascorbic acid may accordingly also remove Zn2+ from the active site of the PPi-ase. It is suggested that in developing dental tissues alkaline phosphatase is not only associated with the transport of phosphate ions towards the mineralization front, but is also involved in the phosphorylation of organic macromolecules, a process activated the PPi-ase part of the enzyme.


Persistent global marine euxinia in the early Silurian.
The second pulse of the Late Ordovician mass extinction occurred around the Hirnantian-Rhuddanian boundary (~444 Ma) and has been correlated with expanded marine anoxia lasting into the earliest Silurian. Characterization of the Hirnantian ocean anoxic event has focused on the onset of anoxia, with global reconstructions based on carbonate δ238U modeling. However, there have been limited attempts to quantify uncertainty in metal isotope mass balance approaches. Here, we probabilistically evaluate coupled metal isotopes and sedimentary archives to increase constraint. We present iron speciation, metal concentration, δ98Mo and δ238U measurements of Rhuddanian black shales from the Murzuq Basin, Libya. We evaluate these data (and published carbonate δ238U data) with a coupled stochastic mass balance model. Combined statistical analysis of metal isotopes and sedimentary sinks provides uncertainty-bounded constraints on the intensity of Hirnantian-Rhuddanian euxinia. This work extends the duration of anoxia to >3 Myrs - notably longer than well-studied Mesozoic ocean anoxic events.


A cross-sectional study on factors associated with health seeking behaviour of Malawians aged 15+ years in 2016.
Health seeking behaviour (HSB) refers to actions taken by individuals who are ill in order to find appropriate remedy. Most studies on HSB have only examined one symptom or covered only a specific geographical location within a country. In this study, we used a representative sample of adults to explore the factors associated with HSB in response to 30 symptoms reported by adult Malawians in 2016. We used the 2016 Malawi Integrated Household Survey dataset. We fitted a multilevel logistic regression model of likelihood of 'seeking care at a health facility' using a forward step-wise selection method, with age, sex and reported symptoms entered as a priori variables. We calculated the odds ratios (ORs) and their associated 95% confidence intervals (95% CI). We set the level of statistical significance at P < 0.05. Of 6909 adults included in the survey, 1907 (29%) reported symptoms during the 2 weeks preceding the survey. Of these, 937 (57%) sought care at a health facility. Adults in urban areas were more likely to seek health care at a health facility than those in rural areas (AOR = 1.65, 95% CI: 1.19-2.30, P = 0.003). Females had a higher likelihood of seeking care from health facilities than males (AOR = 1.26, 95% CI: 1.03-1.59, P = 0.029). Being of higher wealth status was associated with a higher likelihood of seeking care from a health facility (AOR = 1.58, 95% CI: 1.16-2.16, P = 0.004). Having fever and eye problems were associated with higher likelihood of seeking care at a health facility, while having headache, stomach ache and respiratory tract infections were associated with lower likelihood of seeking care at a health facility. This study has shown that there is a need to understand and address individual, socioeconomic and geographical barriers to health seeking to increase access and appropriate use of health care and fast-track progress towards Universal Health Coverage among the adult population.


An evaluation of antenatal fetal acoustic stimulation.
Fetal heart rate reactivity was evaluated following acoustic stimulation testing (AST). The AST and NST (non-stress test) were compared with regards to certain adverse perinatal outcome criteria, and in a selected sample of cases, to other surveillance tests. These tests were the oxytocin challenge test (OCT) and biophysical profile (BPP). 479 tests were performed on 240 high-risk patients. The AST significantly increased fetal heart rate reactivity. With regards adverse perinatal outcome criteria, there was no significant difference between the AST and NST in relation to sensitivity, specificity or predictive values. In the 38 patients with both non-reactive NSTs and reactive ASTs, 5 (13.5%) had immediate follow-up surveillance tests (OCTs and/or BPPs) that were non-reassuring and necessitated delivery. In four of the five cases, there was evidence of potential fetal compromise. These preliminary observations suggest that the AST may have evoked reactivity in fetuses with early compromise, and raise concerns about replacing the NST with the AST as a primary screening test of fetal well-being.


Pachychoroid Neovasculopathy Disguising as Age-Related Macular Degeneration Treated by Spironolactone and Anti-VEGF Combination Therapy.
Nonresponse of neovascular age-related macular degeneration (nAMD) to anti-vascular endothelial growth factor (anti-VEGF) therapy can often be attributed to misdiagnosis, and pathologies mimicking AMD might require different therapeutic concepts. In the following, we want to outline a case of presumed nAMD which revealed to be pachychoroid neovasculopathy (PNV) and was successfully treated by the addition of spironolactone. A 67-year-old female patient was referred for nonresponse of nAMD on her left eye after 29 intravitreal injections of aflibercept with no complete resolution of subretinal fluid. On fundoscopy, both maculae presented with pigment epithelium alterations, while the left eye showed subretinal fluid on optical coherence tomography (OCT) with an associated pigment epithelium detachment, which revealed to contain a neovascular network on OCT angiography. There was faint leakage on fluorescence (FAG) and indocyanine green angiography (ICGA) and some focal vascular dilation of the neovascular network on ICGA. Due to the absence of Drusen on any eye, a thick choroid, and the presence of a gravitational tract on blue autofluorescence (BAF), chronic central serous chorioretinopathy with a choroidal neovascularization, defined as PNV in the pachychoroid disease was diagnosed. Upon the addition of spironolactone to anti-VEGF treatment, choroidal thickness significantly decreased, and subretinal fluid resolution was observed and maintained for the first time. In conclusion, PNV should be ruled out in cases of presumed nAMD nonresponding to anti-VEGF. In these cases, a combination therapy of anti-VEGF and mineralocorticoid antagonists can facilitate fluid resorption.


Rare malformation of glans penis: arteriovenous malformation.
Pediatric glans penis malformations, especially arteriovenous malformations (AVM), are very rare. Herein, we report two rare cases. A 14-year-old boy attended our outpatient clinic with chief complaints of purple swelling and rapidly growing lesion on the glans penis. The lesion was excised surgically after physical and radiological evaluations. Pathology reported AVM and the patient is being followed up. The second case is a 2-year-old boy who was admitted with a big lesion involving glans penis and genital area that has been present since birth. In physical and radiological evaluations, lesion on the glans penis was pulsatile. Parents of the patient did not want any surgery and patient has been in follow-up. Diagnosis of the vascular lesions on glans penis is very easy by physical and radiological examinations today. Long-term follow-up is very important for AVM. Clinicians must make a careful effort to document new glans lesions in the pediatric population and decrease anxiety in the parents of affected children.


Thermographic Changes following Short-Term High-Intensity Anaerobic Exercise.
Current studies report thermographic changes following aerobic or resistance exercise but not short, vigorous anaerobic exercise. Therefore, we investigated body surface temperature changes using thermal imaging following a short session of anaerobic exercise. We studied three different regions of interest (ROIs): the legs, chest, and forehead. Thermal imaging for each participant was performed before and immediately after completing a Wingate anaerobic test and every minute during a 15 min recovery period. Immediately after the test, the maximum temperature was significantly higher in all ROIs (legs, p = 0.0323; chest, p = 0.0455; forehead, p = 0.0444) compared to pre-test values. During the recovery period, both legs showed a significant and continuous temperature increase (right leg, p = 0.0272; left leg, p = 0.0382), whereas a non-significant drop was noted in the chest and forehead temperatures. Additionally, participants with a lower anaerobic capacity exhibited a higher delta increase in surface leg temperature than participants with higher anaerobic capacities, with a minimal change in surface leg temperature. This is the first study to demonstrate body surface temperature changes following the Wingate anaerobic test. This temperature increase is attributed to the high anaerobic mechanical power outputs achieved by the leg muscles and the time taken for temperature reduction post-exercise.


Treatment for severe craniocerebral trauma combined with transtentorial hernia in children.
To explore the treating method for severe craniocerebral trauma combined with transtentorial hernia in children. We treated 58 children with severe craniocerebral trauma combined with transtentorial hernia through evacuating the hematomas, incising the tentorium but preserving the floating bone flap between January 1996 and January 2002. GCS was 3-5 in 17 cases and 6-8 in 41 cases. After treatment, 46 patients (79.30%) recovered well, 6 (10.30%) suffered from mild disability, 1 (1.72%) suffered from severe disability, 1 (1.72%) was in vegetative state, and 4 (6.90%) died. Evacuating hematomas and incising tentorium can effectively treat the child patients with severe craniocerebral trauma combined with transtentorial hernia, which can decrease the disability and mortality rates greatly, preserve the skull, exempt reoperation for cranioplasty and relieve the psychologic and physiologic burden of the child patients.


