Late-onset epilepsy with cognitive symptoms: Comparison of cognitive and imaging profiles with probable Alzheimer's disease.
We aimed to (i) compare the clinical, neuropsychological, and neuroimaging characteristics of unprovoked late-onset epilepsy (LOE) patients with cognitive symptoms against probable Alzheimer's disease (AD) patients; (ii) clarify how neurodegeneration and other processes could be implicated in the cognitive symptoms of unprovoked LOE patients; and (iii) characterize the longitudinal trajectory of unprovoked LOE patients with cognitive symptoms. Twenty-six unprovoked LOE patients with cognitive symptoms and 26 probable AD were retrospectively recruited from epilepsy and memory clinics at a single tertiary referral center. The patients underwent comprehensive clinical, neuropsychological, and 18Fluorodeoxyglucose PET-CT assessments. All LOE patients had clinical follow-up and a subset of 17 patients had repeat neuropsychological assessments. At baseline, 18% of LOE patients with cognitive symptoms had dementia-range cognitive impairment and one received a diagnosis of probable AD. Compared with the probable AD group, the LOE group did not perform significantly better in global measures of cognition (total ACE-III), neuropsychological tests for fluency, working memory, language, attention, or executive function, but performed better in naming, memory, and visuospatial ability. The commonest patterns of cognitive impairment in the LOE group were frontal and left temporal, whereas all AD patients exhibited parietotemporal patterns. The AD group had more 18Fluorodeoxyglucose PET-CT hypometabolism in the parietal and occipital, but not the temporal and frontal lobes. During the 3.0 ± 3.2 years follow-up, improved seizure frequency in the LOE group covaried with improved total ACE-III score, there was no further conversion to probable AD and no group-level cognitive decline. Unprovoked LOE patients with cognitive symptoms had varying severities of cognitive impairment, and different patterns of cognitive and imaging abnormalities compared with AD patients. They were rarely diagnosed with probable AD at presentation or follow-up. Cognitive outcome in LOE may be related to seizure control. Cerebral small vessel disease may play a role in LOE-associated cognitive impairment.


The effect of caffeine on exercise performance is not influenced by ADORA2A genotypes, alone or pooled with CYP1A2 genotypes, in adolescent athletes.
This study investigated the influence of the different genotypes of ADORA2A (1976 C > T, rs 5751876), alone or pooled with CYP1A2 (163 C > A rs 762551) genotypes, on the ergogenic effects of caffeine (CAF) on various aspects of physical performance in male adolescent athletes. Ninety male adolescent athletes (age = 15.5 ± 2 years) were classified according to their genotypes for 1976 C > T ADORA2A (TT homozygous or CADORA2A allele carriers) and 163 C > A CYP1A2 (AA homozygous or CCYP1A2 allele carriers). Participants were further divided in four groups (1-TTADORA2A + AACYP1A2; 2-TTADORA2A + AC/CCCYP1A2; 3-AACYP1A2 + CT/CCADORA2A;4-AC/CCCYP1A2 + CT/CCADORA2A). Using a randomized, crossover, counterbalanced, and double-blind design, participants ingested CAF (6 mg kg-1) or a placebo (PLA, 300 mg of cellulose) one hour before performing a sequence of physical tests: handgrip strength, agility test, countermovement jump (CMJ), Spike Jump (SJ), sit-ups, push-ups, and the Yo-Yo intermittent recovery test level 1 (Yo-Yo IR1). CAF enhanced handgrip strength (CAF: 35.0 ± 9.2 kg force; PLA: 33.5 ± 8.9 kg force; p = 0.050), CMJ height (CAF: 49.6 ± 12.3 cm; PLA: 48.3 ± 13.6 cm; p = 0.013), SJ height (CAF: 54.7 ± 13.3 cm; PLA: 53.1 ± 14.8 cm; p = 0.013), number of sit-ups (CAF: 37 ± 8; PLA: 35 ± 8; p = 0.001), and distance covered on the Yoyo IR1 test (CAF: 991.6 ± 371.0 m; PLA: 896.0 ± 311.0 m; p = 0.001), This CAF-induced improvement on exercise performance was, however, independent of genotypes groups (all p > 0.05). CAF had no effect on agility (CAF: 15.8 ± 1.2 s; PLA: 15.9 ± 1.3 s; p = 0.070) and push-up (CAF: 26.6 ± 12.0; PLA: 25.0 ± 11.0; p = 0.280) tests. The acute caffeine intake of 6.0 mg.kg-1 improves several aspects of physical performance, which seems to be independent of ADORA2A genotypes, alone or in combination with CYP1A2 genotypes.


Functional attributes of responding T cells in HCV infection: the recent advances in engineering functional antiviral T cells.
Hepatitis C virus (HCV) is one of the major causes of hepatocellular carcinoma (HCC) around the world. HCV promotes characteristics of cancer stem cells and the infected cells are insensitive to apoptotic signals, which lead to persistent antigen stimulation and T cell exhaustion in the host. In spite of new effective antiviral drugs, new challenges are around the corner as drug-resistant viral strains and drug-drug interactions have already been reported. Considering that there are few effective treatments available for HCC, novel immunotherapies to prevent HCC and late stage HCV-related liver diseases should be considered. Given that adoptive immunotherapy with antigen-specific T lymphocytes has emerged as an effective therapeutic strategy for combating cancer, there is, therefore, reason to examine the possibility of using highly functional HCV-reactive T cells in immunotherapy. This review aims to provide the current understanding of natural HCV responding T cells in HCV infection and to give an update on the novel approaches that have the capacity to ex vivo generate functional T cells for potential adoptive cell therapy. Approaches based on the pMHC tetramer-associated magnetic enrichment, exogenous HCV T cell receptor transfer, and induced pluripotent stem cell technologies are described herein. Their potentials as immunotherapeutic against HCV-related diseases are discussed.


Cutting edge: IFN-gamma regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection.
T cell responses are important to the control of infection but are deleterious if not regulated. IFN-gamma-deficient mice infected with mycobacteria exhibit enhanced accumulation of activated effector T cells and neutrophils within granulomatous lesions. These cells do not control bacterial growth and compromise the integrity of the infected tissue. We show that IFN-gamma-deficient mice have increased numbers of IL-17-producing T cells following infection with Mycobacterium bovis bacille Calmette Guérin. Furthermore, exogenous IFN-gamma increases IL-12 and decreases IL-23 production by bacille Calmette Guérin-infected bone marrow-derived dendritic cells and reduces the frequency of IL-17-producing T cells induced by these bone marrow-derived dendritic cells. These data support the hypothesis that, during mycobacterial infection, both IFN-gamma- and IL-17-producing T cells are induced, but that IFN-gamma serves to limit the IL-17-producing T cell population. This counterregulation pathway may be an important factor in limiting mycobacterially associated immune-mediated pathology.


[Delayed complications after dislocations and fractures in the pelvic region (author's transl)].
In the case of surgically dressed necroses of the hip condyle and coxarthroses a condition was found after fracture of the pelvis or after dislocation of the hip joint in 7.2% of the cases. In 13.2% of the cases a trauma was found anamnestically. It was subdivided into fractures of the acetabulum, fractures of the pelvic girdle, dislocations, and fractures of the pelvic brim on the basis of the system of Judet and Engler as well as Feldkamp. Fractures of the pelvic brim through muscular traction, traction of the ligament, and direct trauma were discussed. The most frequent delayed consequences arising after dislocations of the hip joint and fractures of the acetabulum are: necroses of the head of the femur, coxarthroses, pseudarthroses, and myositis ossificans. The pathogenesis of the delayed injuries resulted from: capsular and vascular lesions, damage to cartilage with fractures in the spongiosa region, incongruence of the surface of the joint, insufficiency of the static structure of the pelvic ring, deposit of calcium salt outside the bone. In some cases the progress of the necrosis could be arrested by means of osteotomy and spongiosa filling. The rate of necrosis increases in proportion to the period between the time of occurrence of the accident and reposition (limit of 6 h). Even though about half the pelvic girdle fractures show good results with conservative treatment, in the case of fractures of the acetabulum a reconstruction as far as possible continuous and without stages is to be aimed at. In many cases the development of a myositis ossificans cannot be prevented.


Examining the Relations Between Social Competence, Autistic Traits, Anxiety and Depression in Autistic and Non-Autistic Children.
The current study examined whether social competence and autistic traits are related to anxiety and depression in autistic and non-autistic children. Parents of 340 children aged 6 to 12 years old, including 186 autistic and 154 non-autistic children completed the Autism Spectrum Quotient (AQ) to assess their child's autistic traits, the Multidimensional Social Competence Scale (MSCS) to assess their child's social competence, and the Behaviour Assessment Scale for Children 2 (BASC-2) to assess their child's internalizing symptoms of depression and anxiety, and children were administered the Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) to assess their intellectual abilities. Hierarchical multiple regression analyses were conducted to investigate the relations between social competence, autistic traits, anxiety, and depression. Social competence was related to anxiety and depression symptoms in autistic children, but only depression symptoms in non-autistic children, above and beyond the effects of autistic traits, IQ and age. Autistic children were also reported to experience more severe anxiety and depression symptoms, and more autistic traits were related to higher levels of anxiety and depression in both groups. These findings suggest that social competence and internalizing symptoms are intricately connected in autistic children and need to be jointly considered in both assessment and intervention. The social implications are discussed with an emphasis on acceptance of diverse social styles as a viable avenue to reduce children's internalizing symptoms.


The useful technique of laparoscopic segmental ureterectomy with ureteral reimplantation for distal upper tract urothelial carcinoma.
Segmental ureterectomy (SU) has been proven effective in cases of distal upper tract urothelial carcinoma (UTUC). Nonetheless, SU has been performed infrequently in the real world, and there is no consensus on the preferred surgical technique in laparoscopic surgery. We describe our first experience of laparoscopic segmental ureterectomy (LSU) with psoas hitch ureteral reimplantation. LSU starts using a fan-shaped, five-port, transperitoneal approach. First, the cancerous ureter segment is clipped to avoid tumor seeding, and then the diseased segment is dissected. Second, the psoas hitch is performed by fixing the external part of the ipsilateral dome of the bladder to the psoas muscle and its tendon. Third, at the top of the bladder, an incision is made in the muscle layer and mucosa. The ureter is then spatulated. A guide wire is used to place a retrograde ureteral double J stent. Finally, the anastomosis of the bladder and ureter mucosa is performed by interrupted suturing of both ends, followed by continuous suturing, and the muscular layer of the bladder is closed in a double layer. We performed LSU for distal UTUC in 10 patients. There was no decrease in renal function before or after surgery. During follow-up, three patients experienced a recurrence of urothelial carcinoma in the bladder and one patient had a local recurrence. LSU is a safe and feasible procedure in our experience, and it can be recommended for selected cases of distal UTUC with optimal perioperative, renal functional, and oncologic outcomes.


