Astroglial Regulation of Magnocellular Neuroendocrine Cell Activities in the Supraoptic Nucleus.
Studies on the interactions between astrocytes and neurons in the hypothalamo-neurohypophysial system have significantly facilitated our understanding of the regulation of neural activities. This has been exemplified in the interactions between astrocytes and magnocellular neuroendocrine cells (MNCs) in the supraoptic nucleus (SON), specifically during osmotic stimulation and lactation. In response to changes in neurochemical environment in the SON, astrocytic morphology and functions change significantly, which further modulates MNC activity and the secretion of vasopressin and oxytocin. In osmotic regulation, short-term dehydration or water overload causes transient retraction or expansion of astrocytic processes, which increases or decreases the activity of SON neurons, respectively. Prolonged osmotic stimulation causes adaptive change in astrocytic plasticity in the SON, which allows osmosensory neurons to reserve osmosensitivity at new levels. During lactation, changes in neurochemical environment cause retraction of astrocytic processes around oxytocin neurons, which increases MNC's ability to secrete oxytocin. During suckling by a baby/pup, astrocytic processes in the mother/dams exhibit alternative retraction and expansion around oxytocin neurons, which mirrors intermittently synchronized activation of oxytocin neurons and the post-excitation inhibition, respectively. The morphological and functional plasticities of astrocytes depend on a series of cellular events involving glial fibrillary acidic protein, aquaporin 4, volume regulated anion channels, transporters and other astrocytic functional molecules. This review further explores mechanisms underlying astroglial regulation of the neuroendocrine neuronal activities in acute processes based on the knowledge from studies on the SON.


Clinical learning environment and supervision plus nurse teacher (CLES+T) scale: testing the psychometric characteristics of the Italian version.
A clinical learning environment is an "interactive network of forces within the clinical setting that influence the students' learning outcomes". International research indicates the Clinical Learning Environment and Supervision plus Nurse Teacher scale (CLES+T) as the gold standard to assess a good clinical learning environment. This study aims to evaluate the psychometric proprieties of CLES+T Italian version. 875 students attending the Bachelor in Nursing in 3 Universities in Italy participated in the study. Cronbach's alpha, item to total correlations, skewness and kurtosis were calculated; factor analysis was performed using Principal Axis Factoring and an oblique rotation method. Results showed a Cronbach's alpha of 0.95 of the scale and ranging from 0.80 to 0.96 among factors; all items verified item to total correlation and answers' variability criteria. Factor analysis showed a 7-factors model as explaining more than 67% of the variance, the higher variance was explained by the "pedagogical atmosphere" factor (37.61%). The nurse teacher factor in the Italian model is split into 3 sub-factors: theory-practice integration, cooperation with ward staff and relationship with mentor and student. These results enable an international debate concerning the theoretical structure of CLES+T and provide a reliable and valid tool for the comparison of supervisory models in guiding nursing students' clinical learning.


Association Between Small Vessel Disease Markers, Medial Temporal Lobe Atrophy and Cognitive Impairment After Stroke: A Systematic Review and Meta-Analysis.
Two-thirds of stroke survivors suffer from cognitive impairment, and up to one-third of them progress to dementia. However, the underlying pathogenesis is complex and controversial. Recent evidence has found that cerebral small vessel disease (SVD) markers and the Alzheimer's disease (AD) neuroimaging marker medial temporal lobe atrophy (MTLA), alone or in combination, contribute to the pathogenesis of poststroke cognitive impairment (PSCI). In the present systematic review and meta-analysis, we synthesized proof for these neuroimaging risk factors among stroke patients. PUBMED, MEDLINE, EMBASE and the Cochrane Library were searched for studies investigating imaging predictors of cognitive impairment or dementia following stroke. Meta-analysis was conducted to compute the odds ratios (ORs). Thirteen studies were enrolled in the present study, and only ten of them, comprising 2713 stroke patients, were eligible for inclusion in the meta-analysis. MTLA was significantly correlated with PSCI (OR = 1.97, 95% CI: 1.48-2.62, I2 = 0.0%). In addition, white matter hyperintensities (WMH), as a neuroimaging marker of SVD, were associated with PSCI (OR = 1.17, 95% CI: 1.12-1.22, I2 = 0.0%). However, the presence of lacunar infarcts and enlarged perivascular spaces (EPVS) were not associated with the risk of PSCI. The findings of the present study suggest that MTLA and WMH were associated with an increased risk of PSCI.


Enoxaparin for outpatients with COVID-19: 90-day results from the randomised, open-label, parallel-group, multinational, phase III OVID trial.
The benefits of early thromboprophylaxis in symptomatic COVID-19 outpatients remain unclear. We present the 90-day results from the randomised, open-label, parallel-group, investigator-initiated, multinational OVID phase III trial. Outpatients aged 50 years or older with acute symptomatic COVID-19 were randomised to receive enoxaparin 40 mg for 14 days once daily vs. standard of care (no thromboprophylaxis). The primary outcome was the composite of untoward hospitalisation and all-cause death within 30 days from randomisation. Secondary outcomes included arterial and venous major cardiovascular events, as well as the primary outcome within 90 days from randomisation. The study was prematurely terminated based on statistical criteria after the predefined interim analysis of 30-day data, which has been previously published. In the present analysis, we present the final, 90-day data from OVID and we additionally investigate the impact of thromboprophylaxis on the resolution of symptoms. Of the 472 patients included in the intention-to-treat population, 234 were randomised to receive enoxaparin and 238 no thromboprophylaxis. The median age was 57 (Q1-Q3: 53-62) years and 217 (46 %) were women. The 90-day primary outcome occurred in 11 (4.7 %) patients of the enoxaparin arm and in 11 (4.6 %) controls (adjusted relative risk 1.00; 95 % CI: 0.44-2.25): 3 events per group occurred after day 30. The 90-day incidence of cardiovascular events was 0.9 % in the enoxaparin arm vs. 1.7 % in controls (relative risk 0.51; 95 % CI: 0.09-2.75). Individual symptoms improved progressively within 90 days with no difference between groups. At 90 days, 42 (17.9 %) patients in the enoxaparin arm and 40 (16.8 %) controls had persistent respiratory symptoms. In adult community patients with COVID-19, early thromboprophylaxis with enoxaparin did not improve the course of COVID-19 neither in terms of hospitalisation and death nor considering COVID-19-related symptoms.


Endovascular aneurysm repair: is imaging surveillance robust, and does it influence long-term mortality?
Endovascular aneurysm repair (EVAR) is the dominant treatment strategy for abdominal aortic aneurysms. However, as a result of uncertainty regarding long-term durability, an ongoing imaging surveillance program is required. The aim of the study was to assess EVAR surveillance in Scotland and its effect on all-cause and aneurysm-related mortality. A retrospective analysis of all EVAR procedures carried out in the four main Scottish vascular units. The primary outcome measure was the implementation of post-EVAR imaging surveillance across Scotland. Patients were identified locally and then categorized as having complete, incomplete, or no surveillance. Secondary outcome measures were all-cause mortality and aneurysm-related mortality. Cause of death was obtained from death certificates. Data were available for 569 patients from the years 2001 to 2012. All centers had data for a minimum of 5 contiguous years. Surveillance ranged from 1.66 to 4.55 years (median 3.03 years). Overall, 53 % had complete imaging surveillance, 43 % incomplete, and 4 % none. For the whole cohort, all-cause 5-year mortality was 33.5 % (95 % confidence interval 28.0-38.6) and aneurysm-related mortality was 4.5 % (.8-7.3). All-cause mortality in patients with complete, incomplete, and no imaging was 49.9 % (39.2-58.6), 19.1 % (12.6-25.2), and 47.2 % (17.7-66.2), respectively. Aneurysm-related mortality was 3.7 % (1.8-7.4), 4.4 % (2.2-8.9), and 9.5 % (2.5-33.0), respectively. All-cause mortality was significantly higher in patients with complete compared to incomplete imaging surveillance (p < 0.001). No significant differences were observed in aneurysm-related mortality (p = 0.2). Only half of EVAR patients underwent complete long-term imaging surveillance. However, incomplete imaging could not be linked to any increase in mortality. Further work is required to establish the role and deliverability of EVAR imaging surveillance.


Vaccine Hesitancy.
The recent COVID-19 pandemic has caused over 800,000 deaths in the USA as of this writing. Remarkable, several effective vaccines have been developed within 1 year of the occurrence of the pandemic's outbreak in the USA. Although the vaccine has proven to be remarkably effective in preventing hospitalization and death, the number of unvaccinated persons in the USA who are eligible for the vaccine remains over 35%. Unvaccinated persons pose a risk for vaccine mutation and prolongation of the pandemic, with its attendant quarantines and societal shutdowns. The ability of clinicians to address this problem remains unclear in a population suspicious of science and of the health care community.


Olivo-cerebellar activity during harmaline-induced tremor.A 2-[14C]deoxyglucose study.
The specific neuronal activity of the olivo-cerebellar system of the cat under the effect of harmaline has been studied using the 2-[14C]deoxyglucose method. The results obtained in animals treated with tremogenic doses of harmaline, but immobilized with flaxedil, have been compared with those of non-treated controls. An increased radioactivity in specific regions of the olivo-cerebellar system including parts of the medial and dorsal accessory olive and the corresponding receiving molecular layer have been found. No involvement of the granule cell layer nor of the nuclear cells has been observed. It is therefore suggested that the tremogenic rhythmicity of the cerebellar output is organized uniquely by an increased climbing fiber input.


The relation between cognitive and motor dysfunction and motor imagery ability in patients with multiple sclerosis.
Motor imagery (MI) was recently shown to be a promising tool in neurorehabilitation. The ability to perform MI, however, may be impaired in some patients with neurological dysfunction. The objective was to assess the relation between cognitive and motor dysfunction and MI ability in patients with multiple sclerosis (MS). Thirty patients with MS underwent cognitive and motor screening, and also performed a composite test battery to assess their MI ability. This test battery consisted of a questionnaire, a hand rotation task and a test based on mental chronometry. Patients' MI ability was compared with the MI ability of age-matched healthy controls. Moreover, their MI scores were compared between body sides and were correlated with their scores on tests of motor and cognitive functioning. The average accuracy and temporal organization of MI significantly differed between MS patients and controls. Patients' MI accuracy significantly correlated with impairments in cognitive functioning, but was independent of motor functioning. MI duration, on the other hand, was independent of cognitive performance, but differed between the patients' most and least affected side. These findings are of use when considering the application of MI practice in MS patients' rehabilitation.