The clinical course of asymptomatic esophageal candidiasis incidentally diagnosed in general health inspection.
Esophageal candidiasis mostly occurs in the immunocompromised host. However, it may also affect healthy people and is frequently asymptomatic. The clinical significance of asymptomatic esophageal candidiasis (AEC) is still unclear. The aims of the study were to investigate the prevalence of AEC during health inspection and to identify its predisposing factors and clinical significance. A total of 49,497 subjects who underwent a health inspection that included upper endoscopy were enrolled. We retrospectively reviewed the subject's self-reporting questionnaires, medical records and endoscopic findings. We considered "long-term" follow-up to be >6 months with at least one more follow-up endoscopy. One hundred and seventy (0.4%) subjects were endoscopically diagnosed as esophageal candidiasis and 141 subjects were AEC. Multivariate analysis revealed that old age (≥60 years) was an independent risk factor for AEC (OR, 1.862, p = 0.005). The number of subjects with long-term follow-up was 79 (195.3 person-years). Among these, AEC of 64 subjects (81.0%) had disappeared on the follow-up endoscopy and was not recurrent. The other 15 subjects had AEC diagnosed more than once on the follow-up endoscopy, and 5 of them were spontaneously healed during the follow-up period. The remaining 10 subjects whose candidiasis was sustained up to the last endoscopy did not complain of symptoms during the follow-up period, and their endoscopic findings did not worsen. AEC is rare and old age is the only risk factor. AEC does not require medical care because it is a self-limited disease.


Obsessional Disorders in al-Balkhi's 9th century treatise: Sustenance of the Body and Soul.
Some argue that the earliest case of Obsessive-Compulsive Disorder (OCD) was reported by Robert Burton in his compendium The Anatomy of Melancholy (1621) and that only in the 19th century did modern concepts of OCD evolve, differentiating it from other types of mental illness. In this paper, we aim to reveal an even earlier presentation of the malady we now call OCD based on the 9th century work, Sustenance of the Body and Soul, written by Abu Zayd al-Balkhi during the Islamic Golden Era. Discovery of this manuscript reveals that Abu Zayd al-Balkhi should be credited with differentiating OCD from other forms of mental illnesses nearly a millennium earlier than is currently claimed by anthologies documenting the history of mental illness. Particular attention is paid to al-Balkhi's classifications, symptom descriptions, predisposing factors, and the treatment modalities for obsessional disorders. Analysis of this manuscript in light of the DSM-5 and modern scientific discoveries reveals transcultural diagnostic consistency of OCD across many centuries. Theoretical and clinical implications of these findings are also discussed.


Factors of delayed hypersensitity in pulmonary tuberculosis.
In a study of delayed hypersensitivity in 54 patients with pulmonary tuberculosis who were on specific treatment, 33 patients could not be sensitized to dinitrochlorobenzene (DNCB) although 25 of these were tuberculin (PPD) positive. The majority of the patients also had positive skin reactions to another recall antigen, streptokinase-streptodornase. To exclude a drug effect on DNCB reactivity, 40 untreated patients were studied. Twenty-six (65 per cent) of these did not show DNCB reactivity. The cause for nonsensitization to DNCB was not clear. There was no abnormality in the number of T lymphocytes in the peripheral blood of 28 patients.


Chinese primary care providers and motivating factors on performance.
China launched its new health care reform in 2009. One of its goals is to improve primary care system and strengthen primary care workforce. Although it has been studied internationally, motivating factors for primary care workforce have not been examined in China. To provide an overview of major performance motivating factors for primary care providers (PCPs) in China and examine associations between these factors and individual and practice setting characteristics. Data for the study were from the 2011 China Primary Care Workforce Survey that provides the most current assessment of community-based PCPs. Outcome measures were scores indicating performance improvement due to 11 factors. Covariates representing personal and practice characteristics included age, gender, education, location, types of providers and specialties. Outcomes were compared by PCP category and urban/rural setting. Associations were assessed using logistic regressions. The most important motivating factors for PCPs to improve performance were professional development, training opportunities, living environment, benefits, working conditions and income. There were greater needs for improvement in rural than urban settings, especially in living environment. Types of PCPs were associated with needs for improvement in different factors. There were more needs from nurses and village doctors. A new and comprehensive incentive mechanism could be designed and implemented in China, which (i) focuses on more professional development opportunities, enhanced training programs and better compensation and benefits and (ii) targets PCPs practicing in different settings.


Morphological and Functional Parameters in Patients with Tooth Wear before and after Treatment.
Advanced tooth wear often results in lost vertical dimension and impacts facial aesthetics. Complex restorative treatment can replace the lost tooth structure and improve functional occlusal and facial skeleton parameters. The aim of the study is to assess changes in the morphological and functional occlusal parameters of the facial skeleton after prosthetic rehabilitation that increased lost occlusal vertical dimension. 50 patients with advanced tooth wear were clinically examined, to assess the degree of wear. Each subject underwent cephalometric analysis, digital occlusal analysis, and electromyographic analysis, of the anterior temporalis, superficial masetter, anterior digastric, and the sternocleidomastoid muscles. Prosthodontic treatment was performed to restore the occlusal vertical dimension of each subject's occlusion, which was followed by repeating the pretreatment analyses. Pre and post treatment parameters were statistically compared. Pre-treatment cephalometric analysis showed that lost vertical dimension reduced anterior facial height and resulted in small angular skeletal parameters. Post treatment anterior facial height increased from the increased occlusal vertical dimension. The mean value of functional electrical activity during clenching post treatment, increased compared to pretreatment. Increasing the vertical dimension of occlusion improved facial aesthetics by positively affecting facial skeletal angles. The restored occlusal surface morphology changed the pre treatment flat broad occlusal contacts into more point contacts. The increased vertical dimension of occlusion after treatment also increased muscle activity levels over the pretreatment levels after three months period of adaptation.


Trust as Glue in Nanotechnology Governance Networks.
This paper reflects on the change of relations among participants in nanotechnology governance through their participation in governance processes such as stakeholder dialogues. I show that policymaking in practice-that is, the practice of coming and working together in such stakeholder dialogues-has the potential for two-fold performative effects: it can contribute to the development of trust and mutual responsibility on the part of the involved actors, and it may bring about effects on the formation of boundaries of what is sayable and thinkable in nanotechnology governance. Three vignettes about the work of the German NanoKommission indicate the development of new relations of trust, recognition and mutual responsibility among actors. It is concluded that governance in practice can assemble new collectives in which relations of trust are the glue holding the complex structure together. While such a consensus-based progress may be favourable for smooth technology development, it can be considered problematic if evaluated against the ideals of deliberative democracy, which often form the premises on which public engagement is based. Stakeholder forums were set in place with the intention of including various actors, but this is Janus-faced: if a dialogue becomes encapsulated in new governance networks, new exclusions can arise. For example, a policing of which information is released to a wider audience can occur.


LYCAT, a homologue of C. elegans acl-8, acl-9, and acl-10, determines the fatty acid composition of phosphatidylinositol in mice.
Mammalian phosphatidylinositol (PI) has a unique fatty acid composition in that 1-stearoyl-2-arachidonoyl species is predominant. This fatty acid composition is formed through fatty acid remodeling by sequential deacylation and reacylation. We recently identified three Caenorhabditis elegans acyltransferases (ACL-8, ACL-9, and ACL-10) that incorporate stearic acid into the sn-1 position of PI. Mammalian LYCAT, which is the closest homolog of ACL-8, ACL-9, and ACL-10, was originally identified as a lysocardiolipin acyltransferase by an in vitro assay and was subsequently reported to possess acyltransferase activity toward various anionic lysophospholipids. However, the in vivo role of mammalian LYCAT in phospholipid fatty acid metabolism has not been well elucidated. In this study, we generated LYCAT-deficient mice and demonstrated that LYCAT determined the fatty acid composition of PI in vivo. LYCAT-deficient mice were outwardly healthy and fertile. In the mice, stearoyl-CoA acyltransferase activity toward the sn-1 position of PI was reduced, and the fatty acid composition of PI, but not those of other major phospholipids, was altered. Furthermore, expression of mouse LYCAT rescued the phenotype of C. elegans acl-8 acl-9 acl-10 triple mutants. Our data indicate that LYCAT is a determinant of PI molecular species and its function is conserved in C. elegans and mammals.


GH signaling in skeletal muscle and adipose tissue in healthy human subjects: impact of gender and age.
The mechanisms underlying the impact of age and gender on the GH-IGF1 axis remain unclear. We tested the hypothesis that age and gender have impacts on GH signaling in human subjects in vivo. A total of 20 healthy non-obese adults ('young group'<30 years (5F/5M) and 'old group'>60 years (5F/5M)) were studied after: i) an i.v. GH bolus (0.5 mg) and ii) saline. Muscle and fat biopsies were obtained after 30 and 120 min. Total and phosphorylated STAT5B proteins, gene expression of IGF1, SOCS1, SOCS2, SOCS3 and CISH, body composition, VO2max, and muscle strength were measured. In the GH-unstimulated state, women displayed significantly elevated levels of CISH mRNA in muscle (P=0.002) and fat (P=0.05) and reduced levels of IGF1 mRNA in fat. Phosphorylated STAT5B (pSTAT5b) was maximally increased in all subjects 30 min after GH exposure and more pronounced in women when compared with men (P=0.01). IGF1, SOCS1, SOCS2, SOCS3, and CISH mRNA expression increased significantly in muscle after 120 min in all subjects with no impact of age and gender. GH-induced pSTAT5b correlated inversely with lean body mass (LBM; r=-0.56, P=0.01) and positively with the CISH mRNA response (r=0.533, P=0.05). i) GH signaling in muscle and fat after a single GH bolus in healthy human subjects is age independent, ii) we hypothesize that constitutive overexpression of CISH may contribute to the relative GH resistance in women, and iii) experimental studies on the impact of sex steroid administration and physical training on GH signaling in human subjects in vivo are required.