The position of the superior articular process of the cervical spine. Its relationship to cervical spondylotic radiculopathy.
Cervical spondylotic radiculopathy is likely to develop when the superior articular process is anterior to the posterior margin of the vertebral body, as determined by lateral radiographs of the spine.


Load cell: a device to monitor weight bearing for lower extremity amputees.
The PRS-Moore Load Cell for use in immediate postoperative prosthetic fitting for above- and below-knee amputees is described. The design incorporates an audible warning device which will sound whenever the wearer applies more than the predetermined weight on the affected limb. The device is easy to use in a clinical setting and can be incorporated into any endoskeletal pylon. The cost per unit is approximately $125, and the cell can be reused for successive patients.


[Merkel cell tumor].
The authors review 274 cases of Merkel's cells tumor reported in literature and present one case they personally observed. This kind of neoplasm develops itself inside the derma without involving the epidermidis and shows an aggressive biological behaviour. The authors describe its anatomopathologic characteristics and underline the importance of the immunohistochemistry particularly for a differential diagnosis with respect to lymphoma, amelanotic melanoma and the scarcely differentiated metastatic carcinoma. Undoubtedly the surgical treatment is to be preferred. It consists of the removal of the primitive lesion together with a preventive regional lymphadenectomy. Radio and chemotherapy still don't play a standard role, their results are anyway encouraging even if not well defined up to now. These therapies are used in several ways: together with surgery in case of local relapses or metastasis or as sole treatment. In consideration of the small number of available data, we can finally state that Merkel's cells tumor must be further studied in order to come to a certain definition of this neoplasm from a histogenetic and anatomopathologic point of view and, above all, to find out a treatment able to reduce the high mortality rate that still today characterizes the prognosis.


Lamprey snail highlights conserved and novel patterning roles in vertebrate embryos.
snail genes mark presumptive mesoderm across bilaterian animals. In gnathostome vertebrates, snail genes are a multimember family that are also markers of premigratory neural crest (pnc) and some postmigratory neural crest derivatives in the pharyngeal arches. Previous studies of nonvertebrate chordates indicate that they have single snail genes that retain ancestral functions in mesoderm development and perhaps in specification of a pnc-like cell population. Lampreys are the most basal extant vertebrates, with well-defined developmental morphology. Here, we identify a single snail gene from the lamprey Petromyzon marinus that is the phylogenetic outgroup of all gnathostome snail genes. This single lamprey snail gene retains ancestral snail patterning domains present in nonvertebrate chordates. Lamprey snail is also expressed in tissues that are broadly equivalent to the combined sites of expression of all three gnathostome snail paralogy groups, excepting in embryonic tissues that are unique to gnathostomes. Importantly, while snail does not appear to demarcate an early neural crest population in lampreys as it does in gnathostomes, it may be involved in later neural crest development. Together, our results indicate that significant cis-regulatory innovation occurred in a single snail gene before the vertebrate radiation, and significant subfunctionalization occurred after snail gene duplications in the gnathostome lineages.


Natural product drupacine acting on a novel herbicidal target shikimate dehydrogenase.
Natural products are one of the important sources for the creation of new pesticides. Drupacine ((1R,11S,12S,13R,15S)-13-methoxy-5,7,21-trioxa-19-azahexacyclo[11.7.1.02,10.04,8.011,15.015,19]henicosa-2,4(8),9-trien-12-ol), isolated from Cephalotaxus sinensis (Chinese plum-yew), is a potent herbicidal compound containing an oxo-bridged oxygen bond structure. However, its molecular target still remains unknown. In this study, the targets of drupacine in Amaranthus retroflexus were identified by combining drug affinity responsive target stability (DARTS), cellular thermal shift assay coupled with mass spectrometry (CETSA MS), RNA-seq transcriptomic, and TMT proteomic analyses. Fifty-one and sixty-eight main binding proteins were identified by DARTS and CETSA MS, respectively, including nine co-existing binding proteins. In drupacine-treated A. retroflexus seedlings we identified 1389 up-regulated genes and 442 down-regulated genes, 34 up-regulated proteins, and 194 down-regulated proteins, respectively. Combining the symptoms and the biochemical profiles, Profilin, Shikimate dehydrogenase (SkDH), and Zeta-carotene desaturase were predicted to be the drupacine potential target proteins. At the same time, drupacine was found to bind SkDH stronger by molecular docking, and its inhibition on ArSkDH increased with the treatment concentration increase. Our results suggest that the molecular target of drupacine is SkDH, a new herbicide target, which lay a foundation for the rational design of herbicides based on new targets from natural products and enrich the target resources for developing green herbicides.


An empirical assessment of high-performing medical groups: results from a national study.
The performance of medical groups is receiving increased attention. Relatively little conceptual or empirical work exists that examines the various dimensions of medical group performance. Using a national database of 693 medical groups, this article develops a scorecard approach to assessing group performance and presents a theory-driven framework for differentiating between high-performing versus low-performing medical groups. The clinical quality of care, financial performance, and organizational learning capability of medical groups are assessed in relation to environmental forces, resource acquisition and resource deployment factors, and a quality-centered culture. Findings support the utility of the performance scorecard approach and identification of a number of key factors differentiating high-performing from low-performing groups including, in particular, the importance of a quality-centered culture and the requirement of outside reporting from third party organizations. The findings hold a number of important implications for policy and practice, and the framework presented provides a foundation for future research.


Highly enantioselective synthesis of fluorinated gamma-amino alcohols through proline-catalyzed cross-Mannich reaction.
A new, simple route for the synthesis of fluorinated beta-alkyl gamma-amino alcohols in optically pure form in only two steps and featuring proline catalysis from inexpensive and readily available starting materials is described. The applied strategy allows for the introduction of diversity into both the beta-fluoroalkyl and alpha-alkyl groups of these compounds. [reaction: see text]


Sleeping metabolic rate and body size in 12-week-old infants.
Sleeping metabolic rate (SMR) is influenced by body size and body composition. In order to be able to compare SMR between individuals and groups, the best way to remove the effect of body size and body composition was sought. A cohort of 50 infants was studied at 12 weeks. SMR was measured by indirect calorimetry, and body size and body composition by anthropometry and a stable isotope technique. Regression analysis was used to calculate the best way to remove the effect of body size and body composition on SMR. Regression analysis showed that SMR was adjusted for body weight and fat-free mass by raising body weight to the power 0.41, and by raising fat-free mass to the power 0.44. When SMR was at its minimum level, the optimum powers were 0.41 for body weight and 0.45 for fat-free mass. SMR can be adjusted for body weight, or fat-free mass thereby taking both body size and body composition into account, by expressing SMR in terms of weight or fat free mass raised to powers close to 0.50.


Update on Immunotherapy Cardiotoxicity: Checkpoint Inhibitors, CAR T, and Beyond.
Immunotherapy is an innovative approach to cancer treatment that involves using the body's immune system to fight cancer. The landscape of immunotherapy is constantly evolving, as new therapies are developed and refined. Some of the most promising approaches in immunotherapy include immune checkpoint inhibitors (ICIs): these drugs target proteins on the surface of T-cells that inhibit their ability to attack cancer cells. By blocking these proteins, checkpoint inhibitors allow T-cells to recognize and destroy cancer cells more effectively. CAR T-cell therapy: this therapy involves genetically modifying a patient's own T-cells to recognize and attack cancer cells. CAR T-cell therapy exhibits favorable response in many patients with refractory hematological cancers with growing clinical trials in solid tumors. Immune system modulators: these drugs enhance the immune system's ability to fight cancer by stimulating the production of immune cells or inhibiting the activity of immune-suppressing cells. While immunotherapy has shown great promise in the treatment of cancer, it can also pose significant cardiac side effects. Some immunotherapy drugs like ICIs can cause myocarditis, which can lead to chest pain, shortness of breath, and heart failure. Other cardiac side effects of ICIs include arrhythmias, pericarditis, vasculitis, and accelerated atherosclerosis. It is important for patients receiving immunotherapy to be monitored closely for these side effects, as prompt treatment can help prevent serious complications. Patients should also report any symptoms to their healthcare providers right away, so that appropriate action can be taken. CAR T-cell therapy can also illicit an exaggerated immune response creating cytokine release syndrome (CRS) that may precipitate cardiovascular events: arrhythmias, myocardial infarction, and heart failure. Overall, while immune modulating therapy is a promising and expanding approach to cancer treatment, it is important to weigh the potential benefits against the risks and side effects, especially in patients with high risk for cardiovascular complications.


Development of Korean Disaster Mental Health Support Guidelines: Results of a Scoping Review and a Delphi Survey.
It is necessary to develop new guidelines to delineate the best ways of providing psychosocial care to ensure mental health following a disaster. This study applied the scoping review method as a means of establishing evidence-based guidelines for disaster mental health services. A total of 440 literatures were selected through a scoping review of 20,864 documents. Twenty-three recognized experts were invited to participate in the survey and a two-round online Delphi survey was conducted. The concordance rate in the Delphi Round 1 was 95.1%. Six items were excluded and new items were formulated with experts' suggestions. A total of 23 statements were slightly modified to clarify their meaning. In the Delphi Round 2, all items were met with consensus. The three items with the highest consensus among the experts were related to the protection of personal information and privacy. The item with the lowest consensus among experts was related to debriefing. Other items were related to establishing mental health support centers and suicide prevention activities. 140 items were developed through scoping reviews based on evidence-based methodology. These items were used to describe the disaster mental health support identified in Delphi. The guideline will provide a foundation for effective preparation and response in disaster situations.