Outcomes with OAE and AABR screening in the first 48 h--Implications for newborn hearing screening in developing countries.
Early discharge of newborns (<24h after birth) from birthing centres is an important barrier to successful newborn hearing screening (NHS) in developing countries. This study evaluated the outcome of NHS within the first 48 h using an automated auditory brainstem response (AABR) device without the need for costly disposables typically required, and transient evoked otoacoustic emissions (TEOAE). NHS was performed on 150 healthy newborns (300 ears) with TEOAE and AABR techniques before discharge at a hospital. A three-stage screening protocol was implemented consisting of an initial screen with TEOAE (GSI AUDIOscreener+) and AABR (BERAphone(®) MB 11). Infants were screened at several time points as early as possible after birth. Infants were only re-screened if either screening technique (TEOAE or AABR) initially yielded a refer outcome. The same audiologist performed all TEOAE and AABR screenings. Over the three-stage screen AABR had a significantly lower refer rate of 16.7% (24/144 subjects) compared to TEOAE (37.9%; 55/145 subjects). Screening refer rate showed a progressive decrease with increasing age. For both TEOAE and AABR, refer rate per ear screened 24h post birth was significantly lower than for those screened before 24h. For infants screened before 12h post birth, the AABR refer rate per ear (51.1%) was significantly lower than the TEOAE refer rate (68.9%). Overall AABR refer rate per ear was similar for infants screened between 24 to 36 h (20.2%) and 36 to 48 h (18.9%) but significantly lower than for TEOAE (40.7% and 41.9%, respectively). Lowest initial refer rates per ear (TEOAE 25.8%, AABR 3.2%) were obtained after 48 h post birth. In light of the early post birth discharge typical in developing countries like South Africa, in-hospital screening with AABR technology is significantly more effective than TEOAEs. AABR screening with a device like the MB 11 is particularly appropriate because disposable costs are negligible.


Direct compression as an appropriately mechanical environment in bone tissue reconstruction in vitro.
Determining how to apply an appropriately mechanical environment which can improve the quality and function of bone-like construct in vitro is a required problem to be solved for the current development of bone tissue engineering. A specific mechanical force may be a key determinant of tissue development in vitro in bone tissue engineering. From the standpoint of bionics, the mechanical environments applied on bone tissue engineering should work in three aspects: providing adequately mechanical stimuli to the cells seeded in 3-D scaffold; ensuring the efficient mass-transport of the nutrients and waste products of the cells; promoting the development of functionally extracellular matrix in 3-D scaffold. After the analysis of several differently mechanical environments comparing with that in vivo, the directly dynamical compression environment, instead of hydrostatic pressure or microgravity or direct perfusion, can recreate the in vivo mechanisms of mechanosensation, mechanotransduction and mass-transport during engineered bone-like tissue culturing process in vitro. Therefore, it is hypothesized that the directly dynamic compression will be a specific mechanical environment to bone tissue reconstruction in vitro.


Exploring complex-PTSD comorbidity in trauma-exposed Northern Ireland veterans.
Complex posttraumatic stress disorder (CPTSD) describes the results of complex, prolonged, and/or inescapable trauma, and is typified by avoidance, re-experiencing, sense of threat, affect dysregulation, negative self-concept, and interpersonal disturbances. Additionally, CPTSD is highly comorbid with other common psychopathologies. A study was conducted in a trauma-exposed UK Armed Forces Veteran population resident in Northern Ireland (N = 638, NI) to determine the prevalence of CPTSD and comorbid associations. Data from the Northern Ireland Veterans Health and Wellbeing Study (NIVHWS), including self-report data describing traumatic stress, depression, anxiety, and suicidality, were used in a latent class analysis to identify distinct profiles of symptomology in the sample, and in a multinomial logistic regression to identify comorbidities associated with class membership. Three distinct classes emerged: a low endorsement 'baseline' class (36%), a 'Moderate Symptomatic' class (27%), and a high endorsement 'Probable CPTSD' class (37%). Both the Moderate Symptomatic and CPTSD classes were predicted by cumulative trauma exposure. Depression was highly comorbid (OR = 23.06 in CPTSD), as was anxiety (OR = 22.05 in CPTSD) and suicidal ideation (OR = 4.32 in CPTSD), with suicidal attempt associated with the CPTSD class (OR = 2.51). Cases of probable CPTSD were more prevalent than cases of probable posttraumatic stress disorder (PTSD) without Difficulties in Self-Organisation (DSO) symptoms in a UK Armed Forces veteran sample, were associated with repeated/cumulative trauma, and were highly comorbid across a range of psychopathologies. Findings validate previous literature on CPTSD and indicate considerable distress and thus need for support in UK Armed Forces veterans resident in NI.


Unusually high levels of n-6 polyunsaturated fatty acids in whale sharks and reef manta rays.
Fatty acid (FA) signature analysis has been increasingly used to assess dietary preferences and trophodynamics in marine animals. We investigated FA signatures of connective tissue of the whale shark Rhincodon typus and muscle tissue of the reef manta ray Manta alfredi. We found high levels of n-6 polyunsaturated fatty acids (PUFA), dominated by arachidonic acid (20:4n-6; 12-17 % of total FA), and comparatively lower levels of the essential n-3 PUFA-eicosapentaenoic acid (20:5n-3; ~1 %) and docosahexaenoic acid (22:6n-3; 3-10 %). Whale sharks and reef manta rays are regularly observed feeding on surface aggregations of coastal crustacean zooplankton during the day, which generally have FA profiles dominated by n-3 PUFA. The high levels of n-6 PUFA in both giant elasmobranchs raise new questions about the origin of their main food source.


Latent Tuberculosis Infection Among Immigrant and Refugee Children Arriving in the United States: 2010.
Immigrants and refugees age 2-14 years entering the United States from countries with estimated tuberculosis (TB) incidence rate ≥20 per 100,000 population are screened for TB. Children with TB disease are treated before US arrival. Children with positive tuberculin skin tests (TST), but negative TB evaluation during their pre-immigration examination, are classified with latent TB infection (LTBI) and are recommended for re-evaluation post-arrival. We examined post-immigration TB evaluation and therapy for children arriving with LTBI. We reviewed medical exam data from immigrant children with medical conditions and all refugee children arriving during 2010. Medical examination data were available for 67,334 children. Of these, 8231 (12 %) had LTBI pre-immigration; 5749 (70 %) were re-evaluated for TB post-immigration, and 64 % were retested by TST or IGRA. The pre-immigration LTBI diagnosis was changed for 38 % when retested by TST and for 71 % retested by IGRA. Estimated LTBI therapy initiation and completion rates were 68 and 12 %. In this population, testing with IGRA may limit the number of children targeted for therapy. Increased pre-immigration TB screening with post-immigration follow-up evaluation leading to completion of LTBI therapy should be encouraged to prevent TB reactivation.


Differences in reproductive toxicity of TBBPA and TCBPA exposure in male Rana nigromaculata.
Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) are persistent toxic environmental pollutants that cause severe reproductive toxicity in animals. The goal of this study was to compare the reproductive toxic effects of TBBPA and TCBPA on male Rana nigromaculata and to expound on the mechanisms leading to these effects. Healthy adult frogs were exposed to 0, 0.001, 0.01, 0.1, and 1 mg/L of TBBPA and TCBPA for 14 days. Sperm numbers were counted by erythrometry. Sperm mobility and deformities were observed under a light microscope (400 × ). We used commercial ELISA kits to determine the serum content of testosterone (T), estradiol (E2), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Expression of androgen receptor (AR) mRNA was detected using real-time qPCR. Sperm numbers and sperm mobility were significantly decreased and sperm deformity was significantly increased in a concentration dependent manner following exposure to TBBPA and TCBPA. Sperm deformity was significantly greater in the 1 mg/L TCBPA (0.549) treatment group than in the 1 mg/L TBBPA (0.397) treatment group. Serum T content was significantly greater in the 0.01, 0.1 and 1 mg/L TBBPA and TCBPA experimental groups compared with controls, while E2 content was significantly greater in only the 1 mg/L TBBPA and TCBPA experimental groups. Expression levels of LH and FSH significantly decreased in the 1 mg/L TBBPA and TCBPA treatment groups. AR mRNA expression decreased markedly in all the treated groups. Our results indicated that TBBPA and TCBPA induced reproductive toxicity in a dose-dependent manner, with TCBPA having greater toxicity than TBBPA. Furthermore, changes in T, E2, LH, and FSH levels induced by TBBPA and TCBPA exposure, which led to endocrine disorders, also caused disturbance of spermatogenesis through abnormal gene expressions of AR in the testes.


Umbilical sparing robotic partial cystectomy for localized urachal adenocarcinoma: A case report.
Urachal adenocarcinoma, the third most common histopathological type of non-urothelial bladder cancer, is often aggressive, presenting in advanced stages. Increased understanding of the embryologic origin of the tumor with concurrent advances in surgical technique have allowed partial cystectomy to become the gold standard of surgical treatment. However, the benefit of en bloc umbilectomy remains questionable. Here we present the diagnosis and management of 67- year old patient diagnosed with mucinous cystadenocarcinoma of the urachus treated with umbilical-sparing robotic partial cystectomy. We also provide a review of the existing literature on this rare tumor and its management.


HIV-1 inhibits phagocytosis and inflammatory cytokine responses of human monocyte-derived macrophages to P. falciparum infected erythrocytes.
HIV-1 infection increases the risk and severity of malaria by poorly defined mechanisms. We investigated the effect of HIV-1(Ba-L) infection of monocyte-derived macrophages (MDM) on phagocytosis of opsonised P. falciparum infected erythrocytes (IE) and subsequent proinflammatory cytokine secretion. Compared to mock-infected MDM, HIV-1 infection significantly inhibited phagocytosis of IE (median (IQR) (10 (0-28) versus (34 (27-108); IE internalised/100 MDM; p = 0.001) and decreased secretion of IL-6 (1,116 (352-3,387) versus 1,552 (889-6,331); pg/mL; p = 0.0078) and IL-1β (16 (7-21) versus 33 (27-65); pg/mL; p = 0.0078). Thus inadequate phagocytosis and cytokine production may contribute to impaired control of malaria in HIV-1 infected individuals.