Effects of frequency of static stretching on straight-leg raise in elementary school children.
The aim of this study was to evaluate the efficacy of different frequencies of a stretching exercise program on lower extremity range of motion (ROM) in prepubertal schoolchildren. A total of 62 children were divided into 3 groups (experimental groups: A, B; control group: C). Experimental group A performed hamstring stretches for 5 min during the Physical Education classes over a full school term (9 months), 2 sessions per week (31 weeks, 62 sessions of Physical Education). Experimental group B performed hamstring stretches for 5 min during the Physical Education classes and during a specific extracurricular physical activity, over a full school term (9 months), 4 sessions per week (31 weeks, 62 sessions of Physical Education and 62 sessions of after-school physical activities). Control group followed the standard class program of Physical Education classes. Hamstring flexibility was measured using the straight leg raise test before and after the program. No significant differences were revealed in ROM before and after the Physical Education classes for the control group. However, significant improvements in ROM were shown in the two experimental groups (P<0.001). Four days per week produced a greater rate of gains in ROM (16.9 degrees) than 2 days per week (9.3 degrees). For all groups, the initial and the final ROM between the right and left sides were similar. This study indicates that a full school term (9 months) incorporating static stretching as part of the Physical Education classes and the extracurricular physical activities significantly increases the ROM of the hamstrings in prepubertal schoolchildren. The study also suggests that the increase of the frequency of stretching is effective for increasing ROM.


Are there any unique epidemiological and vascular risk factors for ischaemic strokes that occur in the morning hours?
It is now accepted that the incidence of ischaemic stroke is significantly increased in the morning. Any attempts to prevent its occurrence must be based on determining the mechanisms, special risk factors and appropriate protective measures needed during this vulnerable period. We studied the epidemiological features of morning stroke and reviewed the records of 2312 consecutive patients recorded prospectively in the Tel Aviv Stroke Register. Information about time of stroke onset was obtained from the patient, family members or other observers. The study parameters of age, sex, vascular distribution (carotid versus vertebrobasilar), ischaemic heart disease, myocardial infarction, diabetes mellitus, arterial hypertension, smoking, hyperlipidaemia, stroke severity and recurrence were compared between patients with morning stroke and those with stroke occurring at other times. In 599 patients (34%) stroke occurred between 06:00 and 10:00 h. No evaluated parameter was found to be statistically different among the morning stroke patients compared with stroke occurring at other times (P < 0.2). Patients with arterial hypertension and ischaemic heart disease and male patients had a greater likelihood of stroke occurrence between 22:00 and 02:00 h (P < 0.05). Our data suggest that none of the common vascular risk factors could explain the morning peak of stroke occurrence. The next step in the quest for understanding the phenomenon of circadian variation is to identify other physiological factors and the effects of pharmacological agents in morning stroke protection.


Scored Patient-Generated Subjective Global Assessment, albumin and transferrin for nutritional assessment of gastrostomy fed head or neck cancer patients.
Gastrostomy fed head or neck cancer patients frequently have impaired speech capacities. Enteral feeding teams frequently depend on laboratorial or anthropometrical parameters for nutritional assessment. In these patients, this study aimed to evaluate: (1) the practicability of Scored - Patient-Generated Subjective Global Assessment (PG-SGA); (2) their nutritional status using the Scored-PG-SGA; (3) association of serum albumin and transferrin values to the nutritional status rating using PG-SGA. On adult outpatients with head or neck cancer under prolonged (> 1 month) gastrostomy feeding, Scored-PGSGA, albumin and transferrin were evaluated during the same appointment. Scored-PG-SGA was easily feasible in 42 patients, even in patients with speech difficulties. Twenty-five patients were moderately/severely undernourished (PG-SGA/B+C). Scored-PG-SGA rated 41 patients as ≥ 2, thus needing nutritional/ pharmacologic intervention. Albumin was low in 13 patients. Transferrin was low in 19 patients. Average albumin and transferrin in moderately/severely undernourished patients (PG-SGA/B+C) was significantly lower than in well-nourished (PG-SGA/A). There was association between Scored- PG-SGA rating, albumin and transferrin. In PEG fed head or neck cancer patients, PGSGA was practicable and useful, even in patients with impaired speaking skills. Most patients displayed moderate/severe malnutrition (PG-SGA/B+C). Scored-PG-SGA rated 41 patients as needing for nutritional/pharmacological intervention. Scored-PG-SGA should be systematically included in the evaluation of these patients. In these patients, albumin and transferrin levels showed relation with Scored-PG-SGA and should be considered as nutritional biomarkers.


Truncating and zinc-finger variants in GLI2 are associated with hypopituitarism.
Variants in transcription factor GLI2 have been associated with hypopituitarism and structural brain abnormalities, occasionally including holoprosencephaly (HPE). Substantial phenotypic variability and nonpenetrance have been described, posing difficulties in the counseling of affected families. We present three individuals with novel likely pathogenic GLI2 variants, two with truncating and one with a de novo missense variant p.(Ser548Leu), and review the literature for comprehensive phenotypic descriptions of individuals with confirmed pathogenic (a) intragenic GLI2 variants and (b) chromosome 2q14.2 deletions encompassing only GLI2. We show that most of the 31 missense variants previously reported as pathogenic are likely benign or, at most, low-risk variants. Four Zn-finger variants: p.(Arg479Gly), p.(Arg516Pro), p.(Gly518Lys), and p.(Tyr575His) were classified as likely pathogenic, and three other variants as possibly pathogenic: p.(Pro253Ser), p.(Ala593Val), and p.(Pro1243Leu). We analyze the phenotypic descriptions of 60 individuals with pathogenic GLI2 variants and evidence a morbidity spectrum that includes hypopituitarism (58%), HPE (6%) or other brain structure abnormalities (15%), orofacial clefting (17%) and dysmorphic facial features (35%). We establish that truncating and Zn-finger variants in GLI2 are associated with a high risk of hypopituitarism, and that a solitary median maxillary central incisor is part of the GLI2-related phenotypic variability. The most prevalent phenotypic feature is post-axial polydactyly (65%) which is also the mildest phenotypic expression of the condition, reported in many parents of individuals with systemic findings. Our approach clarifies clinical risks and the important messages to discuss in counseling for a pathogenic GLI2 variant.


Comparative Effects of Game Profile-Based Training and Small-Sided Games on Physical Performance of Elite Young Soccer Players.
Dello Iacono, A, Beato, M, and Unnithan, V. Comparative effects of game profile-based training and small-sided games on physical performance of elite young soccer players. J Strength Cond Res 35(10): 2810-2817, 2021-This study was designed to investigate and compare the effects of game profile-based training (GPBT) and small-sided game (SSG) training on physical performances of elite youth soccer players during the in-season period. Twenty young soccer players (18.6 ± 0.6) were randomly assigned to either GPBT or SSG protocols performed twice a week for 8 weeks. The GPBT consisted of 2 sets of 6-10 minutes of intermittent soccer-specific circuits. The SSG training consisted of 3-5 sets of 5 vs. 5 SSGs played on a 42 × 30-m pitch. Before and after the training program, the following physical performances were assessed: repeated sprint ability, change of direction (COD), linear sprinting on 10 m and 20 m, countermovement jump, and intermittent running (YYIRL1). Significant improvements were found in all the assessed variables after both training interventions (p < 0.05). The GPBT group improved more than the SSG group in the 10-m and 20-m sprint tests by 2.4% (g = 0.4; small effect) and 4% (g = 0.9; large effect), respectively. Conversely, the SSG group jumped 4% higher (g = 0.4; small effect) and resulted 6.7% quicker than the GPBT (g = 1.5; large effect) in completing the COD task. These results suggest both GPBT and SSGs to be effective for fitness development among elite young soccer players during the competitive season. More importantly, these 2 conditioning methodologies may be considered in terms of specificity for selectively improving or maintaining specific soccer fitness-related performances in the latter phase of the season.


Mate Value Discrepancy and Mate Retention Behaviors of Self and Partner.
This study investigated the relationship between perceived mate value discrepancy (i.e., the difference between an individual's mate value and their partner's mate value) and perceived frequency of mate retention performed by an individual relative to his or her partner. In two studies, participants in long-term, exclusive, sexual, heterosexual relationships reported their own, and their partner's, mate value and mate retention. Samples included 899 community members (Study 1) and 941 students and community members (Study 2). In Study 1, we documented that individuals with higher self-perceived short-term mate value, and who perceive their partner to have lower (vs. higher) short-term mate value, perform less frequent Benefit-Provisioning mate retention, controlling for the partner's Benefit-Provisioning mate retention. In Study 2, we documented that individuals who perceive that they could less easily replace their partner, and who perceive their partner could more (vs. less) easily replace them, perform more frequent mate retention (Benefit-Provisioning and Cost-Inflicting), controlling for the partner's mate retention. These results highlight the importance of assessing perceived discrepancies in mate value (notably, regarding the replaceability of self and partner with another long-term mate) and perceived mate retention behaviors of self, relative to partner, between men and women in long-term relationships.