Nestin expression in rat adrenal gland.
The constituents of the intermediate filament network of adrenal gland cells have not been deeply investigated in vivo. Adrenocortical cells have been reported to express cytokeratins and vimentin, but the intermediate filament components of the adrenomedullary cells are still unknown. Nestin is an intermediate filament protein that is mainly expressed in the developing nervous and muscle systems. It has been reported to be unable to form filaments by itself and it co-assembles with vimentin. Using immunocytochemical and biochemical approaches, the present study demonstrates that nestin is expressed in situ either in the cortex or in the medulla of adult rat adrenal glands. Nestin-negative cells prevalently form the zona glomerulosa whereas the zona fasciculata and the zona reticularis are mainly nestin-immunoreactive. Nestin-positive cells always express vimentin-like immunoreactivity but several cells apparently expressing only vimentin are detectable too. Nestin is also expressed by adrenomedullary cells that also display a faint vimentin-like immunoreactivity. We hypothesise that the inconstant detection of nestin in adrenocortical cells depends on their different functional moments. Moreover, even though our data do not allow to confirm vimentin in adrenomedullary cells, in situ detection of nestin in the adrenal medulla indirectly supports in vivo expression of vimentin in chromaffin cells.


Eliciting Emotion and Action Increases Social Media Engagement: An Analysis of Influential Orthopaedic Surgeons.
The purpose of this study is to analyze the Instagram practices of current orthopaedic surgeons and the components associated with highest reach and interactions. The top 25 orthopaedic surgeon Instagram profiles using the hashtag #ortho were ranked by the number of followers. Account information regarding followers, posts, engagement percentage, average likes, average comments, average video view, average video likes, average video comments, and estimated cost per post was recorded using social media marketing tools. An analysis of each Instagram profiles' top 10 posts, based on number of likes, was conducted. A coding framework was developed to categorized posting strategies utilized. Twenty-five Instagram accounts and 250 Instagram posts were included in the analysis. Accounts with increased engagement rating had a significantly greater number of likes and video views. When examining post characteristics that influenced the number of likes a post generated, posts that elicited negative emotions received 52.6% and 70.7% more likes than positive emotions (P = .04) and neutral emotions (P < .01), respectively. Upon assessment of posting characteristics that influenced the number of comments a post generated, promotional posts were shown to have 43.7% fewer comments than nonpromotional posts (P = .02). When evaluating factors that influenced total number of interactions a post generated, it was found that posts that asked questions generated 26.4% more interactions (P < .01) than those that do not. The present investigation found that the most effective strategies to generate more interactions on Instagram are those that elicit emotional responses and provoke viewer engagement by asking questions and directing actions. Additionally, it was found that promotional content was not well received by viewers. Orthopaedic surgeons have an opportunity to connect with colleagues, patients, and interested viewers through social media platforms in order to enhance their practice, disseminate educational content, and contribute to the social media presence of orthopaedic surgery.


Neuroendocrine control of vasopressin secretion and its effect on blood pressure in subjects with spinal cord transection.
The osmotic and cardiovascular control of arginine vasopressin (AVP) secretion, and the effect of this hormone on cardiovascular regulation were assessed both in normal controls and in subjects with tetraplegia. Infusion of hypertonic saline caused a marked rise in blood pressure in the tetraplegics but not in the normal controls. Head-up tilt resulted in a greater AVP response in the tetraplegics than in the controls because of the additional hypotensive response in the tetraplegics. Infusion of AVP itself at physiological concentrations had little effect on blood pressure in the normal subjects but resulted in a marked rise in blood pressure in the tetraplegics. Tetraplegics therefore show appropriate release of AVP to both osmotic and cardiovascular stimuli but increased sensitivity to the pressor effects of this hormone.


Activation of cannabinoid receptor 2 alleviates glucocorticoid-induced osteonecrosis of femoral head with osteogenesis and maintenance of blood supply.
In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.


Impaired quality of life in patients with treated acromegaly despite long-term biochemically stable disease: Results from a 5-years prospective study.
Patients with acromegaly demonstrate impaired quality of life (QoL), but data on long-term QoL changes in treated acromegaly are limited. This study evaluates and identifies factors that influence QoL in patients with long-term biochemical remission. The study consists of a cross-sectional arm comparing QoL between patients with treated and controlled acromegaly and healthy controls; and a longitudinal arm assessing QoL changes in patients with biochemically stable disease during 5.7±0.6 years of follow-up. A total of 58 patients and 116 matched controls were recruited for the cross-sectional arm; 28 patients completed the longitudinal arm. Three generic questionnaires (Psychological General Well-Being Schedule [PGWBS], 36-item Short-Form [SF-36], EuroQoL [EQ-5D]) and the disease-specific acromegaly QoL questionnaire (AcroQoL) were applied. Quality of life assessment was performed 11.6±8.2 years following diagnosis and treatment of acromegaly. Patients with treated acromegaly had lower QoL scores compared with controls in all questionnaires with the exception of the PGWBS "Anxiety" subscale. The AcroQoL "Appearance" subscale and the "Physical Function" subscales of the remaining questionnaires were the most underscored domains. No difference in the total and subscale scores of all questionnaires was observed between baseline and follow-up, with the exception of the SF-36 "Physical Function," where a decline was found (58.5±24.7% vs 43.1±31.1%; P=.002). However, after adjusting for covariates, no significant change in any of the QoL scores was seen. Duration of IGF-1/GH control was positively correlated with QoL scores in most questionnaires at baseline, whereas use of GH lowering therapy at the time of QoL assessment was a negative predictive factor of QoL. Patients with biochemically controlled acromegaly demonstrate impaired QoL, which persists despite long-term disease control. This primarily consists of impaired physical function and secondly of impaired psycho-social well-being. Duration of biochemical disease control and current use of GH lowering therapy was the predominant factors determining patients' QoL.


Handheld subcellular-resolution single-fiber confocal microscope using high-reflectivity two-axis vertical combdrive silicon microscanner.
We introduce a handheld single-fiber laser-scanning confocal microscope, incorporating a high-reflectivity two-axis silicon vertical combdrive microscanner, aimed at in vivo early detection of epithelial precancers. The approach adopted is motivated by need for a portable, economical, biopsy-free, early precancer screening technology in low-infrastructure environments. Our microelectromechanical system (MEMS) based handheld probe integrates the microscanners with miniature objective lens system and flexible electrical routing in a forward-imaging configuration, with 4.8 mm distal probe tip outer diameter for unrestricted imaging access in biological sites such as the oral cavity and cervix. Reflectance confocal videos of a USAF 1951 resolution target and biological samples were obtained over 200 microm x 110 microm field of view, with 0.80 and 9.55 microm lateral and axial resolution, at 3.5-5.0 frames per second. With improvements to objective numerical aperture, our probe can enable precise evaluation of nuclear size, density, nucleus-to-cytoplasm ratio and cell density, which are important visual identifiers of epithelial precancers.


Normal cardiac contraction in mice lacking the proline-alanine rich region and C1 domain of cardiac myosin binding protein C.
Cardiac myosin binding protein C (cMyBP-C) is an essential regulator of cross bridge cycling. Through mechanisms that are incompletely understood the N-terminal domains (NTDs) of cMyBP-C can activate contraction even in the absence of calcium and can also inhibit cross bridge kinetics in the presence of calcium. In vitro studies indicated that the proline-alanine rich (p/a) region and C1 domain are involved in these processes, although effects were greater using human proteins compared to murine proteins (Shaffer et al. J Biomed Biotechnol 2010, 2010: 789798). We hypothesized that the p/a and C1 region are critical for the timing of contraction. In this study we tested this hypothesis using a mouse model lacking the p/a and C1 region (p/a-C1(-/-) mice) to investigate the in vivo relevance of these regions on cardiac performance. Surprisingly, hearts of adult p/a-C1(-/-) mice functioned normally both on a cellular and whole organ level. Force measurements in permeabilized cardiomyocytes from adult p/a-C1(-/-) mice and wild type (Wt) littermate controls demonstrated similar rates of force redevelopment both at submaximal and maximal activation. Maximal and passive force and calcium sensitivity of force were comparable between groups as well. Echocardiograms showed normal isovolumetric contraction times, fractional shortening and ejection fraction, indicating proper systolic function in p/a-C1(-/-) mouse hearts. p/a-C1(-/-) mice showed a slight but significant reduction in isovolumetric relaxation time compared to Wt littermates, yet this difference disappeared in older mice (7-8months of age). Moreover, stroke volume was preserved in p/a-C1(-/-) mice, corroborating sufficient time for normal filling of the heart. Overall, the hearts of p/a-C1(-/-) mice showed no signs of dysfunction even after chronic stress with an adrenergic agonist. Together, these results indicate that the p/a region and the C1 domain of cMyBP-C are not critical for normal cardiac contraction in mice and that these domains have little if any impact on cross bridge kinetics in mice. These results thus contrast with in vitro studies utilizing proteins encoding the human p/a region and C1 domain. More detailed insight in how individual domains of cMyBP-C function and interact, across species and over the wide spectrum of conditions in which the heart has to function, will be essential to a better understanding of how cMyBP-C tunes cardiac contraction.


Deletions of MGF110-9L and MGF360-9L from African swine fever virus are highly attenuated in swine and confer protection against homologous challenge.
African swine fever, caused by a large icosahedral DNA virus (African swine fever virus, ASFV), is a highly contagious disease in domestic and feral swine, thus posing a significant economic threat to the global swine industry. Currently, there are no effective vaccines or the available methods to control ASFV infection. Attenuated live viruses with deleted virulence factors are considered to be the most promising vaccine candidates; however, the mechanism by which these attenuated viruses confer protection is unclear. Here, we used the Chinese ASFV CN/GS/2018 as a backbone and used homologous recombination to generate a virus in which MGF110-9L and MGF360-9L, two genes antagonize host innate antiviral immune response, were deleted (ASFV-ΔMGF110/360-9L). This genetically modified virus was highly attenuated in pigs and provided effective protection of pigs against parental ASFV challenge. Importantly, we found ASFV-ΔMGF110/360-9L infection induced higher expression of Toll-like receptor 2 (TLR2) mRNA compared with parental ASFV as determined by RNA-Seq and RT-PCR analysis. Further immunoblotting results showed that parental ASFV and ASFV-ΔMGF110/360-9L infection inhibited Pam3CSK4-triggered activating phosphorylation of proinflammatory transcription factor NF-κB subunit p65 and phosphorylation of NF-κB inhibitor IκBα levels, although NF-κB activation was higher in ASFV-ΔMGF110/360-9L-infected cells compared with parental ASFV-infected cells. Additionally, we show overexpression of TLR2 inhibited ASFV replication and the expression of ASFV p72 protein, whereas knockdown of TLR2 had the opposite effect. Our findings suggest that the attenuated virulence of ASFV-ΔMGF110/360-9L might be mediated by increased NF-κB and TLR2 signaling.