Early complications of endovenous laser ablation.
The aim of this work was to evaluate the frequency, structure and characteristics of complications after endovenous laser ablation (EVLA). The study included 1247 consecutive patients (1417 limbs) with superficial venous insufficiency, treated with EVLA procedures with a wavelength of 1470 nm and automatic pull-back traction of the fiber. Control examinations using Duplex ultrasound were carried out on the second day after EVLA, and in 2 weeks and 1 month after the EVLA procedure. In certain situations, including the detection of complications, timing of the follow-up visits varied. In the postoperative period (up to 1 month after the procedure) complications were detected in 69 cases (4.87% of the EVLA procedures). Complications included the following: deep vein thrombosis (1.55%), pulmonary embolism (0.07%), pain syndrome (1.41%), abscess (0.07%), seroma (0.21%), fragmentations of the laser fiber (0.14%), hyperpigmentation (0.14%), and burn of the skin (0.07%) of the total number of EVLA procedures. EVLA is not a unique surgical method of treatment, and it has the same complications as any other surgical intervention. The complications rate in patients was 4.87% of EVLA procedures. Most complications can be avoided by developing a standard regulation on their detection and treatment as early as possible.


Familial combined sinus node and atrioventricular conduction dysfunctions.
Eighteen members of a family were investigated for cardiac conduction abnormalities following the discovery of a second-degree atrioventricular block in a fetus at 35 weeks of gestation. The conduction disturbance was diagnosed by ultrasonography. Seven of the family members were diagnosed as suffering from sinus node dysfunction and/or various degrees of atrioventricular block. Three of them were children aged 9 months to 6 years and all were asymptomatic. The symptomatic family members were two adults. One of them had a pacemaker inserted for a complete atrioventricular block and Adam-Stokes attacks while the other had had several fainting attacks. The clinical, electrocardiographic and ultrasonographic findings of the family members are presented. Previous reports in literature have documented the dominant transmission of familial sinus node dysfunctions or of familial cardiac conduction disturbances. The coexistence of both dysfunctions in the same family has not been emphasized in previous reports. A review of these previously reported families, as well as our patients, suggests the need of investigation and follow-up of the families in which one member of any age is diagnosed as suffering from an "idiopathic" disturbance of the cardiac conduction system.


New approach to modification of poly (l-lactic acid) with nano-hydroxyapatite improving functionality of human adipose-derived stromal cells (hASCs) through increased viability and enhanced mitochondrial activity.
The aim of this study was to determine the cytocompatibility of poly (l-lactide) (PLLA) scaffolds fabricated using co-rotating twin screw extrusion technique and functionalized with different concentrations of nano-hydroxyapatite (nHAp). The efforts were aimed on the designing bioactive scaffolds improving the viability and metabolic activity of human adipose-derived multipotent stromal cells (hASCs). The in vitro study was designed to determine the optimal nHAp concentration, based on analysis of hASCs morphology, adhesion rate, as well as metabolic and proliferative potential. Initially, the PLLA filled with three different concentrations of the nHAp were tested i.e. 5%, 10% and 15 wt%. The obtained results indicated that the 10 wt% nHAp in the PLLA (10% nHAp/PLLA) matrices improved the adhesion and proliferation of the hASCs, what was in good agreement with the results of tensile properties of the composites. Further, we performed profound studies regarding the cytotoxicity of 10% nHAp/PLLA. The analysis included the evaluation of the biomaterial influence on viability, apoptosis-related markers expression profile and mitochondrial function. The cytocompatibility of 10% nHAp/PLLA scaffolds toward the hASCs was confirmed. The hASCs propagated on 10% nHAp/PLLA were more viable then those propagated on the plain PLLA. The level of pro-apoptotic markers, i.e. caspase-3 and Bax in cultures on 10% nHAp/PLLA was significantly decreased. Obtained results correlated with higher mitochondrial membrane potential of hASCs in those cultures. The obtained composites may improve therapeutic potential of hASCs via directing their adhesion, enhancing proliferation and viability as well as increasing mitochondrial potential, thus may find potential application in tissue engineering.


K+ homeostasis is important for survival of Acinetobacter baumannii ATCC 19606 in the nosocomial environment.
Pathogenic bacteria have developed several mechanisms to thrive within the hostile environment of the human host, but it is often disregarded that their survival outside this niche is crucial for their successful transmission. Acinetobacter baumannii is very well adapted to both the human host and the hospital environment. The latter is facilitated by multifactorial mechanisms including its outstanding ability to survive on dry surfaces, its high metabolic diversity, and, of course, its remarkable osmotic resistance. As a first response to changing osmolarities, bacteria accumulate K+ in high amount to counterbalance the external ionic strength. Here, we addressed whether K+ uptake is involved in the challenges imposed by the harsh conditions outside its host and how K+ import influences the antibiotic resistance of A. baumannii. For this purpose, we used a strain lacking all major K+ importer ∆kup∆trk∆kdp. Survival of this mutant was strongly impaired under nutrient limitation in comparison to the wild type. Furthermore, we found that not only the resistance against copper but also against the disinfectant chlorhexidine was reduced in the triple mutant compared to the wild type. Finally, we revealed that the triple mutant is highly susceptible to a broad range of antibiotics and antimicrobial peptides. By studying mutants, in which the K+ transporter were deleted individually, we provide evidence that this effect is a consequence of the altered K+ uptake machinery. Conclusively, this study provides supporting information on the relevance of K+ homeostasis in the adaptation of A. baumannii to the nosocomial environment.


Drug-induced parkinsonism in the elderly: incidence, management and prevention.
Drug-induced parkinsonism (DIP) has been claimed to be the most prevalent cause of secondary parkinsonism in clinical practice in the Western world. Since the first descriptions in the early 1950s the prevalence of DIP seems to be increasing and approaching that of idiopathic Parkinson's disease (iPD) due to the aging of the population and the rising of polypharmacotherapy. Despite the wide interest this subject has raised in the past, it seems to be frequently overlooked by the medical community. It is particularly burdensome for the elderly and its management includes recognition of symptoms and identification of risk factors and offending agents. Prompt discontinuation of the causative agent leads to a marked improvement, although the condition might persist or remit slowly in up to 10% of the patients. Risk factors for developing DIP include older age; female sex; cognitive impairment; potency, dose and length of treatment; pre-existing extrapyramidal signs; and, very likely, a background of inherited predisposition. The main causative agents are dopamine receptor antagonists but the list of drugs without such a well known and straightforward mechanism of action is large. All antipsychotics, including atypicals (except clozapine) may produce parkinsonism. Although many drugs cause parkinsonism in a dose-related manner, there is an enormous variation in individual susceptibility. The clinical syndrome is less likely to produce tremor than iPD, and is more likely to be symmetrical, but the two syndromes might not be distinguished in any individual patient. Functional neuroimaging tests, which use ligands that bind to the dopamine transporter, are useful for distinguishing iPD from DIP in doubtful cases in patients treated with antipsychotics. The estimated presynaptic dopamine secreting neurons should be diminished in iPD but normal in DIP produced by dopamine receptor blockers, as assessed by molecular imaging techniques evaluating striatal dopamine transporters (DATs). Prompt recognition and discontinuation of the culprit are the keys to the management of DIP. In persistent cases, specific therapies including anticholinergics and amantadine may provide symptomatic relief. Levodopa and dopamine receptor agonists might be an option in selected cases in which dopamine nerve terminal defects are present. The weight and scope of DIP varies with the age and underlying health of the patient, imposing a significant burden on the elderly who, in many cases, experience significant functional deterioration that leads to hospitalization and has vast economic consequences. This article reviews the epidemiology, pathogenic mechanisms, implicated drugs, clinical features and management of DIP and highlights the need for increased awareness of this iatrogenic condition.


[Malignant sacrococcygeal teratoma in an adult woman].
Sacrococcygeal teratomas are neoplasms that are ordinarily diagnosed intrauterinely. In case of complete or partial intrapelvic sacrococcygeal teratoma, it may happen that it is only ascertained at a later age. During a regular monitoring visit for breast cancer a 58-year-old female reported that she had discovered a swelling at the level of her coccyx. MRI imagery appeared to indicate an ectopic ovary. After resection, it appeared that it was a mature teratoma from which mucinous adenocarcinoma had developed. Given the risk of malignant deterioration, it is important that sacrococcygeal teratoma be recognized and treated by means of complete resection, including resection of the coccygeal bone.


Spinal cord injury in the female.
A survey of 200 women, admitted with spinal cord injuries over a 20-year-period, revealed that such injuries were much less common in females than males, with a ratio of 1 female to 4.4 males. Women had a higher ratio of cervical injuries, mainly due to elderly ladies falling downstairs at home. Most women (60 per cent) achieved full independence, pressure sores were seldom a problem, and some women were able to return to work in offices and teaching. Women were very rarely at risk of renal failure. Most complete tetraplegics required permanent catheter drainage, with a 30 per cent incidence of leakage and blockage. Regular cystoscopy was advisable and the danger of autonomic dysreflexia had to be prevented. Partial tetraplegics and most paraplegics could manage without permanent catheters. Most became catheter-free, and the practice of self intermittent catheterisation would be the method of choice for the others. The causes of death were unremarkable, except that only 17 per cent of all late deaths were attributable to the injury.


Reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation with fludarabine and melphalan is associated with durable disease control in myelodysplastic syndrome.
We retrospectively evaluated the outcome of reduced-intensity conditioning (RIC) followed by allogeneic hematopoietic stem cell transplantation (HCT) in 43 patients with myelodysplastic syndrome (MDS) or AML arising from MDS. All patients received fludarabine plus melphalan followed by an allogeneic HCT from an HLA-identical sibling (SIB: n=19) or unrelated donor (MUD: n=24). Median age was 58 years (range: 30-71). Diagnoses at transplantation were RA (n=8), RARS (n=1), RAEB (n=13), RAEB-T (n=6), or AML arising from MDS (n=15). Of 28 patients with MDS, two patients had low, 10 had intermediate-1, nine had intermediate-2 and seven had high-risk MDS by IPSS criteria. All patients initially engrafted with the median neutrophil recovery of 15 days (range: 9-27). The 2-year overall survival, disease-free survival, relapse and transplant-related mortality were 53.5% (CI 45.2-61.1), 51.2% (CI 43.3-58.5), 16.3% (CI 7.9-30.7) and 35.2% (26.4-45.7), respectively. Grade II-IV acute graft-versus-host disease occurred in 27 (63%) patients. There was no significant survival difference between SIB and MUD-HCT, but the relapse rate was higher among SIB donor recipients when compared to MUD (38.5 versus 7%, P=0.02). RIC with fludarabine plus melphalan was associated with durable disease control and acceptable toxicity in this high-risk cohort.