Tree peony PsMYB44 negatively regulates petal blotch distribution by inhibiting dihydroflavonol-4-reductase gene expression.
The tree peony (Paeonia suffruticosa Andr.) has been widely cultivated as a field plant, and petal blotch is one of its important traits, which not only promotes proliferation but also confers high ornamental value. However, the regulatory network controlling blotch formation remains elusive owing to the functional differences and limited conservation of transcriptional regulators in dicots. We performed phylogenetic analysis to identify MYB44-like transcription factors in P. suffruticosa blotched cultivar 'High noon' petals. A candidate MYB44-like transcription factor, PsMYB44, was analysed via expression pattern analysis, subcellular localization, target gene identification, gene silencing in P. suffruticosa petals and heterologous overexpression in tobacco. A blotch formation-related MYB44-like transcription factor, PsMYB44, was cloned. The C-terminal of the PsMYB44 amino acid sequence had a complete C2 motif that affects anthocyanin biosynthesis, and PsMYB44 was clustered in the MYB44-like transcriptional repressor branch. PsMYB44 was located in the nucleus, and its spatial and temporal expression patterns were negatively correlated with blotch formation. Furthermore, a yeast one-hybrid assay showed that PsMYB44 could target the promoter of the late anthocyanin biosynthesis-related dihydroflavonol-4-reductase (DFR) gene, and a dual-luciferase assay demonstrated that PsMYB44 could repress PsDFR promoter activity. On the one hand, overexpression of PsMYB44 significantly faded the red colour of tobacco flowers and decreased the anthocyanin content by 42.3 % by downregulating the expression level of the tobacco NtDFR gene. On the other hand, PsMYB44-silenced P. suffruticosa petals had a redder blotch colour, which was attributed to the fact that silencing PsMYB44 redirected metabolic flux to the anthocyanin biosynthesis branch, thereby promoting more anthocyanin accumulation in the petal base. These results demonstrated that PsMYB44 negatively regulated the biosynthesis of anthocyanin by directly binding to the PsDFR promoter and subsequently inhibiting blotch formation, which helped to elucidate the molecular regulatory network of anthocyanin-mediated blotch formation in plants.


Placebo Response in Pediatric Anxiety Disorders: Results from the Child/Adolescent Anxiety Multimodal Study.
The aim of this study is to identify predictors of pill placebo response and to characterize the temporal course of pill placebo response in anxious youth. Data from placebo-treated patients (N = 76) in the Child/Adolescent Anxiety Multimodal Study (CAMS), a multisite, randomized controlled trial that examined the efficacy of cognitive-behavioral therapy, sertraline, their combination, and placebo for the treatment of separation, generalized, and social anxiety disorders, were evaluated. Multiple linear regression models identified features associated with placebo response and models were confirmed with leave-one-out cross-validation. The likelihood of improvement in patients receiving pill placebo-over time-relative to improvement associated with active treatment was determined using probabilistic Bayesian analyses. Based on a categorical definition of response (Clinical Global Impressions-Improvement Scale score ≤2), nonresponders (n = 48), and pill placebo responders (n = 18) did not differ in age (p = 0.217), sex (p = 0.980), race (p = 0.743), or primary diagnosis (all ps > 0.659). In terms of change in anxiety symptoms, separation anxiety disorder and treatment expectation were associated with the degree of pill placebo response. Greater probability of placebo-related anxiety symptom improvement was observed early in the course of treatment (baseline to week 4, p < 0.0001). No significant change in the probability of placebo-related improvement was observed after week 4 (weeks 4-8, p = 0.07; weeks 8-12, p = 0.85), whereas the probability of improvement, in general, significantly increased week over week with active treatment. Pill placebo-related improvement occurs early in the course of treatment and both clinical factors and expectation predict this improvement. Additionally, probabilistic approaches may refine our understanding and prediction of pill placebo response.


Amiloride-sensitive epithelial Na+ channel currents in surface cells of rat rectal colon.
Surface cells of the mammalian distal colon are shown to molecularly express the amiloride-sensitive epithelial Na+ channel composed of three homologous subunits (alpha-, beta-, and gamma-ENaC). However, because basic electrophysiological properties of amiloride-sensitive Na+ channels expressed in these cells are largely unknown at the cellular level, functional evidence for the involvement of the subunits in the native channels is incomplete. Using electrophysiological techniques, we have now characterized functional properties of native ENaC in surface cells of rectal colon (RC) of rats fed a normal Na+ diet. Ussing chamber experiments showed that apical amiloride inhibited a basal short-circuit current in mucosal preparation of RC with an apparent half-inhibition constant (Ki) value of 0.20 microM. RT-PCR analysis confirmed the presence of transcripts of alpha-, beta-, and gamma-rENaC in rectal mucosa. Whole cell patch-clamp experiments in surface cells of intact crypts acutely isolated from rectal mucosa identified an inward cationic current, which was inhibited by amiloride with a Ki value of 0.12 microM at a membrane potential of -64 mV, the inhibition being weakly voltage dependent. Conductance ratios of the currents were Li+ (1.8) > Na+ (1) >> K+ ( approximately 0), respectively. Amiloride-sensitive current amplitude was almost the same at 15 or 150 mM extracellular Na+, suggesting a high Na+ affinity for current activation. These results are consistent with the hypothesis that a heterooligomer composed of alpha-, beta-, and gamma-ENaC may be the molecular basis of the native channels, which are responsible for amiloride-sensitive electrogenic Na+ absorption in rat rectal colon.


In vitro shear bond strength between fluorinated zirconia ceramic and resin cements.
The purpose of this study was to evaluate the efficiency of a gas-phase fluorination method under different fluorination periods through using two resin cements. 84 zirconia specimens in dimensions of 5 mm × 5 mm × 2 mm were prepared and surface treated with 50 µm aluminum oxide particles or gas phase fluorination for 2 min, 5 min, or 10 min. One specimen in each group was surface analyzed under scanning electron microscope. The remaining specimens were bonded to composite cylinders in dimensions of 2 mm diameter and 3 mm high with Panavia SA Plus or Variolink N. Then, the specimens were stored in 37℃ distilled water for 24 hours and shear bond strength test was applied at a speed of 1 mm/min. The highest shear bond strength values were observed in the samples fluorinated for 5 minutes and cemented with Panavia SA Plus. Variolink N did not elicit any statistical differences between surface treatments. Panavia SA Plus resin cement and Variolink N resin cements featured statistically significant difference in shear bond strength values only in the case of 5 minutes of fluorination treatment. According to the results of this study, application of 5 minutes of fluorination with 10-methacryloyloxydecyl dihydrogen phosphate monomer (MDP) containing Panavia SA Plus resin cement increased the resin bond strength of zirconia. Fluorination of the zirconia surface using conventional resin cement, Variolink N, did not lead to an increase in bond strength.


The influence of physical activity, socioeconomic status, and ethnicity on the weight status of adolescents.
This study examined the effects of physical activity, television viewing, video game play, socioeconomic status (SES), and ethnicity on body mass index (BMI). The sample was 2389 adolescents, 10 to 16 years of age (12.7 +/- 1.0 years); 1240 (52%) females and 1149 (48%) males; 77% white and 23% African American; from rural (77%) and urban (23%) settings. BMI and skinfolds were directly assessed. All other data were obtained from questionnaires. Watching television on non-school days was related to being overweight (p < 0.005). However, when BMI analyses were adjusted for ethnicity and SES, there were no significant effects of television viewing on BMI (p > 0.061). Increased hours of video game play enhanced the risk of being overweight for both genders when analyses were adjusted for ethnicity and SES (p < 0.019). In males, participation in as little as one high-intensity physical activity 3 to 5 days a week decreased the ethnic- and SES-adjusted relative risk of being overweight (RR = 0.646; CI: 0.427 to 0.977). For females, the ethnic- and SES-adjusted relative risk for being overweight was not significantly altered by physical activity. The logistic analyses further indicated the influence of low SES and African American ethnicity overshadowed any direct effect of television or videos. Because weight status of male adolescents appears to be more related to exercise habits than to television or video game habits, increased participation in high-intensity exercise appears to be important. For females, neither videos nor exercise habits appear to be related to risk of being overweight. However, ethnicity and SES may be important factors that can influence body weight status, while television viewing may be of some importance. Thus, programs to reduce obesity in female adolescent should focus their efforts in lower SES communities.


Tetravalent biepitopic targeting enables intrinsic antibody agonism of tumor necrosis factor receptor superfamily members.
Agonism of members of the tumor necrosis factor receptor superfamily (TNFRSF) with monoclonal antibodies is of high therapeutic interest due to their role in immune regulation and cell proliferation. A major hurdle for pharmacologic activation of this receptor class is the requirement for high-order clustering, a mechanism that imposes a reliance in vivo on Fc receptor-mediated crosslinking. This extrinsic dependence represents a potential limitation of virtually the entire pipeline of agonist TNFRSF antibody drugs, of which none have thus far been approved or reached late-stage clinical trials. We show that tetravalent biepitopic targeting enables robust intrinsic antibody agonism for two members of this family, OX40 and DR5, that is superior to extrinsically crosslinked native parental antibodies. Tetravalent biepitopic anti-OX40 engagement co-stimulated OX40low cells, obviated the requirement for CD28 co-signal for T cell activation, and enabled superior pharmacodynamic activity relative to native IgG in a murine vaccination model. This work establishes a proof of concept for an engineering approach that addresses a major gap for the therapeutic activation of this important receptor class.