Bacteria-phagocyte interactions: Fusobacterium-induced secretion of a neutrophil self-regulatory factor.
Direct interaction between Fusobacterium nucleatum and human neutrophils resulted in the secretion of a neutrophil self-regulatory factor(s). The secretion of this factor was bacteria specific, and depended on the integrity of the bacteria cell surface. Factor secretion occurred within 15 min of bacteria--neutrophil interaction. Pre-treatment of neutrophils with cytochalasin B but not sodium fluoride inhibited factor secretion. The factor was sensitive to trypsin and heat treatment. Ultrafiltration experiments showed that it has a molecular weight between 10,000 and 30,000 daltons. Its biologic role may be that of a molecular mediator for the recruitment of resting neutrophils so as to amplify the immunological and inflammatory response.


Ecotoxicity of single and mixture of perfluoroalkyl substances (PFOS and PFOA) in soils to the earthworm Aporrectodea caliginosa.
Per and polyfluoroalkyl substances (PFAS) are persistent compounds that are massively used in industry, consumer goods and fire-fighting foams. Soil contamination by PFAS is a major environmental concern, and there is a lack of knowledge on both their ecotoxicological mechanisms and the concentrations that induce adverse effects especially to non-target organisms, particularly in the case of PFAS mixtures. This study contributes to filling these gaps by assessing and modelling the effects of PFAS (in single and in mixtures for PFOS and PFOA at different environmental doses) on juvenile endogeic earthworms of a common species in European soils (Aporrectodea caliginosa) at different levels of biological organization (sub-individual and individual). The results showed for the first time combined strong ecotoxicological effects of PFAS on earthworm survival, integumental integrity, growth, sexual maturity and on genomic stability notably with the induction of DNA breaks associated with no abnormal oxidative DNA-lesion levels. Our results demonstrated significant effects at 0.3 mg kg-1 and additive effects in case of mixtures.


Erratum: RNF6 promotes the migration and invasion of breast cancer by promoting the ubiquitination and degradation of MST1.
[This corrects the article DOI: 10.3892/etm.2021.11041.].


Evaluation of anticoagulant activity of two algal polysaccharides.
Marine algae are important sources of phycocolloids like agar, carrageenans and alginates used in industrial applications. Algal polysaccharides have emerged as an important class of bioactive products showing interesting properties. The aim of our study was to evaluate the potential uses as anticoagulant drugs of algal sulphate polysaccharides extracted from Ulva fasciata (Chlorophyta) and Agardhiella subulata (Rhodophyta) collected in Ganzirri Lake (Cape Peloro Lagoon, north-eastern Sicily, Italy). Toxicity of algal extracts through trypan blue test and anticoagulant action measured by activated partial thromboplastin time (APTT), prothrombin time (PT) test has been evaluated. Algal extracts showed to prolong the PT and APTT during the coagulation cascade and to avoid the blood coagulation of samples. Furthermore, the algal extracts lack toxic effects towards cellular metabolism and their productions are relatively at low cost. This permits to consider the algae as the biological source of the future.


Dose-Response Matters! - A Perspective on the Exercise Prescription in Exercise-Cognition Research.
In general, it is well recognized that both acute physical exercises and regular physical training influence brain plasticity and cognitive functions positively. However, growing evidence shows that the same physical exercises induce very heterogeneous outcomes across individuals. In an attempt to better understand this interindividual heterogeneity in response to acute and regular physical exercising, most research, so far, has focused on non-modifiable factors such as sex and different genotypes, while relatively little attention has been paid to exercise prescription as a modifiable factor. With an adapted exercise prescription, dosage can be made comparable across individuals, a procedure that is necessary to better understand the dose-response relationship in exercise-cognition research. This improved understanding of dose-response relationships could help to design more efficient physical training approaches against, for instance, cognitive decline.


A caveat concerning the application of the jack-knife to designed data.
The jack-knife is a resampling method that is increasingly used for assessing the uncertainty in regression coefficient estimates, even when the predictor variables (X) are designed. Application of the jack-knife to designed data, however, violates a basic assumption underlying all resampling methods, namely that the resampled units should constitute a random sample from some distribution; the idea is to 'resample the sample.' This paper advances the view that the jack-knife should not be applied to estimate the uncertainty in regression coefficient estimates obtained from designed data, since a sound alternative is available. A literature data set is re-analyzed to lend support to this view.


Appendiceal intussusception masquerading as an ileocolic intussusception.
Appendiceal intussusception is rare occurring with an incidence of 0.1%. It is most commonly encountered in middle-aged females due to endometrial involvement of the appendix. One-quarter of cases occur in the pediatric population where it is usually due to appendiceal inflammation. Classification of appendiceal intussusception (type I-V) is based on the level of appendiceal invagination. Appendectomy is the treatment of choice unless there is a concern for a neoplasm in which case a more extensive resection may be necessary. We report a 47-year-old with an appendiceal intussusception.


Quantification of blending of olive oils and edible vegetable oils by triacylglycerol fingerprint gas chromatography and chemometric tools.
A reliable procedure for the identification and quantification of the adulteration of olive oils in terms of blending with other vegetable oils (sunflower, corn, seeds, sesame and soya) has been developed. From the analytical viewpoint, the whole procedure relies only on the results of the determination of the triacylglycerol profile of the oils by high temperature gas chromatography-mass spectrometry. The chromatographic profiles were pre-treated (baseline correction, peak alignment using iCoshift algorithm and mean centering) before building the models. At first, a class-modeling approach, Soft Independent Modeling of Class Analogy (SIMCA) was used to identify the vegetable oil used blending. Successively, a separate calibration model for each kind of blending was built using Partial Least Square (PLS). The correlation coefficients of actual versus predicted concentrations resulting from multivariate calibration models were between 0.95 and 0.99. In addition, Genetic algorithms (GA-PLS), were used, as variable selection method, to improve the models which yielded R(2) values higher than 0.90 for calibration set. This model had a better predictive ability than the PLS without feature selection. The results obtained showed the potential of this method and allowed quantification of blends of olive oil in the vegetable oils tested containing at least 10% of olive oil.


Risk of relapse within 6 months associated with borderline personality disorder in major depressed individuals treated with electroconvulsive therapy.
Given the limited data in the literature, the aim of this study was to investigate the risk of relapse within 6 months associated with borderline personality disorder (BPD) in major depressed individuals treated with electroconvulsive therapy. Demographic and clinical data from 109 major depressed individuals with partial or complete response to electroconvulsive therapy recruited from the database of the Psychiatry Department of Erasme Hospital were analysed. Cox regression analyses were used to determine the risk of relapse within 6 months associated with BPD in major depressed individuals treated with electroconvulsive therapy. Relapses within 6 months were frequent (37.6%) in our sample of major depressed individuals treated with electroconvulsive therapy. After adjusting for major confounding factors, multivariate Cox regression analyses demonstrated that BPD was a risk factor for relapse within 6 months in major depressed individuals treated with electroconvulsive therapy. In our study, we demonstrated that BPD is associated with higher risk of relapse within 6 months in major depressed individuals treated with electroconvulsive therapy, which seems to justify a more systematic screening for BPD in order to allow the implementation of more effective prevention strategies for relapse within 6 months in this particular subpopulation.


Positive predictive values and outcomes for uninformative cell-free DNA tests: An Italian multicentric Cytogenetic and cytogenomic Audit of diagnOstic testing (ICARO study).
To establish the positive predictive values (PPV) of cfDNA testing based on data from a nationwide survey of independent clinical cytogenetics laboratories. Prenatal diagnostic test results obtained by Italian laboratories between 2013 and March 2020 were compiled for women with positive non-invasive prenatal tests (NIPT), without an NIPT result, and cases where there was sex discordancy between the NIPT and ultrasound. PPV and other summary data were reviewed. Diagnostic test results were collected for 1327 women with a positive NIPT. The highest PPVs were for Trisomy (T) 21 (624/671, 93%) and XYY (26/27, 96.3%), while rare autosomal trisomies (9/47, 19.1%) and recurrent microdeletions (8/55, 14.5%) had the lowest PPVs. PPVs for T21, T18, and T13 were significantly higher when diagnostic confirmation was carried out on chorionic villi (97.5%) compared to amniotic fluid (89.5%) (p < 0.001). In 19/139 (13.9%), of no result cases, a cytogenetic abnormality was detected. Follow-up genetic testing provided explanations for 3/6 cases with a fetal sex discordancy between NIPT and ultrasound. NIPT PPVs differ across the conditions screened and the tissues studied in diagnostic testing. This variability, issues associated with fetal sex discordancy, and no results, illustrate the importance of pre- and post-test counselling.


Peptides as novel smart materials.
Important challenges in biomaterials design include predicting the formation of large-scale self-assembled structures based on local atomic-level interactions and then endowing such structures with the ability to respond sensitively to environmental cues. This responsiveness is referred to as smartness. With the advent of key technological advances in imaging, peptides have recently begun to be exploited for their potential use as biomaterials, such as filaments and fibrils, hydrogels, surfactants and peptide hybrids. Peptides offer attractive features, principally because of our detailed understanding of their ability to fold into specific structures, and the rich chemistry with which their structure and function can be manipulated for environmental response.


Adaptive potential of the Mediterranean mussel Mytilus galloprovincialis to short-term environmental hypoxia.
Environmental hypoxia naturally occurs in coastal ecosystems and bivalve mollusks have to frequently face fluctuations of dissolved oxygen concentrations. Exposure to hypoxia is often associated with the change of the antioxidant and functional status in bivalves, and restoration of the normal oxygen supply is considered to induce oxidative stress in tissues of mollusks. The study investigates changes in the activity of two antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD), as well as the expression level of SOD and CAT genes in gills of the Mediterranean mussel, Mytilus galloprovincialis, under exposure to low dissolved oxygen concentration (2.2 mg L-1) for 24 h and 72 h, and 24 h reoxygenation period. We also evaluated the intracellular level of reactive oxygen species (ROS), mortality and changes in mitochondrial membrane potential in hemocytes following hypoxia-reoxygenation cycle. 24 h exposure to hypoxia significantly decreased activity of both enzymes, which then recovered up to control levels at the end of 72 h experimental period for SOD and after reoxygenation for CAT. Expression of antioxidant enzyme genes was up-regulated following the 72 h hypoxic exposure period and returned to the basal normoxic level after 24 h reoxygenation. Hypoxia demonstrated a time-dependent effect on the functional state of hemocytes. The 24 h exposure period did not influence aerobic respiration of hemocytes, but prolonged hypoxia (72 h) was associated with a substantial decrease in mitochondrial membrane potential of hemocytes. The intracellular ROS level and mortality of hemocytes did not change under hypoxia. Reoxygenation period was accompanied with a significant decrease of intracellular ROS level. This study indicated that hypoxia did not induce the pronounced oxidative stress in gills and the changes in the antioxidant status were reversible within 24 h of reoxygenation. Hemolymph demonstrated a stable functional state indicating the tolerance of mussels to short-time hypoxia.