Nineteen year results of THA using modular 9 mm S-ROM femoral component in patients with small femoral canals.
A retrospective analysis was undertaken of 30 consecutive THA performed in 25 patients with hypoplastic proximal femurs, who had received a 9-mm uncemented modular S-ROM stem. The mean patient age was 42 years (17-69 years), mean height was 152.5 cm (130-170.5 cm), mean weight was 63 kg (39-90 kg), and mean follow-up period was 19 years (range, 12-23 years). Subsidence was seen in 2 hips, with asymptomatic femoral osteolysis present in 11 hips; overall survival of the femoral stem was 93.3%, with two revisions of the femoral component required for aseptic loosening. After a mean follow-up of 19 years, the use of the S-ROM 9 mm femoral stem in the patient with the small femur was associated with a low revision rate due to aseptic loosening of the stem.


Impaired empathy and increased anger following social exclusion in non-intoxicated opioid users.
Social functioning is modulated by the endogenous opioid system. In opioid use disorder, social functioning appears disrupted, but little research has delineated the nature of these deficits and their relationship to acute opioid use. The current study aimed to assess both emotional and cognitive empathy, along with subjective and physiological responses to social exclusion in opioid users who were either acutely intoxicated or non-intoxicated from using opioids. Individuals on an opioid substitution medication (OSM) were divided into 'intoxicated users' (had taken their OSM the same day as testing, n = 20) and 'non-intoxicated users' (had taken their OSM > 12 h ago, n = 20) and compared with opioid-naïve controls (n = 24). Empathy was assessed using the multifaceted empathy test and self-report questionnaire. Participants also underwent a period of social exclusion (Cyberball Game) and completed measures of mood and physiological responses (salivary cortisol and heart rate). Non-intoxicated users had significantly lower emotional empathy (the ability to experience others' emotions), as well as greater anger after social exclusion when compared with the intoxicated users and controls. Anger did not change with social exclusion in the intoxicated user group and cortisol levels were lower overall. Reduced ability to spontaneously share the emotions of others was reported in non-intoxicated users, particularly regarding positive emotions. There was some support for the idea of hyperalgesia to social pain, but this was restricted to an enhanced anger response in non-intoxicated users. Equivalent rates of empathy between the intoxicated users and controls could indicate some remediating effects of acute opioids.


The differences in bioaccumulation and effects between Se(IV) and Se(VI) in the topmouth gudgeon Pseudorasbora parva.
Selenium (Se) might be protective against oxidative stress at nutritional levels, but elevated Se concentrations in the diet has been revealed as the main culprit for the extinction of natural fish populations in Se-contaminated lakes. Though Se predominate as waterborne selenite (IV) and selenate (VI) in the water, the differences in bioaccumulation, effects (e.g., oxidative stress, antioxidants etc.) and molecular mechanisms between Se(IV) and Se(VI) have been relatively understudied in wild fish. In this study, the P. parva were exposed to waterborne Se (10, 200 and 1000 μg/L of Se(IV) or Se(VI)) and sampled at 4, 14 and 28 days. Bioaccumulation, tissue distributions of Se and following effects in different tissues were evaluated. The results showed that the levels of Se in the gills and intestine were significantly elevated with a seemingly concentration-dependent pattern in the Se(IV) treatment, with respectively 173.3% and 57.2% increase after 28 days of exposure, relative to that of Se(VI) treatment. Additionally, significant accumulation of Se was also observed in the muscle of Se(IV) treated fish. Se exposure increased the MDA levels in the brain and gills in the Se(IV) treatment, but less apparent in the Se(VI) treatment. Meanwhile, Se exposure lowered (at least 56%) the activity of GST in the gills, but increased the activity of AChE in the muscle (~69%) and brain (~50%) after 28 d. Most importantly, after 28 d of exposure, Se exposure caused significant decrease in GSH levels in the gills (at least 35%) and in all tissues examined at the highest test concentration. In general, the results showed that Se(IV) led to faster accumulation of Se than Se(VI) in P. parva, and the resulted lipid peroxidation was closely related to the levels of antioxidants, especially GSH. Our results suggest that the ecotoxicological effects of waterborne selenite and selenate differ in this freshwater species in the field.


Ibuprofen attenuates the inflammatory response and allows formation of migratory neuroblasts from grafted stem cells after traumatic brain injury.
There is hope for neural stem and progenitor cells (NSPC) to enhance regeneration when transplanted to the injured brain after traumatic brain injury (TBI). So far, the therapeutic effects of NSPC transplantation have been hampered mainly by the notable death of the transplanted cells. Neuroinflammation may lead to additional cell death after TBI and we hypothesized that survival of grafted NSPC could be enhanced by anti-inflammatory treatment. Mice that were subjected to controlled cortical impact TBI and grafted with NSPC, were treated with the non-steroidal anti-inflammatory drug ibuprofen. Ibuprofen was found to down-regulate the TBI-induced inflammatory response. In addition, migrating neuroblasts from transplanted cells were observed near the contusion and in the ipsilateral hippocampus in ibuprofen-treated animals only, suggesting that the anti-inflammatory treatment had beneficial effects on graft survival and/or differentiation. However, Morris Water Maze performance or TBI-induced tissue loss was not influenced by ibuprofen treatment. Our data suggests that anti-inflammatory strategies may be a complement to enhance the outcome for the cell transplants following TBI.


[Diagnostic image (175). A man with fast and irregular palpitations. Atrial fibrillation and Wolff-Parkinson-White syndrome].
A 51-year-old man with palpitations had fast, broad and irregular QRS complexes on his ECG, due to atrial fibrillation and Wolff-Parkinson-White syndrome.


Heterologous resistance to Fasciola hepatica conferred upon rats by passive transfer of serum from different breeds of sheep.
Two experiments compared the protection against oral challenge with 20 metacercariae of Fasciola hepatica conferred on rats by intraperitoneal injection of serum from three breeds of sheep infected with F. hepatica (Barbados Blackbelly, St. Croix, Florida Native). Experiment 1 used serum from sheep 5-6 months of age following two infections of 250 metacercariae each, while Experiment 2 utilized serum collected from the same sheep at 10-11 months of age following either a primary (first exposure) or challenge (after two previous exposures of 250 metacercariae each) infection with 500 metacercariae. Similar numbers of flukes were recovered from rats given either immune or nonimmune (control) serum from each breed of sheep in Experiment 1. In Experiment 2, rats given serum from infected St. Croix sheep had significantly fewer flukes than rats given either control or immune serum from Barbados Blackbelly or Florida Native sheep. There was no significant correlation of fluke counts between individual serum donors (sheep) and serum recipients (rats).


Stable self-assembly of dipolar molecules on an Au(111) surface under UHV and an inert-atmosphere.
The growth of an extended supramolecular network using dipolar molecules as the building blocks is of great technological interest. We investigated the self-assembly of a dipolar molecule on an Au(111) surface. The formation of an extended two-dimensional network was demonstrated by scanning tunnelling microscopy under ultra-high vacuum and explained in terms of molecule-molecule interactions. This 2D-network is still stable under the pressure of one atmosphere of nitrogen, which demonstrated its interest for the development of submolecular-precisely polyfunctional smart surfaces.


Smallpox vaccine and its stockpile in 2005.
Smallpox vaccine was the most important tool in the successful eradication of smallpox. In 1980, this achievement made it possible for all nations to cease smallpox vaccination. However, the threat of smallpox bioterrorism has made it necessary to reconsider the need for vaccination. Over the past 3 years, many nations have set up action plans for use in the event of such an attack. The setting up of these plans was not simple. Several factors needed to be considered, including the judgement of risk, vaccine complications, conventional vaccines versus new vaccines, optimal stockpile of smallpox vaccine, and its use for different target populations in different emergency situations. Here, I review measures taken by the USA, Japan, and other nations, and discuss likely national and global efforts in 2005 and subsequently, in view of the fact that half of the world's population is now apparently unvaccinated and that this proportion will increase with time.


An analysis of margin configurations for metal-ceramic crowns.
Major types of margin configurations for ceramometal crowns are reviewed. This is one of the most commonly misunderstood and poorly practiced aspects of fixed prosthodontics. The resultant underprepared teeth produce discolored gingiva and chalky crowns.


Severe external apical root resorption--local cause or genetic predisposition?
Current data suggest that a large extent of the variation in orthodontic root resorption may be explained by differences in individual genetic predisposition. This would imply, however, a similar root resorption reaction in all teeth. To determine the incidence and extent of severe external apical root resorptions (SEARR) in maxillary incisors during multibracket (MB) appliance treatment. Of the whole sample of patients having completed MB treatment at the University of Giessen between 1991 and 2010 (P(Total)=3198), all subjects exhibiting severe root resorptions on at least one maxillary incisor were selected. SEARR were defined according to Malmgren et al. [39] (grade-IV RR=resorption >1/3 root length). Evaluation was performed using orthopantomograms from before and after MB treatment. The crown and root length of the affected teeth were measured. The extent of SEARR was assessed taking pretreatment crown length into consideration. SEARR was detected in 16 patients. Thus, the incidence of SEARR on maxillary incisors during MB treatment totalled 0.5%. The median of SEARR of the affected incisors was 38.6% of the initial root length (minimum=33.4%, maximum=61.0%). Most subjects exhibited only single affected teeth. Only two subjects (0.06% absolute/12.5% relative) presented four maxillary incisors with SEARR. The incidence of SEARR on maxillary incisors during MB treatment (0.5%) was very low compared to the literature. With only 12.5% of SEARR patients presenting four affected teeth, local rather than systemic/genetic factors seem to have predisposed the present subjects to SEARR.