Association of left atrial reservoir function with left atrial structural remodeling related to left ventricular dysfunction in asymptomatic patients with hypertension: evaluation by two-dimensional speckle-tracking echocardiography.
Left atrial (LA) structural and functional abnormalities are vital steps on the pathway toward heart failure with preserved ejection fraction in asymptomatic patients. The purpose of this study was to assess the relationship of LA function, particularly reservoir function, with LA structural remodeling related to the left ventricular (LV) dysfunction in asymptomatic patients with hypertension (HT) using conventional, tissue Doppler, and 2-D speckle-tracking echocardiography. Fifty age-matched healthy individuals and 140 patients with HT, including 75 with LA volume index (LAVI)<29 ml/m2 (normal LA group) and 65 with LAVI≥29 ml/m2 (large LA group), were enrolled. We defined peak early diastolic transmitral flow velocity/peak early diastolic mitral annular motion velocity (E/e')/peak systolic LA strain (S-LAs) as LA diastolic stiffness. The LV mass index, relative LV wall thickness, peak atrial systolic transmitral flow velocity, LA total, active, and passive emptying volume indexes, and E/e'/S-LAs were greatest, and S-LAs, peak early diastolic LA strain, peak systolic LV longitudinal strain and circumferential strain rate, and peak early diastolic LV radial strain rate were lower in the large LA group compared with control and/or normal LA group. Multivariate linear regression analysis revealed that aging, LA remodeling, and LV systolic and diastolic dysfunction are defined as strong predictors related to increased LA diastolic stiffness in the large LA group. HT alters LA dynamics significantly, with resultant increased LA volume and diastolic stiffness related to LV diastolic and systolic dysfunction, even in asymptomatic patients. Earlier treatment with renin–angiotensin system inhibitors may improve abnormal LA-LV interaction in this patient population.


Assessing the impact of petrol stations on their immediate surroundings.
This paper describes a novel methodology for evaluating the extent to which petrol stations affect their surroundings. The method is based on the fact that the ratio of the concentrations of aliphatic and aromatic hydrocarbon pollutants in the air of the petrol stations and their surroundings (basically determined by vapor emissions from unburned gasoline) differs from the ratio found in urban air, which is mainly influenced by traffic emissions. Bearing this in mind, the spatial limit of influence of petrol stations in any direction would be the first point, moving away from the station, where the ratio becomes equal to the urban background ratio. Application of the methodology involves multipoint measuring campaigns of the air at the studied petrol station and built-up area in general and processing the data with software capable of providing isoconcentration contours. The procedure should help local authorities in terms of land management, so that a "belt" can be established around petrol stations where housing or vulnerable populations and activities such as those in schools, hospitals and community centers should be restricted.


JCOA The Japanese Clinical Orthopaedic Association the questionnaire survey on the physical changes after the self-restraint of outdoor activities with the COVID-19 crisis (2nd report).
In March 2021, the 3rd wave of COVID-19 pandemic had ended and the second emergency declaration in January in Tokyo and 3 other prefectures had been lifted. The restrictions on the social activities imposed on the Japanese people and it had become established as "the new lifestyle norm" for each age group. Following our first survey, we conducted a questionnaire survey again to determine the physical changes in all age groups and compared the findings. The 1st survey was conducted after the initial emergency declaration lifted in July 2020, and the 2nd survey was 10 months after the first survey March 2021. And the analysis was conducted by simple and cross tabulation. The number of valid responses were obtained over 12,000 samples for the both surveys. One year later, "Corona locomo" decreased from the previous year in all age groups, especially school students, while it increased in "80s∼". "Corona stress" decreased sharply among children, especially elementary school students, while it increased slightly in 20s, 30s, and "80s∼". The physical condition was closely related to the proportion of exercising population and duration in each age group. "The new lifestyle norm" as a countermeasure against COVID-19 crisis had a significant influence on physical condition in each age group as "the secondary health damage". Forcusing on "With Corona era", it is considered necessary for preventing "locomo-frail", to improve the exercise lifestyles by selecting tailor-made training methods.


Somatosensory gating is altered and associated with migraine chronification: A magnetoencephalographic study.
Background Brain excitability is changed in migraine but not fully characterized yet. This study explored if somatosensory gating is altered in migraine and linked to migraine chronification. Methods Paired electrical stimuli were delivered to the left index fingers of 21 patients with migraine without aura (MO), 22 patients with chronic migraine (CM), and 36 controls. The first and second responses to the paired stimuli were obtained from the contralateral primary (cSI), contralateral secondary (cSII) and ipsilateral secondary (iSII) somatosensory cortices to compute the gating ratios (second vs. first response strengths). Results The first and second cSI responses and gating ratios differed in all groups ( p < 0.05); the responses were typically smaller in the MO and CM groups. The cSI gating ratio increased as a continuum across controls (0.73 ± 0.04, p < 0.001), MO (0.83 ± 0.04) to CM (0.97 ± 0.06) and was higher in CM vs. controls ( p < 0.001). When MO and CM were combined, cSI gating ratio was associated with headache frequency (r = 0.418, p = 0.005). Paired responses and gating ratios of cSII and iSII did not differ among the groups. Conclusions Somatosensory gating is altered in migraine and associated with headache chronification. Further studies must clarify if this abnormal sensory modulation is a true gating deficit independent of low preexcitation level.


CMT2A-linked MFN2 mutation, T206I promotes mitochondrial hyperfusion and predisposes cells towards mitophagy.
Mutations in Mitofusin2 (MFN2) associated with the pathology of the debilitating neuropathy Charcot-Marie-Tooth type 2A (CMT2A) are known to alter mitochondrial morphology. Previously, such mutations have been shown to elicit two diametrically opposite phenotypes - while some mutations have been causally linked to enhanced mitochondrial fragmentation, others have been shown to induce hyperfusion. Our study identifies one such MFN2 mutant, T206I that causes mitochondrial hyperfusion. Cells expressing this MFN2 mutant have elongated and interconnected mitochondria. T206I-MFN2 mutation in the GTPase domain increases MFN2 stability and renders cells susceptible to stress. We show that cells expressing T206I-MFN2 have a higher predisposition towards mitophagy under conditions of serum starvation. We also detect increased DRP1 recruitment onto the outer mitochondrial membrane, though the total DRP1 protein level remains unchanged. Here we have characterized a lesser studied CMT2A-linked MFN2 mutant to show that its presence affects mitochondrial morphology and homeostasis.


When physicians get stuck in sick-listing consultations: a qualitative study of categories of sick-listing dilemmas.
Many physicians find sick-listing tasks problematic. The aim of this study was to identify categories of dilemmas experienced by physicians in their sick-listing practice. Data was collected at courses that were aimed at improving physicians' sick-listing skills, arranged in different parts of Sweden. Before the course the participants, general practitioners (GP) sent in a written report of a sick-listing case they found problematic. The material consisted of group discussions of some 100 case reports from GPs. The process of categorisation of the dilemmas was a one-step, straightforward qualitative analysis. Eight different categories of sick-listing dilemmas experienced by the physicians were identified. Examples of them are "Not the doctors' pigeon" (when the patients' problem was perceived as not being medical in nature), "Diagnosis as disguise" (when there is a discrepancy between how the patient describes the problems and what the physician apprehends), and "Harmed by sick listing-reversible" (when the physician perceives that the main problem is the iatrogenic adverse effects of sick listing per se). The contribution of the study is to provide understanding of and labels to the specific difficulties experienced by physicians in their sick-listing practice face to face with patients.


Biosynthesis of dermatan sulphate in cultured fibroblasts. Characterization of newly synthesized glycans from cells and microsomes.
Fibroblasts in culture were incubated with 35SO4 and [3H]glucosamine for periods ranging from 5 min to 24 h. 35S radioactivity was incorporated linearily into intracellular sulphated glycosaminoglycans for 10 min. At this time the rate of incorporation levelled off and radioactive glycans started to emerge in the pericellular pool. 20 min later radioactive glycans could be isolated from the medium. Incorporation of [3H]glucosamine into corresponding glycans was delayed by about 2-3 h. Dermatan sulphate isolated from the cells after half an hour of incubation contained much less iduronic acid than did chains obtained at a later times. The uronate composition of dermatan sulphate from the pericellular and medium fractions did not change appreciably during the incubation period. To obtain further information about the structure of newly synthesized glycosaminoglycans as well as intermediates thereof, microsomes were incubated with UDP-[14C]glucuronic acid, 3'-phosphoadenosine 5'-phospho-[35S]sulphate and UDP-N-acetylgalactosamine. Polymeric acceptors for the synthesis of hyaluronate, heparan sulphate and dermatan sulphate were present. Chondroitin, an intermediate in dermatan sulphate synthesis could also be demonstrated. The copolymeric structure of newly synthesized, microsomal, dermatan sulphate was similar to that of dermatan sulphate obtained after 0.5-1 h of synthesis in cultured cells.