Impact of fasting on thyrotropin and thyroid status during Ramadan in 292 previously well controlled hypothyroid patients. IFTAR study.
Fasting during Ramadan affects thyrotropin both in healthy subjects and hypothyroid patients on adequate levothyroxine replacement. Few studies have addressed this effect in hypothyroid patients with pre-Ramadan euthyroidism. This study aims to report the impact of fasting in a relatively large cohort. This was a prospective study including hypothyroid patients who fasted Ramadan during the years 2018, 2019, and 2020 in Alexandria, Egypt. All patients were euthyroid. Patients chosen one of three levothyroxine regimens during Ramadan, regimen 1: 60 min before Iftar, regimen 2: 3-4 h after Iftar, 60 min before Suhor, regimen 3: before the start of next fast, 3-4 h after an early Suhor. Thyroid status was assessed in pre-Ramadan visit and reassessed in post-Ramadan visit within 6 weeks from the end of Ramadan. The study included 292 hypothyroid patients. Most patients were adherent, 249 patients (85.3%), one sixth of patients were non-adherent, 43 patients (14.7%). Post-Ramadan TSH was 2.13 ± 1.88 mIU/L versus 1.60 ± 0.96 mIU/L pre-Ramadan [P = 0.001]. Most patients were still euthyroid post-Ramadan, 233 patients (79.8%), while 59 patients (20.2%) were dysthyroid. Post-Ramadan TSH significantly correlated to pre-Ramadan TSH [P < 0.001]. Post-Ramadan TSH was significantly higher in non-adherent patients, 3.57 ± 3.11 mIU/L compared to adherent patients, 1.88 ± 1.44 mIU/L [P < 0.001]. Fasting Ramadan in well controlled hypothyroid patients resulted in a significant increase in post-Ramadan TSH, yet 80% the patients remain euthyroid after Ramadan. Post-Ramadan TSH and euthyroidism are related to adherence and pre-Ramadan TSH.


White matter predicts tDCS antidepressant effects in a sham-controlled clinical trial study.
Transcranial direct current stimulation (tDCS) has been used as treatment for depression, but its effects are heterogeneous. We investigated, in a subsample of the clinical trial Escitalopram versus Electrical Direct Current Therapy for Depression Study (ELECTTDCS), whether white matter areas associated with depression disorder were associated with tDCS response. Baseline diffusion tensor imaging data were analyzed from 49 patients (34 females, mean age 41.9) randomized to escitalopram 20 mg/day, tDCS (2 mA, 30 min, 22 sessions), or placebo. Antidepressant outcomes were assessed by Hamilton Depression Rating Scale-17 (HDRS) after 10-week treatment. We used whole-brain tractography for extracting white matter measures for anterior corpus callosum, and bilaterally for cingulum bundle, striato-frontal, inferior occipito-frontal fasciculus and uncinate. For the rostral body, tDCS group showed higher MD associated with antidepressant effects (estimate = -5.13 ± 1.64, p = 0.002), and tDCS significantly differed from the placebo and the escitalopram group. The left striato-frontal tract showed higher FA associated with antidepressant effects (estimate = -2.14 ± 0.72, p = 0.003), and tDCS differed only from the placebo group. For the right uncinate, the tDCS group lower AD values were associated with higher HDRS decrease (estimate = -1.45 ± 0.67, p = 0.031). Abnormalities in white matter MDD-related areas are associated with tDCS antidepressant effects. Suggested better white matter microstructure of the left prefrontal cortex was associated with tDCS antidepressant effects. Future studies should investigate whether these findings are driven by electric field diffusion and density in these areas.


On methods of spatial analysis for genotyped individuals.
Spatial autocorrelation methods have commonly been applied to individual-based spatial genetic studies, although their properties and the relations among the statistics have not been carefully examined. This paper first introduces a reformulation of widely used spatial statistics using point processes. When Moran's I statistics are applied to allele frequencies within an individual, the frequencies are no longer continuous variables but have only three discrete values and specific interpretations of Moran's I statistics and the number of alleles in common (NAC) can be expressed as the weighted sum of join-count statistics. The distributions of minor genotypes are amplified in Moran's I depending on the allele frequency in the population, while NAC uses a constant weighting system. Under the point process framework, spatial analysis can be conducted on the common theoretical base, from individual locations to genetic distributions of different levels, (for example, genotype and allele). The methodology is demonstrated by application to field data for molecular ecological studies of Fagus crenata population dynamics.


"Maturational lag" hypothesis of attention deficit hyperactivity disorder: an update.
This article discusses the relationship of maturation to ADHD and hyperkinetic disorder (HKD), with an emphasis on current research in ADHD and HKD, persistence and remission of ADHD symptoms over time and brain maturational trajectories. ADHD is a broad, heterogeneous syndrome and only a subgroup of subjects has a diagnosis of HKD, which is a subset of individuals with severe ADHD combined subtype. Children showing symptoms above the threshold for a diagnosis of ADHD are at risk of developing comorbid conditions and increasing stress in both parents and teachers. In some subjects, ADHD symptoms can improve over time during maturation and development. These children with a diagnosis of ADHD could be viewed as showing variants of normal childhood behaviour with maturational trajectories that are lagging behind but will catch up. ADHD could therefore represent a continuum from normality at one extreme to a severe disorder, HKD according to ICD-10, at the other extreme.


Heparin added to cardioplegic solution inhibits tumor necrosis factor-alpha production and attenuates myocardial ischemic-reperfusion injury.
Tumor necrosis factor (TNF)-alpha is known to be a proinflammatory cytokine that has a pronounced negative inotropic effect and plays an important role in ischemic-reperfusion injury. Twenty isolated rat hearts were randomly divided equally into two groups (heparin and non-heparin) and were perfused with a Krebs-Henseleit solution using a modified Langendorff model. The influence of heparin on the synthesis and release of TNF-alpha by isolated rat hearts after 1 h of global cardioplegic ischemia and on left ventricular (LV) performances during 30 min of postischemic reperfusion was investigated. Significant mean (+/- SEM) amounts of TNF-alpha in myocardial tissue (1,149 +/- 33.7 pg/g) and effluent (951.8 +/- 27.3 pg/mL) from the coronary sinus were detected after global cardioplegic ischemia. The addition of heparin to the cardioplegic solution significantly improved the recovery of LV function in the postischemic heart (p < 0.0001 for all measurements). TNF-alpha protein production in the heparin-treated hearts was below detectable levels despite a postischemic increase of TNF-alpha messenger RNA expression in both heparin-treated hearts and nontreated hearts (0.71 +/- 0.06 and 0.8 +/- 0.12 relative optical density, respectively). This study shows, for the first time, that heparin causes the inhibition of TNF-alpha protein synthesis and release from the isolated ischemic rat heart within the posttranscriptional stage, and that it prevents the depression of LV function caused by ischemic-reperfusion injury.


Interacting with the Human Insulin Receptor.
Insulin is an essential regulator of glucose homeostasis. In this issue of Structure, Croll et al. (2016) reports a significantly improved model of the Fab-complexed IR ectodomain refined against a dataset extending to 3.3 Å.


Comparison of a high-carbohydrate and a high-monounsaturated fat, olive oil-rich diet on the susceptibility of LDL to oxidative modification in subjects with Type 2 diabetes mellitus.
To compare the effects of a high-carbohydrate (CHO) diet and a high-monounsaturated fatty acid (MUFA) diet on LDL oxidative resistance in free-living individuals with Type 2 diabetes mellitus. Twenty-two men and women out-patients with Type 2 diabetes, with mean age 61 years and in fair metabolic control (HbA1c<8.0%), were enrolled at a university hospital lipid clinic in a randomized, crossover feeding trial comparing two isocaloric diets for 6 weeks each: CHO (fat, 28% energy) and MUFA (fat, 40% energy) based on virgin olive oil. Outcome measurements were changes in LDL susceptibility to oxidation, body weight, glycaemic control, and lipoprotein profiles. Planned and observed diets were well matched. Participants preferred the MUFA diet over the CHO diet. The lag time of conjugated diene formation during Cu2+-induced LDL oxidation was similar after the CHO and MUFA diets (36.4 +/- 12.2 min and 36.0 +/- 13.7 min, respectively). Body weight, glycaemic control, total triglycerides, and total, LDL- and HDL-cholesterol levels also were similar after the two diets. Compared with the CHO diet, the MUFA diet lowered VLDL-cholesterol by 35% (P=0.023) and VLDL triglyceride by 16% (P=0.016). Natural food-based high-CHO and high-MUFA diets have similar effects on LDL oxidative resistance and metabolic control in subjects with Type 2 diabetes. A MUFA diet is a good alternative to high-CHO diets for nutrition therapy of diabetes because it also has a beneficial effect on the lipid profile and superior patient acceptance.


Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients.
In cyclosporine (CsA)-treated renal transplant recipients complete corticosteroid withdrawal followed by CsA monotherapy has been associated with severe rejection episodes in a significant proportion of patients. We report the results of replacement of steroids by azathioprine (AZA) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone (MP). MP taper was started 8.8 +/- 5.6 months posttransplant when the MP dose was either 10 mg/day or 20 mg every other day. MP was tapered off over a 5-month period. At the initiation of MP taper, AZA was added at 1 mg/kg/day and increased to 1.5 mg/kg/day after two months. The CsA dose was adjusted to maintain trough serum levels as measured by radioimmunoassay (RIA) of 50-75 ng/ml, during and after MP withdrawal. Seventeen patients have remained continuously off MP for 14.6 +/- 5.0 months with stable renal function. Reinstitution of MP at 10 mg/day was required in 8 patients, 6 for rejection (1.8 +/- 0.7 months after MP withdrawal), 1 for AZA-induced leukopenia, and 1 for de novo glomerulopathy. Renal function returned to baseline in all 6 patients with rejection after reinstitution of MP. Two of these patients have again been successfully retapered off MP. In the patients withdrawn from MP, body weight and mean arterial blood pressure had decreased by 2.1 +/- 1.3 kg (P less than .05) and 11 +/- 7 mmHg (P less than .05), respectively, at the time of the most recent follow-up compared with values at the initiation of steroid withdrawal. The number of blood pressure medications per patient decreased by 38% (P less than .05) and 6 patients were able to discontinue all antihypertensive drugs after cessation of steroids. Discontinuation of MP also resulted in a decrease in serum cholesterol concentration from 248 +/- 50 to 217 +/- 55 mg/dl (P less than .05). We conclude that steroids can be replaced by AZA in the majority of CsA-treated primary cadaveric renal transplant recipients by the end of the first posttransplant year without an adverse effect on graft survival. This protocol resulted in significant reductions in serum cholesterol, mean arterial blood pressure, and body weight, and may avoid the long-term side effects of steroid therapy.


Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axon.
Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury, spinal cord injury, cerebral ischemia, neurodegenerative diseases, and peripheral neuropathies. The calpain family of proteases has been mechanistically linked to the dysfunction and degeneration of axons. While the direct mechanisms by which transection, mechanical strain, ischemia, or complement activation trigger intra-axonal calpain activity are likely different, the downstream effects of unregulated calpain activity may be similar in seemingly disparate diseases. In this review, a brief examination of axonal structure is followed by a focused overview of the calpain family. Finally, the mechanisms by which calpains may disrupt the axonal cytoskeleton, transport, and specialized domains (axon initial segment, nodes, and terminals) are discussed.


Self-efficacy and its influencing factors of breast cancer screening for female college students in China.
This investigation aimed to study the general self-efficacy level and its influential factors of breast cancer screening for the female college students in Changchun city of China. A three-part questionnaire was designed to investigate 220 female college students' general self-efficacy for breast cancer screening and its associated factors and knowledge of breast cancer screening. The data were analyzed with spss 23.0 using descriptive statistics, independent sample t-tests and multiple regression analysis. The mean total score of general self-efficacy for breast cancer screening was 22.2 ± 5.213 (average ± standard deviation [SD])). About 37.7% of participants had lower level of general self-efficacy for breast cancer screening. The average score of knowledge about breast cancer and screening was 5.26 ± 3.974 (average ± SD). About half (48.6%) of the students had poor breast cancer screening knowledge. Multivariate logistic regression analysis demonstrated that the level of breast cancer knowledge (P = 0.011) and sleep satisfaction (P = 0.008) were two predictive factors of good general self-efficacy for breast cancer screening in female college students. Female college students in Changchun did not have enough knowledge and self-efficacy to cope with the breast cancer screening through this survey. Therefore, primary healthcare professionals have the responsibility to improve their awareness of breast cancer screening by delivering enough breast cancer knowledge and implementing effective health promotion strategies to keep better health status and have satisfied sleep.


[Phase II trial of improved regimen with gemcitabine in patients with advanced non-small cell lung cancer].
Gemcitabine-platinum-combined with chemotherapy is the most common treatment for advanced non-small cell lung cancer (NSCLC). Gemcitabine is administered once a week in a general three-week schedule. In the present study, gemcitabine is administered on d1 and d5 to improve compliance, and the efficacy and safety of the improved regimen is evaluated in untreated patients with advanced NSCLC. A total of 83 patients were enrolled between October 2007 and October 2009. In each cycle, gemcitabine was administered at a dose of 1,000 mg/m²-1,250 mg/m² via a 30 min intravenous infusion on d1 and d5 followed by cisplatin at a dose of 75 mg/m² or carboplatin (AUC=5) on d1 every three weeks. At least two cycles of chemotherapy were completed in each case, and clinical response and toxicity of the regimen were observed. The objective response rate was 37.3%. The median progression free survival and overall survival time were 6.1 months and 15.0 months, respectively. The one-year and two-year survival rates were 57.8% and 16.2%, respectively. Myelosuppression and gastrointestinal responses were the main toxicities. The incidence of grade 3/4 of leucopenia, hypohemia, and thrombocytopenia were 26.5%, 10.8% and 7.2%, respectively. A total of 27.5% of the patients in the cisplatin group had grade 3/4 gastrointestinal responses. Treatment related deaths were not observed in this study. The regimen is active and well-tolerated in untreated patients with advanced NSCLC. Further randomized controlled studies are necessary.


The renin axis and vasoconstriction volume analysis for understanding and treating renovascular and renal hypertension.
Information defining the renin-angiotension-aldosterone axis as a control system concurrently regulating salt balance and blood pressure has been applied to reexamine the role of renin in experimental and clinical forms of renovascular and renal hypertension, and thence to develop criteria for differentiating these entities. Experimentally, there are two models of renovascular hypertension; one is characterized by excess renin with reduced sodium (vasoconstrictor form) and the other by excess sodium with reduced renin (volume form). But with sodium depletion, the volume form converts to a vasoconstrictor form illustrating how the two factors coordinate to maintain blood pressure. In man, renovascular and renal hypertensions appear to be sustained by the same two mechanisms. Studies in man show that, in the absence of unilateral disease, the supine renal venous renin level in each kidney is consistently 24 percent higher than the peripheral level. Because of this constant relationship, the peripheral renin level is a measure of the renal secretion rate. Our studies indicate the curable unilateral renovascular hypertension is, in fact, renin-dependent vasoconstrictor hypertension. Three criteria, derived from four renin measurements, identify this situation: (1) Hypersecretion of renin is reflected by a high peripheral level when indexed against sodium excretion. (2) Lateralization of renin secretion with contralateral suppression rules out occult bilateral disease. It is indicated by V-A equal 0 from the uninvolved kidney. (3) (V-A)/A greater than 48 per cent from the ipsilateral kidney supports unilateralization. With data derived from patients with essential hypertension as a reference, the degree to which (V-A)/A is greater than 0.48 can be used to estimate the degree of renal ischemia, using Fick's principle. Corroborative evidence to support these three criteria can be developed from the blood pressure response to angiotensin blocking drugs or to antirenin therapy with propranolol. Clinical analysis validates these criteria to identify curable hypertension from unilateral renovascular or parenchymal disease. In patients with either occult or overt bilateral renal disease, the volume factor often predominates and is expressed by some suppression of plasma renin levels. Continued


LPS impairs steroidogenesis and ROS metabolism and induces PPAR transcriptional activity to disturb estrogen/androgen receptor expression in testicular cells.
Inflammation can deregulate the testicular functions of steroidogenesis and spermatogenesis, consequently contributing to male infertility. Animals and cells treated with lipopolysaccharide (LPS) exhibit infection- and inflammation-induced testicular dysfunction. However, the precise mechanisms affecting steroidogenesis and spermatogenesis in response to LPS-treatment remain poorly understood. We isolated distinct testicular cells including spermatocytes, round spermatids and late spermatids to analyze distribution of peroxisome proliferator-activated receptor (PPAR) family, plays central roles in the regulation of metabolism. Our results suggested Pparα/Pparγ mRNA was highly expressed in late spermatids, while Pparβ mRNA was highly expressed in round spermatids. To analyze the effect of LPS on testicular cells, we established an LPS infection model using primary Sertoli cells and testicular cell lines (TM4, GC2 and MLTC1). We observed that PPARγ and SIRT1 were concentrated in the nuclear region and that the mRNA expression levels of antioxidative enzymes (Cat and Homx1) and PPARγ were upregulated in primary Sertoli cells after LPS-treatment. Moreover, luciferase reporter gene assays of the testicular cell lines revealed that the activity of the PPAR response element (PPRE) was significantly increased. Importantly, the transcriptional activity of the androgen response element was significantly reduced, whereas activity of estrogen response element was strongly induced in LPS-treated TM4 cells, consistent with the RT-PCR results. Meanwhile, the qRT-PCR results revealed that the LPS-induced upregulation of Ar mRNA in MLTC1 cells and Erβ mRNA in TM4 cells were significantly recovered after treatment with the specific PPARγ-antagonist GW9662. In addition, we also found that LPS induced alterations in enzymes involved in steroidogenesis in testicular cell lines. Taken together, our results revealed that LPS may induce PPAR transcriptional activity to disturb estrogen/androgen receptor expression and impair steroidogenesis and ROS metabolism in testicular cells.


Epidemiology of strawberry haemangioma in low birthweight infants.
The prevalence of cutaneous haemangiomas in a representative population of low birthweight infants was determined by tracing and assessing survivors of pre-school age. Data from hospital case-notes and follow-up assessments were used to investigate whether prevalence of haemangiomas was related to perinatal factors and childhood morbidity. Eleven point one per cent of 615 infants developed a haemangioma. Haemangiomas were more common in girls than boys, and in infants of lower gestational age. Hypothermia in the first hours of life and neonatal illness were associated with lower prevalence, suggesting that neonatal skin perfusion influences haemangioma development; this is consistent with a tendency for haemangiomas to be distributed centripetally. However, the major aetiological determinants are unknown. Children with a haemangioma were more likely to have had a febrile convulsion than those without a haemangioma.


Tcf3 function is required for the inhibition of oligodendroglial fate specification in the spinal cord of zebrafish embryos.
The generation of various subtypes of neurons and glial cells at the right time and place is crucial for the proper development of the vertebrate CNS. Although the mechanisms and factors for the regulation of neuronal diversity in the CNS have been well studied, the mechanisms regulating the sequential production of neuronal and glial cells from neural precursors remain poorly understood. This study shows that Tcf3, a member of the Lef/Tcf family of proteins, is required to inhibit the premature oligodendroglial fate specification of spinal cord precursors using the transgenic zebrafish, which expresses a dominant repressor form of Tcf3 under the control of a heat-shock inducible promoter. In addition, the data revealed that Tcf3 function in oligodendroglial fate specification is mediated independently of canonical Wnt signaling. Altogether, these results show a novel function for Tcf3 in regulating the timing of oligodendroglial fate specification in the spinal cord.