Effect of CO2 on growth and toxicity of Alexandrium tamarense from the East China Sea, a major producer of paralytic shellfish toxins.
In recent decades, the frequency and intensity of harmful algal blooms (HABs), as well as a profusion of toxic phytoplankton species, have significantly increased in coastal regions of China. Researchers attribute this to environmental changes such as rising atmospheric CO2 levels. Such addition of carbon into the ocean ecosystem can lead to increased growth, enhanced metabolism, and altered toxicity of toxic phytoplankton communities resulting in serious human health concerns. In this study, the effects of elevated partial pressure of CO2 (pCO2) on the growth and toxicity of a strain of Alexandrium tamarense (ATDH) widespread in the East and South China Seas were investigated. Results of these studies showed a higher specific growth rate (0.31±0.05day-1) when exposed to 1000μatm CO2, (experimental), with a corresponding density of (2.02±0.19)×107cellsL-1, that was significantly larger than cells under 395μatm CO2(control). These data also revealed that elevated pCO2 primarily affected the photosynthetic properties of cells in the exponential growth phase. Interestingly, measurement of the total toxin content per cell was reduced by half under elevated CO2 conditions. The following individual toxins were measured in this study: C1, C2, GTX1, GTX2, GTX3, GTX4, GTX5, STX, dcGTX2, dcGTX3, and dcSTX. Cells grown in 1000μatm CO2 showed an overall decrease in the cellular concentrations of C1, C2, GTX2, GTX3, GTX5, STX, dcGTX2, dcGTX3, and dcSTX, but an increase in GTX1 and GTX4. Total cellular toxicity per cell was measured revealing an increase of nearly 60% toxicity in the presence of elevated CO2 compared to controls. This unusual result was attributed to a significant increase in the cellular concentrations of the more toxic derivatives, GTX1 and GTX4.Taken together; these findings indicate that the A. tamarense strain ATDH isolated from the East China Sea significantly increased in growth and cellular toxicity under elevated pCO2 levels. These data may provide vital information regarding future HABs and the corresponding harmful effects as a result of increasing atmospheric CO2.


Effects of Thyroid Hormone Withdrawal and Recombinant Human Thyrotropin on Glomerular Filtration Rate During Radioiodine Therapy for Well-Differentiated Thyroid Cancer.
Renal function is related to thyroid hormonal status, and glomerular filtration rate (GFR) seems to be impaired in patients with hypothyroidism. The aim of this work was to evaluate quantitatively the effect of hypothyroidism on GFR using a (51)Cr-EDTA radioisotope assay. Twenty-eight patients without known renal disease or dysfunction who had been referred for radioiodine therapy (RIT) after total thyroidectomy were enrolled in this study and divided into two groups. Group A underwent thyroid hormone withdrawal (THW) resulting in hypothyroidism, while group B underwent recombinant human thyrotropin (rhTSH) stimulation and hence remained euthyroid. GFR was assessed by (51)Cr-EDTA before and after THW or rhTSH. No clinical differences were observed between the two groups. The mean ± SD GFRs were 94 ± 19 mL/min/1.73 m(2) before THW and 76 ± 16 mL/min/1.73 m(2) after THW for group A (p = 0.009), and 91 ± 18 mL/min/1.73 m(2) before rhTSH and 93 ± 15 mL/min/1.73 m(2) after rhTSH for group B (p = 0.613). The percent decrease in GFR during hypothyroidism is approximately 18-22%. GFR decreases in patients with normal kidney function during THW for RIT, and rhTSH preserves GFR in these patients. This GFR impairment following thyroidectomy is related to hypothyroidism due to a significant reduction in thyroid hormone levels and is not due to a rise in the TSH level.


A highly sensitive chelator for metal staining, bromopyridylazo-diethylaminophenol.
2-(5-Bromo-2-pyridylazo)-5-diethylaminophenol has been found to be capable of staining very small amounts of metals, particularly copper, iron, lead, and zinc, in tissue. The differentiation of a target metal from interfering metals is achieved by using masking agents, polyphosphates, and potassium cyanide.


Plant litter decomposition in wetlands is closely associated with phyllospheric fungi as revealed by microbial community dynamics and co-occurrence network.
Phyllospheric microbes play a crucial role in the biological decomposition of plant litter in wetland ecosystems. Previous studies have mainly focused on single stages of decomposition process, and to date there have been no reports on dynamic changes in the composition of phyllospheric microbes during the multiple stages of decomposition from living plant to death. Here we investigated fungal and bacterial community succession in the leaf litter of Schoenoplectus tabernaemontani, a wetland plant species using sequencing of the both fungal ITS and bacterial 16S genes. Our results revealed that, over the whole period of decomposition, the fungal communities underwent more distinct succession than did the bacterial communities. Proteobacteria dominated throughout the entire period, while, across different decomposition stages, the Ascomycete fungi were gradually replaced by the Ciliophora and Rozellomycota as the dominant fungi. Network analysis revealed higher degrees of species segregation and shorter average path lengths between species of fungi compared with species of bacteria. This suggests that fungal communities may harbor more niches and functional diversity and are potentially more susceptible to external interference than are bacterial communities. During decomposition, the contents of leaf cellulose, hemicellulose and lignin in the litter were significantly (p < 0.01) correlated with the fungal communities, and abiotic factors accounted for 89.8% of the total variation in the fungal communities. In contract, abiotic factors only explained 6.10% of the total variation in bacterial communities, suggesting external environments as drivers of fungal community succession. Overall, we provide evidence that the complex litter decay in wetlands is the result of a dynamic cross-kingdom succession, and this process is accompanied by distinct phyllospheric fungal community dynamics.


Endometrial cancer arising from atypical complex hyperplasia: The significance in an endometrial biopsy and a diagnostic challenge.
We investigated the features of endometrial hyperplasia with concurrent endometrial cancer that had been diagnosed by endometrial sampling. Further, we attempted to identify an accurate differential diagnostic method. We retrospectively studied 125 patients who underwent a diagnostic endometrial biopsy or were diagnosed after the surgical treatment of other gynecological lesions, such as leiomyoma or polyps. Patients were diagnosed between January 2005 and December 2013 at Busan Paik Hospital. Clinical and histopathological characteristics were compared in patients who had atypical endometrial hyperplasia with and without concurrent endometrial cancer. The patients were grouped based on the final pathology reports. One hundred seventeen patients were diagnosed with endometrial hyperplasia and eight patients were diagnosed with endometrioid adenocarcinoma arising from atypical hyperplasia. Of the 26 patients who had been diagnosed with atypical endometrial hyperplasia by office-based endometrial biopsy, eight (30.8%) were subsequently diagnosed with endometrial cancer after they had undergone hysterectomy. The patients with endometrial cancer arising from endometrial hyperplasia were younger (39.1 vs. 47.2 years, P=0.0104) and more obese (body mass index 26.1±9.6 vs. 23.8±2.8 kg/m(2), P=0.3560) than the patients with endometrial hyperplasia. The correlation rate between the pathology of the endometrial samples and the final diagnosis of endometrial hyperplasia was 67.3%. In patients with atypical endometrial hyperplasia, the detection of endometrial cancer before hysterectomy can decrease the risk of suboptimal treatment. The accuracy of endometrial sampling for the diagnosis of concurrent endometrial carcinoma was much lower than that for atypical endometrial hyperplasia. Therefore, concurrent endometrial carcinoma should be suspected and surgical intervention should be considered in young or obese patients who present with atypical endometrial hyperplasia.


Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR-mutant non-small-cell lung cancer.
RNA 5-methylcytosine (m5C) modification plays critical roles in the pathogenesis of various tumors. However, the function and molecular mechanism of RNA m5C modification in tumor drug resistance remain unclear. The correlation between RNA m5C methylation, m5C writer NOP2/Sun RNA methyltransferase family member 2 (NSUN2) and EGFR-TKIs resistance was determined in non-small-cell lung cancer (NSCLC) cell lines and patient samples. The effects of NSUN2 on EGFR-TKIs resistance were investigated by gain- and loss-of-function assays in vitro and in vivo. RNA-sequencing (RNA-seq), RNA bisulfite sequencing (RNA-BisSeq) and m5C methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the target gene of NSUN2 involved in EGFR-TKIs resistance. Furthermore, the regulatory mechanism of NSUN2 modulating the target gene expression was investigated by functional rescue and puromycin incorporation assays. RNA m5C hypermethylation and NSUN2 were significantly correlated with intrinsic resistance to EGFR-TKIs. Overexpression of NSUN2 resulted in gefitinib resistance and tumor recurrence, while genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib in vitro and in vivo. Integrated RNA-seq and m5C-BisSeq analyses identified quiescin sulfhydryl oxidase 1 (QSOX1) as a potential target of aberrant m5C modification. NSUN2 methylated QSOX1 coding sequence region, leading to enhanced QSOX1 translation through m5C reader Y-box binding protein 1 (YBX1). Our study reveals a critical function of aberrant RNA m5C modification via the NSUN2-YBX1-QSOX1 axis in mediating intrinsic resistance to gefitinib in EGFR-mutant NSCLC.


Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims.
Teenage suicide is a major public health concern, but its neurobiology is not well understood. Proinflammatory cytokines play an important role in stress and in the pathophysiology of depression-two major risk factors for suicide. Cytokines are increased in the serum of patients with depression and suicidal behavior; however, it is not clear if similar abnormality in cytokines occurs in brains of suicide victims. We therefore measured the gene and protein expression levels of proinflammatory cytokines interleukin (IL)-1β, IL-6, and tissue necrosis factor (TNF)-α in the prefrontal cortex (PFC) of 24 teenage suicide victims and 24 matched normal control subjects. Our results show that the mRNA and protein expression levels of IL-1β, IL-6, and TNF-α were significantly increased in Brodmann area 10 (BA-10) of suicide victims compared with normal control subjects. These results suggest an important role for IL-1β, IL-6, and TNF-α in the pathophysiology of suicidal behavior and that proinflammatory cytokines may be an appropriate target for developing therapeutic agents.