The potential role of omentin-1 in obesity-related metabolic dysfunction-associated steatotic liver disease: evidence from translational studies.
Obesity, characterized by visceral adipose tissue (VAT) expansion, is closely associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). Recent research has highlighted the crucial role of the adipose tissue-liver axis in the development of MASLD. In this study, we investigated the potential role of omentin-1, a novel adipokine expressed by VAT, in obesity-related MASLD pathogenesis. Through in silico analysis of differentially expressed genes in VAT from obese patients with and without MASH, we identified omentin-1 as a significant candidate. To validate our findings, we measured omentin-1 levels in VAT and plasma of lean controls and obese patients with biopsy-proven MASLD. Additionally, we assessed omentin-1 expression in the VAT of diet-induced mice MASLD model. In vitro and ex vivo studies were conducted to investigate the effects of omentin-1 on MASLD-related mechanisms, including steatosis, inflammation, endoplasmic reticulum (ER) stress, and oxidative stress. We also analyzed the impact of D-glucose and insulin on VAT omentin-1 levels ex vivo. Compared to the lean group, the obese groups exhibited significantly lower VAT and plasma levels of omentin-1. Interestingly, within the obese groups, omentin-1 is further decreased in MASH groups, independent of fibrosis. Likewise, VAT of mice fed with high-fat diet, showing histological signs of MASH showed decreased omentin-1 levels as compared to their control diet counterpart. In vitro experiments on fat-laden human hepatocytes revealed that omentin-1 did not affect steatosis but significantly reduced TNF-α levels, ER stress, and oxidative stress. Similar results were obtained using ex vivo VAT explants from obese patients upon omentin-1 supplementation. Furthermore, omentin-1 decreased the mRNA expression of NF-κB and mitogen-activated protein kinases (ERK and JNK). Ex vivo VAT explants showed that D-glucose and insulin significantly reduced omentin-1 mRNA expression and protein levels. Collectively, our findings suggest that reduced omentin-1 levels contribute to the development of MASLD. Omentin-1 supplementation likely exerts its beneficial effects through the inhibition of the NF-κB and MAPK signaling pathways, and it may additionally play a role in the regulation of glucose and insulin metabolism. Further research is warranted to explore omentin-1 as a potential therapeutic target and/or biomarker for MASLD.


The serotonin transporter promoter repeat length polymorphism, seasonal affective disorder and seasonality.
Conflicting results have been reported in previous association studies of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR), seasonal affective disorder (SAD) and seasonality (seasonal variations in mood and behaviour). The aim of this study was to test for association in new case-control and population-based materials, and to perform a combined analysis of all published studies of 5-HTTLPR and SAD. One hundred and forty-seven new SAD cases and 115 controls were genotyped for 5-HTTLPR and in total 464 patients and 414 controls were included in the pooled analysis. In addition, 226 individuals selected for unusually high or low seasonality scores from a population based material and 46 patients with non-seasonal depression were analysed. Different genetic models were tested and seasonality was analysed both as a qualitative (high v. low) and as a quantitative trait in the different sample sets. No association between 5-HTTLPR and SAD was found in the new case-control material, in the combined analysis of all samples, or when only including 316 patients with controls (N = 298) selected for low seasonality. A difference was detected between the population based high and low seasonality groups, when assuming a recessive effect of the short allele (20% and 10% short allele homozygotes, respectively, OR (95% CI): 2.24 (1.03-4.91)). Quantitative analysis of seasonality revealed no association with 5-HTTLPR in any sample set. These results do not suggest a major role of the short variant of 5-HTTLPR in susceptibility to SAD, but provide modest evidence for an effect on seasonality.


Recolonization and succession of marine macrobenthos in organic-enriched sediment deposited from fish farms.
High organic loading deposited on the sea bottom by marine fish farming activities often eliminates benthic organisms in the vicinity. In this study, organic-enriched sediment collected underneath a fish farm was defaunated, placed in settling trays and exposed to the subtidal area of a clean site of similar hydrography. Trays were sampled monthly for a consecutive period of 5 months, and recolonization and successional patterns of macrobenthos were studied using univariate and multivariate statistics. Recolonization occurred rapidly, and averages of 144 animals/tray and 26 species/tray were recorded within the first month. Molluscs accounted for 49% of species and polychaetes for 77% of abundance during the first month of recolonization. Temporal changes in abundance, diversity and species composition found in subsequent months resembled spatial changes of benthic community along a decreasing pollution gradient generalised by Pearson and Rosenberg (1978, Oceanography & Marine Biology Annual Review 16, 229-311). Abundance reached a peak after 3 months (434 animals/tray) and then declined. Species number also increased, peaked after 4 months (47 species/tray), and was followed by a decrease. The polychaete Prionospio malmgreni succeeded Pseudopolydora paucibranchiata as the dominant species after the first month, reached a peak (194 animals/tray) after 3 months, then declined sharply. The rapid recolonization and succession of the macrobenthic community on organic-enriched sediment suggested that present fish farming methods are unlikely to have a long-term impact on benthic communities once farming activities are reduced/ceased.


Expanding vocabularies for complementary and alternative medicine therapies.
There is a significant consumer demand for complementary and alternative medicine (CAM) therapies as possible alternatives to drugs in the treatment and prevention of chronic diseases. Expanding controlled vocabularies to include CAM treatment relations could help meet those needs by facilitating information retrieval from the published literature. The purpose of this study is to design and evaluate two methods to semi-automatically extract CAM treatment-related semantic predications (subject-predicate-object triplets) from the biomedical literature using the Semantic Medline database (SemMedDB). Predications were retrieved from SemMedDB, a database of semantic predications extracted from article abstracts available in Medline. Predications were retrieved for 20 biologically-based and 3 mind-body CAM therapies. The first method (allMedline) retrieved predications from any Medline citation, while the second method (soundStudies) only retrieved predications from scientifically sound clinical studies. Filtering criteria were applied to identify the predications focusing on the treatment and prevention of medical disorders using various CAM modalities. The disorders were extracted for each CAM therapy and ranked by occurrence. A reference vocabulary, composed of 20 biologically-based and 3 mind-body CAM therapies, was developed to evaluate the performance of each method according to precision and recall of the top 100 ranked concepts as well as average precision and recall. The difference between allMedline and soundStudies in terms of median precision for the top 100 concepts ranked by occurrence was significant (21.0% versus 27.0%, p < .001). The soundStudies method had significantly higher precision (7.0% vs 11.5%, p < .001) and the allMedline had significantly higher recall (37.1% vs 25.6%, p < .001). The soundStudies method may be useful for extracting treatment-related predications from the biomedical literature for the highest ranked concepts. Additional work is needed to improve the algorithm as well as identify and report shortcomings for future enhancements of the tools used to populate SemMedDB.


Mutational analysis of Ctnnb1 and Apc in tumors from rats given 1,2-dimethylhydrazine or 2-amino-3-methylimidazo[4,5-f]quinoline: mutational 'hotspots' and the relative expression of beta-catenin and c-jun.
There is growing interest in beta-catenin and its role in various human cancers. We recently reported that 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)- and 1,2-dimethylhydrazine (DMH)-induced colon tumors in the rat contain mutations in Ctnnb1, the gene for beta-catenin, but the mutation spectrum was influenced by postinitiation exposure to chlorophyllin (CHL) and indole-3-carbinol (I3C) [Blum et al., Carcinogenesis 2001;22:315-320]. The present paper describes a follow-up study in which all of the target organs for IQ- and DMH-induced tumorigenesis were screened; Ctnnb1 mutations were found in 44 of 119 DMH-induced colon tumors, six of 13 IQ-induced colon tumors, 28 of 81 DMH-induced small intestine tumors, none of five IQ-induced small intestine tumors, four of 106 IQ-induced liver tumors, none of 14 DMH-induced Zymbal's gland tumors, none of 24 IQ-induced Zymbal's gland tumors, and none of 29 IQ-induced skin tumors. In tumors from rats given carcinogen alone, or carcinogen plus CHL or I3C, Ctnnb1 mutations frequently substituted amino acids adjacent to Ser33, a critical Ser/Thr residue in the glycogen synthase kinase-3beta regulatory domain of beta-catenin. However, substitution of critical Ser/Thr residues themselves was detected in only three of 24 (12.5%) of the tumors from rats given carcinogen alone, compared with 23 of 58 (40%) of the tumors from rats given carcinogen and treated postinitiation with I3C or CHL (P < 0.02). More than 50 of the colon tumors with wild-type beta-catenin were examined further for their Apc status; the overall frequency of Apc mutations was <10%, and these genetic changes occurred exclusively in the 'Mutation Cluster Region' of Apc. A subset of colon tumors also was examined for expression of beta-catenin and c-jun; these proteins were overexpressed in all tumors containing Ctnnb1 mutations, but the expression was highest in tumors with Ctnnb1 mutations affecting Thr41 and Ser45 residues in the glycogen synthase kinase-3beta region of beta-catenin. Thus, Ctnnb1 mutations occurred more frequently than Apc mutations in colon and small intestine tumors of the rat, and certain mutations upregulated beta-catenin/T-cell factor target genes more effectively than others, perhaps influencing the response to phytochemicals administered postinitiation.