Acute effects of D-1 and D-2 dopamine receptor agonist and antagonist drugs on basal ganglia [Met5]- and [Leu5]-enkephalin and neurotensin content in the rat.
The effects of acute systemic injection of the D-1 agonist SKF 38393 (2.5-20 mg/kg) or the D-1 antagonist SCH 23390 (0.25-2.0 mg/kg), and of the D-2 agonist quinpirole (0.12-1.0 mg/kg) or the D-2 antagonist sulpiride (25-100 mg/kg) on the neuropeptide content of rat basal ganglia were investigated. In striatum, the [Met5]- and [Leu5]-enkephalin content was unaffected by administration of SKF 38393 or SCH 23390. Quinpirole had no effect on [Met5]- and [Leu5]-enkephalin levels but sulpiride produced an increase in both [Met5]- and [Leu5]-enkephalin content. In the nucleus accumbens, SKF 38393 decreased and SCH 23390 increased [Met5]- and [Leu5]enkephalin levels. Quinpirole decreased [Met5]- and [Leu5]-enkephalin levels, while sulpiride decreased [Leu5]-enkephalin levels alone. The content of [Leu5]- but not [Met5]-enkephalin levels in the substantia nigra was increased by administration of SKF 38393, and decreased by SCH 23390. Quinpirole and sulpiride were without effect on the [Met5]- or [Leu5]-enkephalin content of substantia nigra. Neurotensin levels in striatum were increased by administration of SKF 38393 and decreased by SCH 23390. Similarly, quinpirole decreased the neurotensin content while sulpiride caused an increase. In the nucleus accumbens, the neurotensin content was not affected by administration of SKF 38393 but increased by SCH 23390. Neither quinpirole nor sulpiride altered neurotensin levels in the nucleus accumbens. Neurotensin levels in substantia nigra were unaffected by the administration of SKF 38393 and SCH 23390, or by quinpirole and sulpiride. These results indicate that acute administration of D-1 and D-2 agonist and antagonist drugs can alter the levels of [Met5]- and [Leu5]-enkephalin and neurotensin in basal ganglia. However, there are marked differences between brain regions in the regulation of peptide levels by acute D-1 and D-2 receptor occupation.


A general route to protected quaternary alpha-amino acids from beta-amino alcohols via a stereocontrolled radical approach.
A radical-based approach facilitates the highly stereocontrolled functionalisation of beta-amino alcohols, opening up a new, generally applicable methodology for the preparation of quaternary alpha-amino acids.


Indications for upper extremity surgery in rheumatoid arthritis patients.
In selected circumstances, especially those associated with pain and mechanical instability, early surgical therapy is indicated for patients with rheumatoid arthritis. Close consultation between the rheumatologist and surgeon enables identification of focused goals attainable by synovectomy, ligament or tendon reconstruction, joint replacement, or arthrodesis. If these goals are met, the result can be a gratifying return of function and independence. This article describes some of the more common deformities of the hand, wrist, and elbow in patients with rheumatoid arthritis. Current surgical therapy, along with outcome and complications, is also discussed. Emphasis is placed on decisions and indications for surgical evaluation.


Foxp3+ Tregs are recruited to the retina to repair pathological angiogenesis.
Neovascular retinopathies are major causes of vision loss; yet treatments to prevent the condition are inadequate. The role of regulatory T cells in neovascular retinopathy is unknown. Here we show that in retinopathy regulatory T cells are transiently increased in lymphoid organs and the retina, but decline when neovascularization is established. The decline is prevented following regulatory T cells expansion with an IL-2/anti-IL-2 mAb complex or the adoptive transfer of regulatory T cells. Further, both approaches reduce vasculopathy (vaso-obliteration, neovascularization, vascular leakage) and alter the activation of Tmem119+ retinal microglia. Our in vitro studies complement these findings, showing that retinal microglia co-cultured with regulatory T cells exhibit a reduction in co-stimulatory molecules and pro-inflammatory mediators that is attenuated by CTLA-4 blockade. Collectively, we demonstrate that regulatory T cells are recruited to the retina and, when expanded in number, repair the vasculature. Manipulation of regulatory T cell numbers is a previously unrecognized, and promising avenue for therapies to prevent blinding neovascular retinopathies.The local immune responses in the eye are attenuated to preserve sight. Surprisingly, Deliyanti et al. show that regulatory T cells (Tregs) take an active role in protecting the eye from neovascularization in oxygen-induced retinopathy, and that interventions that augment the retinal Treg numbers reduce neovascular retinopathy in mice.


Are recessions really good for your health? Evidence from Canada.
This study investigates the relationship between business cycle fluctuations and health in the Canadian context, given that a procyclical relationship between mortality rates and unemployment rates has already been well established in the U.S. literature. Using a fixed effects model and provincial data over the period 1977-2009, we estimate the effect of unemployment rates on Canadian age and gender specific mortality rates. Consistent with U.S. results, there is some evidence of a strong procyclical pattern in the mortality rates of middle-aged Canadians. We find that a one percentage point increase in the unemployment rate lowers the predicted mortality rate of individuals in their 30s by nearly 2 percent. In contrast to the U.S. data, we do not find a significant cyclical pattern in the mortality rates of infants and seniors.


Spontaneous brain activity in mild cognitive impairment revealed by amplitude of low-frequency fluctuation analysis: a resting-state fMRI study.
Spontaneous low-frequency fluctuations (LFF) in the blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal have been shown to reflect cerebral spontaneous neural activity. The objective of this study was to explore brain functional changes in patients with mild cognitive impairment (MCI) by measuring the amplitude of the BOLD signals. Eighteen amnestic MCI patients and 20 healthy elderly individuals underwent the fMRI scan. The amplitude of LFF (ALFF) was calculated using REST software. MCI patients showed decreased ALFF in the right hippocampus and parahippocampal cortex, left lateral temporal cortex and right ventral medial prefrontal cortex and increased ALFF in the left temporal-parietal joint (TPJ) and inferior parietal lobule. The ALFF value in the right hippocampus and parahippocampal cortex was positively correlated with the scores of Mini-Mental State Exam. Reduced medial temporal lobe activity may implicate the underlying memory impairment mechanisms in MCI. Increased TPJ and inferior parietal lobule activity may indicate the compensatory mechanism in MCI patients. These findings suggest that ALFF analysis could provide a useful tool in the fMRI study of MCI.


Meiosis: Deciphering the dialog between recombination and the synaptonemal complex.
A meiotic-specific structure, the synaptonemal complex, regulates meiotic recombination, but the 'language' used for this regulation has yet to be fully decoded. A new study identifies a novel phosphorylation site on the synaptonemal complex that regulates DNA repair pathway choice, revealing a new corner of the 'Rosetta Stone' for meiosis.


Dietary Curcumin Alleviated Aflatoxin B1-Induced Acute Liver Damage in Ducks by Regulating NLRP3-Caspase-1 Signaling Pathways.
Aflatoxin B1 (AFB1) is a mycotoxin widely distributed in animal feed and human food; it represents a serious threat to human and animal health. This study investigates the mechanism by which dietary curcumin protected liver against acute damage caused by AFB1 administration in ducks. One-day-old male ducks (n = 450) were randomly assigned to three groups, the control group, the AFB1 group, and the AFB1 + curcumin group; the first group were fed with basic diet, while the third group was fed basic diet containing 500 mg/kg curcumin. Ducks in the AFB1 group and AFB1 + curcumin group were challenged with AFB1 at the age of 70 days. The results show that AFB1 administration caused liver damage, increased CYP450 content and AFB1-DNA adducts in the liver, and induced oxidative stress and inflammatory response in the liver. Dietary curcumin significantly inhibited the generation of H2O2 and MDA in liver, activated the Nrf2-ARE signaling pathway, and suppressed the NLRP3-caspase-1 signaling pathway in the liver of ducks. Conclusively, curcumin in diet could protect duck liver against the generation of AFB1-DNA adducts, toxicity, oxidation stress and inflammatory response induced by AFB1 through regulating the NLRP3-caspase-1 signaling pathways, demonstrating that curcumin is a potential feed additive agent to reduce the serious harmful effects of AFB1 on duck breeding.


Impaired coronary dilator responses to substance P and impaired flow-dependent dilator responses in heart transplant patients with graft vasculopathy.
Because pathologic mechanisms for transplant vasculopathy are still uncertain, we tested the hypothesis that endothelial function, in terms of the release of endothelium-derived relaxing factor (EDRF), is impaired in patients with evidence of angiographic transplant vasculopathy. The long-term prognosis after heart transplantation is mainly determined by the development of transplant vasculopathy. The study included 23 patients undergoing diagnostic cardiac catheterization approximately 40 months after heart transplantation. Patients were classified into those with (n = 8) and those without (n = 15) angiographic evidence of transplant vasculopathy. Coronary flow velocity (by intravascular Doppler echocardiography) and epicardial coronary diameter (by quantitative angiography) were determined after intracoronary bolus injections (1 ml) of the endothelium-dependent dilator substance P (20 pmol) and the endothelium-independent dilators nitroglycerin (0.1 mg) and papaverine (8 mg). Substances were injected through the lumen of the Doppler catheter, which was placed into the midportion of the left anterior descending artery. Increases in blood flow velocity in response to substance P were significantly less in patients with than in patients without evidence of transplant vasculopathy. In addition, flow-mediated dilation of epicardial coronary arteries in response to papaverine was abolished in patients with such evidence. Vasodilation of epicardial coronary arteries in response to nitroglycerin and increases in flow velocity in response to papaverine were similar in both groups. These results suggest that transplant vasculopathy in heart transplant patients is associated with endothelial dysfunction (that is, impaired EDRF-mediated vasodilation). Furthermore, responsiveness of epicardial arteries to increased flow appears to be abolished in patients with evidence of transplant vasculopathy. These abnormal vascular functions may contribute to the pathogenesis of transplant vasculopathy and its vascular complications.


Decreased intracellular free magnesium in erythrocytes of spontaneously hypertensive rats.
Using 31p-NMR (the phosphorus nuclear magnetic resonance) spectroscopy, we measured intracellular free Mg levels in the erythrocytes of untreated (n = 7) and diltiazem-treated spontaneously hypertensive rats (SHR) (n = 8), and compared them with age-matched Wistar-Kyoto rats (WKY) (n = 10). The intracellular free Mg levels were significantly (p less than 0.01) decreased in untreated SHR compared with those in control WKY. A successful antihypertensive treatment with diltiazem increased the intracellular free Mg levels compared with untreated SHR (p less than 0.05). Furthermore, an inverse correlation was observed between intracellular free Mg levels and blood pressure levels in all groups (r = -0.48, p less than 0.01, n = 25). These observations suggest that abnormalities of intracellular Mg metabolism may be, in part, related to the development or the maintenance of hypertension in SHR.