Effects of thromboxane agonists on cardiac adrenergic neurotransmission.
The effects of thromboxane B2 (TxB2) and of two thromboxane mimetics, dl-(9,11), (11,12)-dimethano-TxA2 (ONO 11006) and 9,11-dideoxy-11,9-epoxymethano prostaglandin F2 alpha (U46619) on the cardiac response to adrenergic nerve stimulation in isolated guinea-pig atria were evaluated. All the agonists dose dependently reduced the positive inotropic effect induced by field stimulation, U46619 being the most active. The inhibitory effect of U46619 was reduced by the thromboxane receptor antagonists, sulotroban and AH 23848B. U46619 did not significantly reduce the positive inotropic effect induced by exogenous noradrenaline. However U46619 was unable to modify the tritium overflow induced by field stimulation in preparations preloaded with [3H]noradrenaline. In addition to this influence on adrenergic neurotransmission, U46619 also had a direct positive inotropic effect on cardiac contractility, which was antagonized by AH 23848B. These results indicate that U46619 reduces the cardiac response to sympathetic nerve stimulation and that is also has a direct stimulatory effect on cardiac muscle.


The evolution of chromosomal instability in Chinese hamster cells: a changing picture?
To investigate the kinetics of chromosomal instability induced in clones of Chinese hamster cells following X-irradiation. X-irradiated clones of GM10115, human-hamster hybrid cells containing a single human chromosome 4 (HC4), have been previously established. These clones were defined as unstable if they contained > or = three subpopulations of cells with unique rearrangements of HC4 as detected by FISH. Stable and unstable clones were analysed by FISH and Giemsa staining at various times post-irradiation. While most of the stable clones continued to show chromosomal stability of HC4 over time, one became marginally unstable at approximately 45 population doublings post-irradiation. Clones exhibiting chromosomal instability had one of several fates. Many of the unstable clones were showed similar levels of instability over time. However, one unstable clone became stable with time in culture, while another became even more unstable over time. Cytogenetic analyses of all clones after Giemsa staining indicated that in some clones the hamster chromosomes were rearranged independent of HC4, demonstrating increased frequencies of chromatid breaks and dicentric chromosomes. The majority of the unstable clones also had higher yields of chromatid gaps. These data demonstrate the dynamic nature of chromosomal instability as measured by two different cytogenetic assays.


Elimination of senescent cells by treatment with Navitoclax/ABT263 reverses whole brain irradiation-induced blood-brain barrier disruption in the mouse brain.
Whole brain irradiation (WBI), a commonly employed therapy for multiple brain metastases and as a prophylactic measure after cerebral metastasis resection, is associated with a progressive decline in neurocognitive function, significantly impacting the quality of life for approximately half of the surviving patients. Recent preclinical investigations have shed light on the multifaceted cerebrovascular injury mechanisms underlying this side effect of WBI. In this study, we aimed to test the hypothesis that WBI induces endothelial senescence, contributing to chronic disruption of the blood-brain barrier (BBB) and microvascular rarefaction. To accomplish this, we utilized transgenic p16-3MR mice, which enable the identification and selective elimination of senescent cells. These mice were subjected to a clinically relevant fractionated WBI protocol (5 Gy twice weekly for 4 weeks), and cranial windows were applied to both WBI-treated and control mice. Quantitative assessment of BBB permeability and capillary density was performed using two-photon microscopy at the 6-month post-irradiation time point. The presence of senescent microvascular endothelial cells was assessed by imaging flow cytometry, immunolabeling, and single-cell RNA-sequencing (scRNA-seq). WBI induced endothelial senescence, which associated with chronic BBB disruption and a trend for decreased microvascular density in the mouse cortex. In order to investigate the cause-and-effect relationship between WBI-induced senescence and microvascular injury, senescent cells were selectively removed from animals subjected to WBI treatment using Navitoclax/ABT263, a well-known senolytic drug. This intervention was carried out at the 3-month post-WBI time point. In WBI-treated mice, Navitoclax/ABT263 effectively eliminated senescent endothelial cells, which was associated with decreased BBB permeability and a trend for increased cortical capillarization. Our findings provide additional preclinical evidence that senolytic treatment approaches may be developed for prevention of the side effects of WBI.


Oxidative stress, autophagy, and apoptosis induced by doxycycline in loach fin cells in vitro.
Cytotoxicity, molecular function disorder, mitophagy, and apoptosis were studied in loach fin cells in vitro after exposure to doxycycline (DOX). The semi-lethal concentration of DOX in loach cells was calculated as 668.96 ± 2.83 mol/L. Loss of cell viability and increases in vacuoles and autolysosomes were evident in cells exposed to DOX at 200 and 400 μmol/L, and apoptotic bodies occurred at 600 μmol/L. In addition, Superoxide Dismutase (SOD), catalase (CAT), Na+-K+-ATPase, and Ca2+-ATPase activities increased significantly in cells exposed to 200 μmol/L DOX, and dose-dependent inhibitory effects on activities were observed in cells exposed to 400 and 600 μmol/L DOX. Quantitative gene expression showed that 400 and 600 μmol/L DOX could induce caspase-3- and caspase-8-mediated apoptosis as well as caspase-activated DNase in loach cells. Transcriptome sequencing in DOX vs. control groups found 16,288 differentially expressed genes, among which protein binding (2633, 31.91%) was the most significant in Gene Ontology terms. Furthermore, 11,930 genes were enriched in 298 Kyoto Encyclopedia of Genes and Genomes (KEGG)pathways. The top three upregulated pathways included "lysosome", "protein processing in endoplasmic reticulum", and "proteasome". FPKM analysis indicated that most genes associated with autophagy and in "protein processing in the endoplasmic reticulum", "TNF signaling pathway", and "NF-kappa B signaling pathway" were upregulated. This suggests that at lower concentrations, DOX induces reactive oxidative species (ROS) in loach fin cells to reduce cell proliferation. ROS in turn stimulate oxidant stress, ion excretion capability and mitophagy to maintain cell homeostasis. Apoptosis was induced in cells subjected to higher concentrations of DOX. The transcriptome data and pathways determined in this study will provide a foundation for the analysis of DOX toxicity in loach cells, which must be examined thoroughly to further understand the cytotoxic mechanism of antibiotics in fish cells.


Feasibility study of FEC-chemotherapy with dose-intensive epirubicin as initial treatment in high-risk breast cancer.
The prognosis of patients with stage III B breast carcinoma with metastasis to the apical axillary lymph nodes is poor despite adequate local control achieved by surgery and/or radiation therapy. This study evaluated the feasibility of a dose-intensive up-front chemotherapy regimen in this subgroup of patients. A preoperative chemotherapy regimen consisting of 3 courses of fluorouracil 500 mg/m2, dose-intensive epidoxorubicin 120 mg/m2 and cyclophosphamide 500 mg/m2 (DIE-FEC), was administered at 21-day intervals without hematopoietic growth factors to 31 patients with apex-positive disease. All patients were below 60 years of age and none had had prior chemotherapy or radiotherapy. Seven patients achieved clinical complete responses (23%), and 21 achieved clinical partial responses (68%); three patients had stable disease (10%), one of whom had only ductal carcinoma in situ at histopathologic evaluation, which suggested an additional response to therapy. The major toxicity was moderate bone marrow suppression with a median WBC nadir of 1650/microliters (range 500-4600). Other toxic effects were mild. DIE-FEC is well-tolerated and highly effective as up-front chemotherapy in relatively young patients with high-risk breast cancer, with a 90% (CI 74%-98%) clinical objective response rate.


Simplifying record linkage: software and strategy.
Although the methodology of record linkage is fairly well developed, there is a need for less expensive methods and simpler software to facilitate trying out different tactics to generate good linkages. The present work has built on a fourth generation language SAS (Statistical Analysis System) with accompanying macroprocessor, to develop a user-friendly and flexible system for both exact and probabilistic matching. The major features of the LINKS system are presented and illustrated using 1979-1984 information from the Manitoba Health Services Commission (MHSC) registry file with the Canadian Mortality Data Base. Initial runs with exact, then probabilistic, matching linked approximately 91% of the Vital Statistics records to corresponding MHSC records. Subsequent modification of parameters improved the linkage to 95%.


Familial risk and sibling mentalization: Links with preschoolers' internalizing problems.
The current study explored whether older sibling mentalization moderated the relationship between familial risk for internalizing symptoms and the development of future internalizing problems in the younger siblings, referred to as target children. Data were collected on 397 older siblings at Time 1 (T1) when target children were newborn and their older siblings were on average 2.61 years old (SD = .75). Target children were on average 1.60 years old at Time 2 (T2). Internalizing problems were assessed via mother and partner reports. Familial risk was operationalized as the average of all older siblings' level of internalizing problems. Older sibling mentalization, indexed by internal state talk and reasoning, was observed and coded during a sibling pretend-play interaction at T2. Results revealed a significant interaction between familial risk of internalizing problems and older siblings' mentalizing abilities, showing that familial risk was related to target children's internalizing problems in the absence of sibling mentalization. Familial risk was not associated with target children's internalizing problems when siblings demonstrated mentalizing abilities. Findings support the need to consider sibling mentalization as a protective factor for children's internalizing problems. (PsycINFO Database Record


Design, synthesis and biological evaluation of benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of glycogen synthase kinase-3β (GSK-3β).
Glycogen synthase kinase-3β (GSK-3β) plays a key role in type II diabetes and Alzheimer's diseases, to which non-ATP competitive inhibitors represent an effectively therapeutical approach due to their good specificity. Herein, a series of small molecules benzothiazepinones (BTZs) as novel non-ATP competitive inhibitors of GSK-3β have been designed and synthesized. The in vitro evaluation performed by luminescent assay showed most BTZ derivatives have inhibitory effects in micromolar scale. Among them compounds 6l, 6t and 6v have the IC50 values of 25.0 μM, 27.8 μM and 23.0 μM, respectively. Moreover 6v is devoid of any inhibitory activity in the assays to other thirteen protein kinases. Besides, SAR is analyzed and a hypothetical enzymatic binding mode is proposed by molecular docking study, which would be useful for new candidates design.