Role of excision repair in UVB-induced depletion and recovery of human epidermal Langerhans cells.
Skin exposure to UVB radiation deprives the antigen-presenting function and OKT6 monoclonal antibody-binding characteristics of Langerhans cells. Decrease of Langerhans cell population could be relevant to immune surveillance disturbance in the UV-exposed skin. Patients with xeroderma pigmentosum exhibit a thousandfold higher risk for sunlight-induced skin cancers than patients with normal skin, and also have various defects in cellular immunity. Therefore, studies of numerical and structural changes in epidermal Langerhans cells of patients with xeroderma pigmentosum after UVB irradiation compared with normal subjects may contribute to understanding the role of antigen-presenting cells in photocarcinogenesis. The effect of UVB radiation on OKT6+ Langerhans cells was studied in epidermal sheets obtained from irradiated normal subjects (36 and 49 years old) and subjects with xeroderma pigmentosum complementation group A (21 years old), complementation group D (32 years old), and variant (35 and 60 years old). Langerhans cell densities in chronically sunlight-exposed skin were remarkably reduced in patients with xeroderma pigmentosum group A but only slightly in those with xeroderma pigmentosum variant and in normal subjects compared with covered skin. Structural changes were substantial in Langerhans cells of chronically exposed patients with xeroderma pigmentosum group A but fewer in subjects with other xeroderma pigmentosum groups and in normal subjects. A single irradiation of three times the minimal erythema dose induced a large reduction of Langerhans cells from 3 to 7 days in all subjects. However, subsequent reappearance and return to preirradiated levels was delayed more in patients with xeroderma pigmentosum group A than in those with xeroderma pigmentosum variant and normal subjects. These results indicate (1) an essential role for excisional repair in the UVB-induced depletion, recovery, and maintenance of the epidermal Langerhans cell population, and (2) a possible, but not confirmed, relationship between depletion of Langerhans cells and earlier photocarcinogenesis in xeroderma pigmentosum.


A system for identifying post-invasion functions of invasion genes: requirements for the Mxi-Spa type III secretion pathway of Shigella flexneri in intercellular dissemination.
Invasion and intercellular spread are hallmarks of Shigella pathogenicity. Invasion of the eukaryotic cell cytosol requires a type III secretion system (Mxi-Spa) and its cognate set of secreted Ipa invasins. Once intracellular, the IcsA protein directs a form of actin-based motility that helps to drive intracellular bacterial movement, formation of cellular protrusions and cell-to-cell spread. Work in our laboratory has focused on identifying additional factors required for this intercellular form of dissemination. In this study, we sought to identify novel contributions of the type III secretion pathway to post-invasion-specific processes, distinct from its previously characterized roles in invasion. Studies of post-invasion Ipa and Mxi-Spa functions are complicated by an absolute requirement for these virulence proteins in invasion. To circumvent this problem, we developed a system called TIER (for test of intracellular expression requirements), whereby specific ipa, mxi or spa loci are transiently expressed before infection of tissue culture cell monolayers (thus supporting invasion), but then repressed after invasion in the intracellular environment. Such invasive type III secretion mutants (called TIER mutants) were severely restricted in their ability to spread intercellularly and form plaques in confluent tissue culture cell monolayers. Intercellular spread defects were associated with the repression of most type III pathway components examined, including structural (MxiM and Spa33), secreted effector (IpaB, IpaC and IpaD) and regulatory elements (VirF and VirB). A kinetic analysis of bacterial growth in L2 cell monolayers showed that each of the TIER mutants was defective with respect to long-term intracellular proliferation and viability. Examination of TIER mutant-infected monolayers by electron microscopy revealed that the type III pathway was required for a late step in intercellular spread - bacterial escape from protrusion-derived, double-membrane-bound vacuoles. The TIER mutants were eventually degraded in a process involving vacuolar acidification. Based on these findings, we propose that Ipa secretion via Mxi-Spa is required in the protrusion vacuole for double-membrane lysis.


First line treatment of metastatic renal cell carcinoma: two standards with different toxicity profile.
Tyrosine kinase inhibitors are de facto the more used targeted therapies for upfront treatment of metastatic renal cell carcinoma (mRCC). Among these, sunitinib and pazopanib have reported greater activity in term of progression-free survival and overall survival compared with interferon-α or placebo in two independent large phase III studies. Despite a large use in clinical practice these molecules had never been compared. The COMPARZ study recently published in the New England Journal of Medicine reports the results of a non-inferiority trial that comparing pazopanib to sunitinib as first line of therapy in mRCC patients. Here we report the activity and safety data of the study and we discuss several critical aspects related to the study design and possible confounding factors that may alter the results' interpretation.


Gastrointestinal findings in 26 adults with common variable immunodeficiency: The fickle nature of the disease manifests in gastrointestinal biopsies.
The aim of the present study was to demonstrate the histopathological findings in gastrointestinal (GI) biopsies in adults with common variable immunodeficiency (CVID). A total of 172 GI biopsies of 26 patients with CVID obtained over a 16-year period were reevaluated. Findings were analyzed using descriptive analyzes and χ2 test. Female-to-male ratio was 1.36. The median age at diagnosis was 36±13.94 (16-72) years. Chronic esophagitis was noted in 3 patients. The absence of plasma cells in the stomach, duodenum, and colon was observed in 16, 14, and 9 patients, respectively. Divergent results for the presence of plasma cells in concurrent stomach and duodenum samples were found in 11 (44%) patients. Nodular lymphoid hyperplasia (NLH) was notable in the duodenum (56%). The mean number of eosinophils in one high-power field was significantly higher in duodenal biopsies with NLH (27.21 vs. 14.37, p=0.002). Active inflammation was more prominent in the colon (91%) than in the stomach (65%) and duodenum (60%). Helicobacter pylori infection was found in 57.6%, including a case with persistent infection by the coccoid form. Celiac-like villous blunting and increased intraepithelial lymphocytes were seen in 40% and 24%, respectively. In addition, 23% had giardiasis associated with acute duodenitis and duodenal NLH (p<0.05). CVID gastroenteropathy is a challenging entity, and due to the heterogeneity in the presence and distribution of plasma cells throughout the GI tract and diverse disease course, multiple concurrent biopsies may be needed for tissue diagnosis. Duodenal CVID may present with villous alterations and giardiasis, and NLH appears to be an important clue in the duodenum. The association between duodenal NLH and eosinophil infiltration deserves further investigation.


Research Gaps and Controversies in Chronic Traumatic Encephalopathy: A Review.
Scientific and lay interest in negative outcomes associated with exposure to repetitive brain trauma (RBT) continues to strengthen. Concerns about the association between RBT and dementia began more than a century ago, but have resurfaced in the last decade with the more recently described chronic traumatic encephalopathy (CTE). Chronic traumatic encephalopathy is a tauopathy associated with RBT that has become inextricably linked to conversations about sport-related concussion and mild traumatic brain injury. Accordingly, specific populations such as collision sport athletes and certain military personnel are of particular interest owing to their unique exposure to RBT. The gaps and controversies in our understanding of the epidemiologic factors, mechanism, and clinicopathological correlates of CTE reflect the current reliance on postmortem case series investigations. This review discusses the state of the science of CTE and raises considerations for researching and interpreting cognitive changes in members of at-risk populations. The recent development of pathological diagnostic criteria for CTE represented an important step for differentiating CTE from other neurodegenerative diseases. By comparison, defining the clinical syndrome(s) associated with CTE and the necessary and sufficient symptoms needed for its diagnosis lags behind. The absence of validated in vivo biomarkers of pathological characteristics of CTE and longitudinal tracking with neuropsychological evaluation remains a significant hurdle. Attribution of candidate symptoms in retired athletes to CTE is complicated by the presence of multiple premorbid and comorbid factors affecting cognitive reserve that influence normal or expected cognitive functioning. This is a critical issue in appropriately defining reference groups for normative comparisons. Available data, while limited and complicated by selection bias, indicate that exposure to RBT represents the greatest risk factor for CTE pathological features, although clinicopathological correlates and the nature of onset and progression of symptoms are largely unknown. Considering aspects of cognitive reserve is likely essential for both interpreting cognitive outcomes associated with CTE and for developing preventive treatment programs. Research on CTE would benefit greatly from incorporating principles established within other areas of neurodegenerative disease and the nuances of clinicopathological considerations.


Relatives of patients with severe mental disorders: unique traits and experiences of primary, nonprimary, and lone caregivers.
The authors examined caregivers' characteristics and experiences. Previously suggested principles for identifying the primary caregiver in 22 multiple-caregiver families were assessed, but none reliably distinguished the primary caregiver. The authors then compared primary (n = 22), nonprimary (n = 22), and lone caregivers' (n = 43) appraisals of caregiving and psychological distress. Lone and primary caregivers' experiences were similar, but nonprimary caregivers' experiences were less adverse. Despite these findings, greater psychological distress in primary caregivers indicated greater psychological distress in nonprimary caregivers.