Structure-activity trends analysis between amino acid compositions and minimal inhibitory concentrations of antimicrobial peptides.
Antimicrobial peptides (AMPs) provide large structural libraries of molecules with high variability of constitutional amino acids (AAs). Highlighting structural organization and structure-activity trends in such molecular systems provides key information on structural associations and functional conditions that could usefully help for drug design. This work presents link analyses between minimal inhibitory concentration (MIC) and different types of constitutional AAs of anti-Pseudomonas aeruginosa AMPs. This scope was based on a dataset of 328 published molecules. Regulation levels of AAs in AMPs were statistically ordinated by correspondence analysis helping for classification of the 328 AMPs into nine structurally homogeneous peptide clusters (PCs 1-9) characterized by high/low relative occurrences of different AAs. Within each PC, negative trends between MIC and AAs were highlighted by iterated multiple linear regression models built by bootstrap processes (bagging). MIC decrease was linked to different AAs that varied with PCs: alcohol-type AAs (Thr, Ser) in Cys-rich and low Arg PCs (PCs 1-3); basic AAs (Lys, Arg) in Pro-rich and low Val PCs (PCs 4-8); Trp (heterocyclic AA) in Arg-rich PCs (PCs 6, 7, 9). Aliphatic AAs (more particularly Gly) showed MIC reduction effects in different PCs essentially under interactive forms.


Absence of polycystic ovary syndrome features in human immunodeficiency virus-infected women despite significant hyperinsulinemia and truncal adiposity.
HIV-infected women increasingly demonstrate insulin resistance and fat redistribution characterized by relative truncal adiposity. It is unknown whether insulin resistance and truncal adiposity are associated with features of the polycystic ovary syndrome in this population. The objective of the study was to characterize ovarian morphology and reproductive indices in a large cohort of HIV-infected women in comparison with healthy age- and body mass index-matched control subjects. The study was conducted at an academic medical center. Eighty-eight HIV-infected women were compared with 94 age- and body mass index-matched healthy control subjects. Androgen, SHBG, and gonadotropin levels and ovarian morphology were measured. HIV-infected subjects demonstrated increased visceral adipose tissue (VAT) (101 +/- 6 vs. 71 +/- 5 cm2; P < 0.0001), increased VAT to s.c. adipose tissue ratio, and a trend toward decreased abdominal s.c. adipose tissue. Fasting insulin (12 +/- 1 vs. 6 +/- 1 microIU/ml; P < 0.001) and 2-h glucose (124 +/- 4 vs. 106 +/- 4 mg/dl; P = 0.001) were also significantly increased in the HIV-infected women, compared with control subjects, respectively. Despite significant hyperinsulinemia and visceral adiposity, HIV-infected women did not demonstrate irregular menses or an increased number of small ovarian follicles (8.0 +/- 0.9 vs. 8.5 +/- 0.7 follicles; P = 0.65, HIV-infected vs. controls). Rather, SHBG (124 +/- 10 vs. 84 +/- 4 nmol/liter; P < 0.001) was increased significantly in HIV-infected women, and free testosterone by equilibrium dialysis was significantly reduced (2.2 +/- 0.2 vs. 2.7 +/- 0.2 pg/ml; P = 0.04), as was LH to FSH ratio (0.62 +/- 0.05 vs. 0.83 +/- 0.07; P = 0.03). Menstrual function, androgen levels, and ovarian morphology by ultrasonography were not different between HIV-infected women and healthy controls. These data demonstrate that among HIV-infected subjects with severe abdominal fat accumulation and hyperinsulinemia, common features of polycystic ovary syndrome are not seen.


Trial into the effects of repeated neck retractions in normal subjects.
This investigation measured the immediate effects of 10, 20, and 30 repeated neck retraction movements on the retraction range of motion and resting neck posture in asymptomatic subjects. The results provide baseline gross kinematic data concerning the effects of neck retraction movements. Future work involving patients is anticipated and proposed. Neck retraction movements are an assessment maneuver and a treatment technique advocated by Robin McKenzie for patients with neck pain. They are a commonly prescribed physical therapy technique used to treat patients with neck pain and dysfunction. No previous studies of this maneuver have been reported. Two groups of 15 subjects, one group 20-29 years old and the other 50-59 years old, participated. Each group performed three sets of 10 repeated movements. The position of the head and neck were recorded by the 3Space Isotrak System using markers placed over the spinous processes of selected vertebrae and the tragus of the ear. After the repeated movements, no statistically significant difference was found in neck retraction range of motion, but a statistically significant change in the resting neck posture was detected. Any changes in neck retraction range of motion observed after the execution of this maneuver in patients with neck pain may be the result of changes in a pathological process. If the postural change were to occur in patients, this treatment maneuver could be beneficial for those attempting to maintain a more retracted neck position for pain relief.


Prophylactic Greenfield filter placement in selected high-risk trauma patients.
Pulmonary embolus (PE) remains a major factor in morbidity and death in severely injured patients, especially those in specific high-risk groups. PEs have been documented to occur despite routine deep venous thrombosis prophylaxis. The purpose of this study was to evaluate the safety and efficacy of prophylactic Greenfield filter (PGF) placement in patients who have multiple trauma with known high-risk injuries for PE. From January 1992 to June 1994, PGF were prospectively placed in 108 patients who had an injury severity score greater than 9 and met one of the following criteria: (1) severe head injury with prolonged ventilator dependence, (2) severe head injury with multiple lower extremity fractures, (3) spinal cord injury with or without paralysis, (4) major abdominal or pelvic penetrating venous injury, (5) pelvic fracture with lower extremity fractures. These patients were compared with 216 patients, historically matched for age, sex, mechanism of injury, injury severity score, and days in the intensive care unit. Data analysis was done with chi-squared and Student's t testing. There were no statistical differences between the PGF and control group with regard to age (35.9 +/- 1.5 vs 38.3 +/- 1.4), sex (male 76% vs 75.5%), days in the intensive care unit (21.2 +/- 1.4 vs 18.1 +/- 1.5), ISS (28.0 +/- 1.0 vs 25.4 +/- 0.8) and mechanism of injury (blunt 85% vs 81%). None of the patients in the PGF group had a PE. In the control group, however, 13 patients had a PE, nine of which were fatal. These differences were statistically significant for both PE (p < 0.009) and PE-related death (p < 0.03). The overall mortality rate was reduced in the PGF group (18 of 108, 16%) versus the control group (47 of 216, 22%); however, this did not achieve statistical significance. PGF insertion in selected patients at high risk who had trauma effectively prevented both fatal and nonfatal PE. The lower incidence of fatal PE in the PGF group may have contributed to a reduction in the overall mortality rate. Patients who have trauma with high risk for PE should be considered for PGF placement.


Longitudinal Movements and Stiffness of Lower Extremity Nerves Measured by Ultrasonography and Ultrasound Elastography in Symptomatic and Asymptomatic Populations: A Systematic Review With Meta-analysis.
This study was aimed at analyzing the effectiveness of ultrasonography (US) and ultrasound elastography (UE) in evaluating longitudinal sliding and stiffness of nerves. In line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, we analyzed 1112 publications (range: 2010-2021) extracted from MEDLINE, Scopus and Web of Science focusing on specific outcomes, including shear wave velocity (m/s), shear modulus (kPa), strain ratio (SR) and excursion (mm). Thirty-three papers were included and evaluated for overall quality and risk of bias. From the analysis of data concerning 1435 participants, mean shear wave velocity (SWV) in the sciatic nerve was 6.70 ± 1.26 m/s in controls and 7.51 ± 1.73 m/s in participants presenting with leg pain; in the tibial nerve, mean SWV was 3.83 ± 0.33 m/s in controls and 3.42 ± 3.53 m/s in participants presenting with diabetic peripheral neuropathy (DPN). The mean shear modulus (SM) was 20.9 ± 9.33 kPa for sciatic nerve, whereas it was an average of 23.3 ± 7.20 kPa for the tibial nerve. Considering 146 subjects (78 experimental, 68 controls) no significant difference was observed in SWV when comparing participants with DPN with controls (standard mean difference [SMD]: 1.26, 95% confidence interval [CI]: 0.54, 1.97), whereas a significant difference was observed in the SM (SMD: 1.78, 95% CI: 1.32, 2.25); furthermore, we found significant differences between left and right extremity nerves (SMD:1.14. 95% CI: 0.45, 1.83) among 458 participants (270 with DPN and 188 controls). No descriptive statistics are available for excursion because of the variability in participants and limb positions, whereas SR is considered only a semiquantitative outcome and therefore not comparable among different studies. Despite the presence of some limitations in study designs and methodological biases, on the basis of our findings, we can conclude that US and UE are effective methods in assessing longitudinal sliding and stiffness of lower extremity nerves in both symptomatic and asymptomatic subjects.


Electrochemical biosensing of circulating microRNA-21 in cerebrospinal fluid of medulloblastoma patients through target-induced redox signal amplification.
Monitoring of cerebrospinal fluid (CSF) microRNAs (miRs) offers a promising option for the diagnosis and management of patients with central nervous system tumors. However, the sensitive detection of miRs in clinical CSF samples has been hindered by the ultra-low abundance of target miRs. Here, we report an electrochemical biosensor for the highly sensitive label-free detection of CSF miR-21 relying on target-induced redox signal amplification (eTIRSA). The biosensor was developed by covalently assembling the capture stands partially complementary to miR-21 on the gold nanoparticle-coated glassy carbon electrode. In the presence of miR-21, the short capture stand hybridized with the partial bases of miR-21, allowing the rest sequence of the target molecule to further bind with a long guanine-rich sequence which could specifically adsorb a number of methylene blue indicators, thus generating an amplified electrochemical redox signal, typically at a working potential of - 0.19 V (vs. SCE). The response of the surface-bound methylene blue indicators was positively correlated to the concentration of miR-21, providing a dynamic range of 0.5-80 pM and a limit of detection down to 56 fM. Moreover, the eTIRSA biosensor had high specificity with single-base resolution and exhibited good performance for label-free quantification of miR-21 in medulloblastoma cell extracts and clinical CSF samples and for accurate discrimination of medulloblastoma against non-cancer controls, indicating its potential application in CSF miR-based liquid biopsy of brain cancers.