Searching for a Reliable Density Functional for Molecule-Environment Interactions, Found B97M-V/def2-mTZVP.
In the present study, we have examined density functional theory methods for the calculation of the interaction energy between a small molecule and its environment. For simple systems such as a neutral solute in a neutral solvent, good accuracy can be attained using low-cost "3c" methods, in particular r2SCAN-3c. When part(s) of the system is charged, the accurate computation of the interactions is more challenging. In these cases, we find the B97M-V/def2-mTZVP method to agree well with reference values; it also shows good accuracy for the more straightforward neutral systems. Thus, B97M-V/def2-mTZVP provides a means for accurate and low-cost computation of interaction energies, notably the binding between a substrate or a drug molecule and an enzyme, which may facilitate rational drug design.


A program of balanced physical fitness in the preventive care of elderly ambulatory patients.
A program of balanced physical fitness incorporated into a medical "team" approach to treatment contributed significantly to the general health of elderly ambulatory patients. Each week for eleven months, 13 patients were given one hour of balanced exercise and encouraged to perform it for two additional hours per week. Initial differences favoring the control group. Physicians' single-blind assessment of the two groups resulted in significantly better health ratings for the patients who had received the therapeutic exercise program than for those who did not participate.


Vasoconstriction caused by cocaine is enhanced by sodium salicylate: is inducible nitric oxide synthase mRNA related?
We have previously found that sodium salicylate (NaSal), injected into chicken eggs at nontoxic doses used for quantifying hydroxyl free radicals in hearts and brains of embryos, caused or exacerbated hemorrhages and dramatically reduced hatchability when combined with cocaine (Coc). It has also been reported that inducible nitric oxide synthase (iNOS) gene expression is altered in brain in response to vascular damage and inflammation. In this study we measured diameters of membrane-bound blood vessels (BV) before and after pretreatment with saline (NaCl) or NaSal (100 mg/kg egg), followed by infusion of either NaCl or Coc HCl (total of 67.5 mg/kg egg) during 15 min. Brains and hearts of the embryos were then analyzed for iNOS messenger RNA (mRNA) concentrations. Coc caused vasoconstriction that was significant 5 min postinfusion (5 min PI) of the entire dose (ie after 67.5 mg/kg egg). Significant vasoconstriction was evident within 5 min in the group injected with NaSal followed by infusion with Coc (ie after 22.5 mg Coc/kg egg). Expression of iNOS mRNA was significantly increased only in the brains of the group exposed to NaSal plus Coc, and the increase was inversely related to BV diameter. These data are discussed in relation to effects of salicylate upon prostanoid synthesis and/or nitric oxide synthesis via iNOS inhibition and their possible relationship to Coc-associated cerebral vascular and/or cardiovascular events in abusing humans.


Effect of hypergastrinemia on pancreatic carcinogenesis.
Previous studies in our laboratory demonstrated that pancreatic carcinomas in rodents express receptors for the peptide hormone gastrin that are not present in normal adult pancreas. In view of an abundant literature suggesting that gastrin may promote growth of various gastrointestinal tissues and tumors, the effect of hypergastrinemia on the process of pancreatic carcinogenesis was evaluated. Rats received subcutaneous injections of the pancreatic carcinogen azaserine at 19 and 26 days of age. Starting at 12 months of age, animals were randomized to treatment with the proton pump inhibitor lansoprazole or vehicle by gavage for 6 months. At autopsy, pancreatic wet weight normalized to body weight was recorded, as well as the number of benign and malignant pancreatic lesions. Serum gastrin levels were determined by radioimmunoassay and showed a greater than two-fold increase in lansoprazole-treated animals. Pancreatic wet weight in hypergastrinemic rats was increased compared to controls (p <0.05). Premalignant lesions such as acidophilic atypical acinar cell foci, adenomas, heterogeneous phenotypic populations of nodules within nodules, and carcinoma-in-situ were not increased in the hypergastrinemic group. Likewise, there was no difference in the incidence of invasive carcinoma in hypergastrinemic animals (10%) compared to controls (5.7%). Hypergastrinemia stimulated an increase in pancreatic weight, but did not stimulate development of premalignant lesions or progression to cancer in the azaserine model of rat pancreatic acinar cell carcinoma.


Cyclophosphamide, vincristine, adriamycin, and prednisone (CHOP) with and without intermediate dose methotrexate for the treatment of non-Hodgkin's lymphomas of diffuse histology.
Seventy three patients with disseminated diffuse non-Hodgkin's lymphomas were treated with combinations of cyclophosphamide, vincristine sulfate, prednisone, and doxorubicin with and without 2 weekly doses of oral methotrexate in "intermediate" doses, followed by calcium leucovorin rescue. The addition of methotrexate did not increase the complete remission rate, the remission duration, or the survival (P value = 1.0, 0.74, and 0.78, respectively) in patients who did not have previous chemotherapy treatment. In previously treated patients, the complete remission rate was somewhat higher and the remission duration and survival were longer among those patients treated with the methotrexate containing program; however these differences were not statistically significant (P values = 0.88, 0.81, and 0.46, respectively). There was substantial morbidity and mortality during treatment with both treatment arms, among patients aged more than 60 years.


Obesity influences composition of salivary and fecal microbiota and impacts the interactions between bacterial taxa.
Obesity is an increasing global health concern and is associated with a broad range of morbidities. The gut microbiota are increasingly recognized as important contributors to obesity and cardiometabolic health. This study aimed to characterize oral and gut microbial communities, and evaluate host: microbiota interactions between clinical obesity classifications. We performed 16S rRNA sequencing on fecal and salivary samples, global metabolomics profiling on plasma and stool samples, and dietary profiling in 135 healthy individuals. We grouped individuals by obesity status, based on body mass index (BMI), including lean (BMI 18-124.9), overweight (BMI 25-29.9), or obese (BMI ≥30). We analyzed differences in microbiome composition, community inter-relationships, and predicted microbial function by obesity status. We found that salivary bacterial communities of lean and obese individuals were compositionally and phylogenetically distinct. An increase in obesity status was positively associated with strong correlations between bacterial taxa, particularly with bacterial groups implicated in metabolic disorders including Fretibacterium, and Tannerella. Consumption of sweeteners, especially xylitol, significantly influenced compositional and phylogenetic diversities of salivary and fecal bacterial communities. In addition, obesity groups exhibited differences in predicted bacterial metabolic activity, which was correlated with host's metabolite concentrations. Overall, obesity was associated with distinct changes in bacterial community dynamics, particularly in saliva. Consideration of microbiome community structure and inclusion of salivary samples may improve our ability to understand pathways linking microbiota to obesity and cardiometabolic disease.


Resection of Vestibular Schwannoma Through Middle Cranial Fossa Approach with Endoscopic Assistance.
We sought to report the outcome of resection of vestibular schwannomas (VSs) originating from the inferior vestibular nerve that extended into the fundus of the internal auditory canal through the middle cranial fossa (MCF) approach with endoscopic assistance. Seven patients with VSs who underwent resection through MCF approach with endoscope assistance and 12 patients with conventional microsurgery in our department were enrolled in this study. These patients' characteristics were acquired, and the surgical outcomes, as well as postoperative complications, were evaluated. In the endoscope group, the VS was first removed by a conventional microscopic procedure and then an endoscope was used to find and remove any residue lesions. In 3 of 7 patients, residue tumor in the space below transverse crest was found and completely removed under endoscope. Six of 7 patients (85.7%) had House-Brackmann grade I at the time of last follow-up in the endoscope group compared with 10 of 12 patients (83.3%) in the conventional microsurgery group. Serviceable hearing was successfully maintained in 2 of 3 patients (66.7%) in the endoscope group compared with 6 of 10 patients (60%) in the conventional microsurgery group. Total resections were achieved in all the patients (100%) in the endoscope group compared with 9 of 12 patients (75%) in the conventional microsurgery group. Using an endoscope in VS resection through the MCF approach could facilitate complete removal of the lesion while minimizing the risk of hearing loss and facial paralysis. The endoscope-assisted MCF approach is especially suitable for removing an intracanalicular VS with lateral extension involving the space below the transverse crest.


A thermodynamic evaluation of antibody-surface interactions in multimodal cation exchange chromatography.
In this study, the thermodynamics of binding of two industrial mAbs to multimodal cation exchange systems was investigated over a range of buffer and salt conditions via a van't Hoff analysis of retention data. Isocratic chromatography was first employed over a range of temperature and salt conditions on three multimodal resins and the retention data were analyzed in both the low and high salt regimes. While mAb retention decreased with salt for all resins at low salts, retention increased at high salts for two of the resins, suggesting a shift from electrostatic to more hydrophobic driven interactions. The retention data at various temperatures were then employed to generate non-linear van't Hoff plots which were fit to the quadratic form of the van't Hoff equation. At low salts, retention of both mAbs decreased with increasing temperature and the van't Hoff plots were concave downward on Capto MMC and Nuvia cPrime, while being concave upward on Capto MMC ImpRes. Different trends were observed on some of the resins with respect to both the concavity of the van't Hoff plots as well as the impact of temperature on the favorable enthalpies in the low salt regime. Interestingly, while increasingly favorable enthalpy with temperature was observed with Capto MMC and Nuvia cPrime at low salt, favorable enthalpy decreased with temperature for Capto MMC ImpRes. At high salts, binding of both mAbs on the two Capto resins were consistently entropically driven, consistent with desolvation. While the negative heat capacity data at low salts indicated that desolvation of polar/charged groups were important in Capto MMC and Nuvia cPrime, the positive data suggested that desolvation of non-polar groups were more important with Capto MMC ImpRes. Finally, the data at high salts indicated that desolvation of non-polar groups was the major driver for binding of both mAbs to the Capto resins under these conditions.


Risk stratification system for skin and soft tissue infections after allogeneic hematopoietic stem cell transplantation: PAH risk score.
Skin and soft tissue infections (SSTIs) refer to infections involving the skin, subcutaneous tissue, fascia, and muscle. In transplant populations with hematological malignancies, an immunocompromised status and the routine use of immunosuppressants increase the risk of SSTIs greatly. However, to date, the profiles and clinical outcomes of SSTIs in hematopoietic stem cell transplantation (HSCT) patients remain unclear. This study included 228 patients (3.67%) who developed SSTIs within 180 days after allogeneic HSCT from January 2004 to December 2019 in Peking University People's Hospital. The overall annual survival rate was 71.5%. We compared the differences between survivors and non-survivors a year after transplant and found that primary platelet graft failure (PPGF), comorbidities of acute kidney injury (AKI), and hospital-acquired pneumonia (HAP) were independent risk factors for death in the study population. A PPGF-AKI-HAP risk stratification system was established with a mortality risk score of 1×PPGF+1×AKI+1×HAP. The areas under the curves of internal and external validation were 0.833 (95% CI 0.760-0.906) and 0.826 (95% CI 0.715-0.937), respectively. The calibration plot revealed the high consistency of the estimated risks, and decision curve analysis showed considerable net benefits for patients.