Palladium-Catalyzed Aryldifluoromethylation of Aryl Halides with Aryldifluoromethyl Trimethylsilanes.
Diaryl difluoromethanes are valuable targets for medicinal chemistry because they are bioisosteres of diaryl ethers and can function as replacements for diaryl methane, ketone, and sulfone groups. However, methods to prepare diaryl difluoromethanes are scarce, especially methods starting from abundant aryl halides. We report the Pd-catalyzed aryldifluoromethylation of aryl halides with aryldifluoromethyl trimethylsilanes (TMSCF2 Ar). The reaction occurs when the catalyst contains a simple, but unusual, dialkylaryl phosphine ligand that promotes transmetallation of the silane. Computational studies show that reductive elimination following transmetallation occurs with a low barrier, despite the fluorine atoms on the α-carbon, due to coordination of the difluorobenzyl π-system to palladium. The co-development of a cobalt-catalyzed synthesis of the silanes broadened the scope of the process including several applications to the synthesis biologically relevant diaryl difluoromethanes.


Influenza pandemic intervention planning using InfluSim: pharmaceutical and non- pharmaceutical interventions.
Influenza pandemic preparedness plans are currently developed and refined on national and international levels. Much attention has been given to the administration of antiviral drugs, but contact reduction can also be an effective part of mitigation strategies and has the advantage to be not limited per se. The effectiveness of these interventions depends on various factors which must be explored by sensitivity analyses, based on mathematical models. We use the freely available planning tool InfluSim to investigate how pharmaceutical and non-pharmaceutical interventions can mitigate an influenza pandemic. In particular, we examine how intervention schedules, restricted stockpiles and contact reduction (social distancing measures and isolation of cases) determine the course of a pandemic wave and the success of interventions. A timely application of antiviral drugs combined with a quick implementation of contact reduction measures is required to substantially protract the peak of the epidemic and reduce its height. Delays in the initiation of antiviral treatment (e.g. because of parsimonious use of a limited stockpile) result in much more pessimistic outcomes and can even lead to the paradoxical effect that the stockpile is depleted earlier compared to early distribution of antiviral drugs. Pharmaceutical and non-pharmaceutical measures should not be used exclusively. The protraction of the pandemic wave is essential to win time while waiting for vaccine development and production. However, it is the height of the peak of an epidemic which can easily overtax general practitioners, hospitals or even whole public health systems, causing bottlenecks in basic and emergency medical care.


A review of the published literature into cannabis withdrawal symptoms in human users.
Recent experimental papers have been published suggesting the appearance of withdrawal symptoms upon the cessation of cannabis use in human users and proposing the introduction of a diagnostic category for such symptoms. Research also continues to be published into the physiological effects of cannabis on animals via self-administration paradigms and the use of cannabinoid antagonists. Animal research does not provide a clear picture of a consistent withdrawal effect. The literature on withdrawal symptoms appearing in human users following the cessation of cannabis is investigated in this paper to clarify this issue further and enhance the scientific and lay debate on the status of the drug. Methodological weaknesses in the literature are highlighted. These include variable levels of drug-dose administered in laboratory conditions, lack of controlled studies and the absence of definitions of the withdrawal syndrome sought. It is suggested that the studies conducted to date do not provide a strong evidence base for the drawing of any conclusions as to the existence of a cannabis withdrawal syndrome in human users, or as to the cause of symptoms reported by those abstaining from the drug. On the basis of current research cannabis cannot be said to provide as clear a withdrawal pattern as other drugs of abuse, such as opiates. However, cannabis also highlights the need for a further defining of withdrawal, in particular the position that rebound effects occupy in this phenomenon. It is concluded that more controlled research might uncover a diagnosable withdrawal syndrome in human users and that there may be a precedent for the introduction of a cannabis withdrawal syndrome before the exact root of it is known.


Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis.
Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are autoimmune disorders in which the acetylcholine receptor (AChR) is the major autoantigen. Microarray technology was used to identify new potential drug targets for treatment of myasthenia that would reduce the need for the currently used nonspecific immunosuppression. The chemokine IFN-gamma-inducible protein 10 (IP-10; CXCL10), a CXC chemokine, and its receptor, CXCR3, were found to be overexpressed in lymph node cells of EAMG rats. Quantitative real-time PCR confirmed these findings and revealed up-regulated mRNA levels of another chemoattractant that activates CXCR3, monokine induced by IFN-gamma (Mig; CXCL9). TNF-alpha and IL-1beta, which act synergistically with IFN-gamma to induce IP-10, were also up-regulated. These up-regulations were observed in immune response effector cells, namely, lymph node cells, and in the target organ of the autoimmune attack, the muscle of myasthenic rats, and were significantly reduced after suppression of EAMG by mucosal tolerance induction with an AChR fragment. The relevance of IP-10/CXCR3 signaling in myasthenia was validated by similar observations in MG patients. A significant increase in IP-10 and CXCR3 mRNA levels in both thymus and muscle was observed in myasthenic patients compared with age-matched controls. CXCR3 expression in PBMC of MG patients was markedly increased in CD4(+), but not in CD8(+), T cells or in CD19(+) B cells. Our results demonstrate a positive association of IP-10/CXCR3 signaling with the pathogenesis of EAMG in rats as well as in human MG patients.


Mitotic effects of the aqueous leaf extract of Cymbopogon citratus in Allium cepa root tips.
Aqueous extracts of the lemon grass, Cymbopogon citratus, were used to clear the malaria parasite in infected mice, although they died some days later. Allium cepa roots grown in aqueous extracts from 3, 6, 12 and 20 g of chopped leaves for 1, 3, and 6 h, showed some mitotic abnormalities including c-mitotic and mitodepressive effects. The abnormalities were not peculiar to any concentration or duration of extract treatment. The highest frequency of affected cells was 0.75% in the treatment with the 20 g concentration, but the 3 h treatment group had the greatest variety of effects. The mitodepressive effect of the extract increased significantly with concentration and time, and persisted even after 24 h in tap water. The chromosomal effects of the extract occur at a very low frequency but the mitodepressive effects may have implications for man.


Fringe-orientation estimation by use of a Gaussian gradient filter and neighboring-direction averaging.
We analyze the effect of image noise on the estimation of fringe orientation in principle and interpret the application of a texture-analysis technique to the problem of estimating fringe orientation in interferograms. The gradient of a Gaussian filter and neighboring-direction averaging are shown to meet the requirements of fringe-orientation estimation by reduction of the effects of low-frequency background and contrast variances as well as high-frequency random image noise. The technique also improves inaccurate orientation estimation at low-modulation points, such as fringe centers and broken fringes. Experiments demonstrate that the scales of the Gaussian gradient filter and the direction averaging should be chosen according to the fringe spacings of the interferograms.


The treatment of recurrent anterior shoulder dislocation by the modified Bristow-Helfet procedure.
South African orthopaedic surgeons have been in the forefront of the development of reconstructive procedures performed for recurrent anterior shoulder dislocation. In addition to the Johannesburg stapling operation described by G. T. du Toit and D. Roux, Professor A. Helfet of Cape Town was the first to describe the coracoid transplantation operation in 1958. A modified form of this operation was performed on 31 patients between August 1975 and February 1981. Patients were followed up for a mean period of 38 months, and no recurrences were encountered in patients who had had true involuntary recurrent subluxation or dislocation. The operative technique is described in detail as it is considered that adequate exposure and accurate placement of the coracoid process are very important factors in obtaining a satisfactory result and in the prevention of complications. It has been postulated that this operation, which does not attempt to shorten the capsular structures or subscapularis tendon, affords a superior result in respect of patients who participate in throwing sports. It has been noted that patients who play cricket, baseball and basketball have encountered problems in regaining their ability to throw overhand after having had operations such as the Putti-Platt procedure, which entails intentional shortening of the capsular structures and subscapularis tendon.


A Topological Cluster of Differentially Regulated Genes in Mice Lacking PER3.
Polymorphisms in the human circadian clock gene PERIOD3 (PER3) are associated with a wide variety of phenotypes such as diurnal preference, delayed sleep phase disorder, sleep homeostasis, cognitive performance, bipolar disorder, type 2 diabetes, cardiac regulation, cancer, light sensitivity, hormone and cytokine secretion, and addiction. However, the molecular mechanisms underlying these phenotypic associations remain unknown. Per3 knockout mice (Per3-/- ) have phenotypes related to activity, sleep homeostasis, anhedonia, metabolism, and behavioral responses to light. Using a protocol that induces behavioral differences in response to light in wild type and Per3-/- mice, we compared genome-wide expression in the eye and hypothalamus in the two genotypes. Differentially expressed transcripts were related to inflammation, taste, olfactory and melatonin receptors, lipid metabolism, cell cycle, ubiquitination, and hormones, as well as receptors and channels related to sleep regulation. Differentially expressed transcripts in both tissues co-localized with Per3 on an ∼8Mbp region of distal chromosome 4. The most down-regulated transcript is Prdm16, which is involved in adipocyte differentiation and may mediate altered body mass accumulation in Per3-/- mice. eQTL analysis with BXD mouse strains showed that the expression of some of these transcripts and also others co-localized at distal chromosome 4, is correlated with brain tissue expression levels of Per3 with a highly significant linkage to genetic variation in that region. These data identify a cluster of transcripts on mouse distal chromosome 4 that are co-regulated with Per3 and whose expression levels correlate with those of Per3. This locus lies within a topologically associating domain island that contains many genes with functional links to several of the diverse non-circadian phenotypes associated with polymorphisms in human PER3.