Novel methodologies for automatically and simultaneously determining BTEX components using FTIR spectra.
This study introduced a patented novel methodological system for automatically analysis of Fourier Transform Infrared Spectrometer (FTIR) spectrum data located at 'fingerprint' region (wavenumber 670-800 cm(-1)), to simultaneously determinate multiple petroleum hydrocarbons (PHs) in real mixture samples. This system includes: an object oriented baseline correction; Band decomposition (curve fitting) method with mathematical optimization; and Artificial Neural Network (ANN) for determination, which is suitable for the characteristics of this IR regions, where the spectra are normally with low signal to noise ratio and high density of peaks. BTEX components are potentially lethal carcinogens and contained in many petroleum products. As a case study, six BTEX components were determinate automatically and simultaneously in mixture vapor samples. The robustness of the BTEX determination was validated using real petroleum samples, and the prediction results were compared with gas chromatography-mass spectrometry (GC-MS).


Primary hypothyroidism resolves after switching from L-thyroxine solid tablets to liquid oral substitution. A rare case without evidence of an underlying gastrointestinal malabsorption syndrome.
A case of refractory primary hypothyroidism is presented. Despite laboratory-guided hormonal substitution, the patient remained hypothyroid. Multiple diagnostic tests ruled out all known causes of levothyroxine malabsorption. Interestingly, clinical and laboratory responding was promptly achieved, after switching the application format from solid tablets to liquid formula.


Artificial induction of intravascular lipolysis by lipid-heparin infusion leads to insulin resistance in man.
Although extensive evidence indicates that free fatty acids can decrease glucose utilization in vitro, it is still controversial how an increase in lipolysis affects glucose metabolism in man. To test the hypothesis that an increase in lipolysis is related to insulin resistance, we examined the effect of lipid-heparin infusion on glucose metabolism in ten normal subjects by the euglycaemic glucose clamp technique and isotopic determination of glucose turnover. In the control euglycaemic clamp studies with insulin infusion at 0.2 and 1.0 mU.kg-1.min-1, endogenous glucose production was suppressed from the basal rate of 2.0 +/- 0.3 mg.kg-1min-1 to 1.1 +/- 0.7 mg.kg-1.min-1 and -0.4 +/- 0.7 mg.kg-1min-1 respectively. Glucose utilization increased from the basal rate of 2.0 +/- 0.3 mg.kg-1min-1 to 2.3 +/- 0.5 mg.kg-1min-1 and 5.9 +/- 1.8 mg.kg-1min-1 respectively. When the euglycaemic clamp studies were coupled with lipid-heparin infusion at comparable low and high rates of insulin infusion, endogenous glucose production increased (1.8 +/- 0.7 mg.kg-1.min-1, p less than 0.001, and 0.3 +/- 0.6 mg.kg-1.min-1, p less than 0.05, respectively), and glucose utilization decreased (2.1 +/- 0.3 mg.kg-1.min-1, not significant, and 3.2 +/- 0.7 mg.kg-1.min-1, p less than 0.001 respectively). These data suggest that the artificial induction of intravascular lipolysis by lipid-heparin infusion leads to a state of insulin resistance in man.


Physical appearance comparisons in ethnically diverse college women.
Research demonstrates ethnic differences in rates of body dissatisfaction and disordered eating. Appearance comparison frequency is related to these outcomes, however, research has not examined possible ethnic differences in levels of appearance comparisons nor their relation to body dissatisfaction and disordered eating. The current study examined the frequency of appearance comparisons and the strength of the relationships between appearance comparisons, appearance evaluation, and disordered eating among White, Black, and Hispanic women. Measures of appearance comparison, appearance evaluation, and disordered eating were administered to 895 college women. Compared with White and Hispanic women, Black women reported fewer appearance comparisons, more positive appearance evaluation, and lower levels of disordered eating. Associations between examined variables were generally weaker among Black women. Results suggest that the reduced frequency and impact of appearance comparisons may contribute to more positive appearance evaluation and reduced levels of disordered eating among Black women.


Single-arm study for the characterization of human tissue response to injectable poly-L-lactic acid.
Injectable poly-L-lactic acid (PLLA) is a synthetic polymer indicated for the correction of facial wrinkles and folds. Animal studies have shown that implantation of PLLA stimulates collagen synthesis; human studies have been limited. To investigate human tissue response to injectable PLLA. In this exploratory single-arm, open-label study, 14 healthy subjects were administered injectable PLLA; punch biopsies at 3, 6, and 12 months were analyzed for qualitative and quantitative changes from baseline in collagen types I and III and assessed for inflammatory responses. Quantitative and qualitative increases were observed for collagen types I and III at 3 and 6 months and were statistically significant for collagen type I at 3 and 6 months. Post hoc analyses at 12 months showed nominal collagen increases but were hindered by technical difficulties. The degree of inflammatory response was similar to baseline at 3, 6, and 12 months; all subjects were found to have no or mild inflammation after baseline. Adverse events were mild and among those reported previously. Results of this study in humans found statistically significant stimulation of collagen type I with no or mild inflammatory response after administration of injectable PLLA.


The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells.
Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P(1) inhibited the generation of extrathymic and natural T(reg) cells while driving T(H)1 development in a reciprocal manner and disrupted immune homeostasis. S1P(1) signaled through the kinase mTOR and antagonized the function of transforming growth factor-β mainly by attenuating sustained activity of the signal transducer Smad3. S1P(1) function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 cells and T(reg) cells. Our studies establish an S1P(1)-mTOR axis that controls T cell lineage specification.


Antibody responses against heterologous A/H5N1 strains for an MF59-adjuvanted cell culture-derived A/H5N1 (aH5N1c) influenza vaccine in healthy pediatric subjects.
Vaccines are the main prophylactic measure against pandemic influenza. Adjuvanted, cell culture-derived vaccines, which are not subject to limitations of egg-based vaccine production, have the potential to elicit an antibody response against heterologous strains and may be beneficial in the event of an A/H5N1 pandemic. A prespecified exploratory analysis of data from a phase 2, randomized, controlled, observer-blind multicenter trial (NCT01776554) to evaluate the immunogenicity of a MF59-adjuvanted, cell culture-based A/H5N1 influenza vaccine (aH5N1c), containing 7.5 µg hemagglutinin antigen per dose, in subjects 6 months through 17 years of age was conducted. Geometric mean titers (GMT) were determined using hemagglutination inhibition (HI) and microneutralization (MN) assays, and proportions of patients achieving seroconversion, HI and MN titers ≥ 1:40, and a 4-fold increase in MN titers against 5 heterologous strains (influenza A/H5N1 Anhui/2005, Egypt/2010, Hubei/2010, Indonesia/2005, and Vietnam/1203/2004) three weeks after administration of the second dose were assessed. After the second dose, HI GMTs against heterologous strains increased between 8- and 40-fold, and MN GMTs increased 13- to 160-fold on Day 43 vs Day 1. On Day 43, 32-72% of subjects had HI titers ≥ 1:40 and achieved seroconversion against the heterologous strains. Using the MN assay, 84-100% of subjects had MN titers ≥ 1:40 and 83-100% achieved an at least 4-fold increase in MN titers against the heterologous strains. The highest responses were consistently against A/H5N1 Egypt/2010. When given to children aged 6 months through 17 years, aH5N1c resulted in increased immunogenicity from baseline against all 5 heterologous A/H5N1 strains tested, demonstrating the potential of an MF59-adjuvanted, cell-derived A/H5N1 vaccine to provide cross-protection against other A/H5N1 strains (NCT01776554).


Situs ambiguous, levocardia, right sided stomach, obstructing duodenal web, and intestinal nonrotation: a case report.
When approaching a case with a situs abnormality, using the proper terminology, making a specific diagnosis, and understanding the other often associated abnormalities that need to be excluded are of great importance. We present a case of situs ambiguous in the presence of intestinal nonrotation and an obstructing duodenal web. Our patient initially presented at two days old with bilious emesis and failure to pass meconium after birth. An abdominal radiograph demonstrated an unusual bowel gas pattern, a reversed "double bubble" sign. A subsequent thorough imaging survey was crucial to further characterize our patient's unique anatomy. Overall, our case demonstrates many of the unusual plain radiographic and sonographic findings associated with our patient's situs abnormality and allows for review of situs abnormalities and their significance.


Metabolic regulation of the squid nerve Na⁺/Ca²⁺ exchanger: recent kinetic, biochemical and structural developments.
The Na⁺/Ca²⁺ exchangers are structural membrane proteins, essential for the extrusion of Ca²⁺ from most animal cells. Apart from the transport sites, they have several interacting ionic and metabolic sites located at the intracellular loop of the exchanger protein. One of these, the intracellular Ca²⁺ regulatory sites, are essential and must be occupied by Ca²⁺ to allow any type of ion (Na⁺ or Ca²⁺) translocation. Intracellular protons and Na⁺ are inhibitory by reducing the affinity of the regulatory sites for Ca²⁺; MgATP stimulates by antagonizing H⁺ and Na⁺. We have proposed a kinetic scheme to explain all ionic and metabolic regulation of the squid nerve Na⁺/Ca²⁺ exchanger. This model uniquely accounts for most of the new kinetic data provided here; however, none of the existing models can explain the trans effects of the Ca(i)²⁺-regulatory sites on external cation transport sites; i.e. all models are incomplete. MgATP up-regulation of the squid Na⁺/Ca²⁺ exchanger requires a cytosolic protein, which has been recently identified as a member of the lipocalin super family of Lipid Binding Proteins (LBP or FABP) of 132 amino acids (ReP1-NCXSQ, access to GenBank EU981897). This protein was cloned, expressed and purified. To be active, ReP1-NCXSQ must be phosphorylated from MgATP by a kinase present in the plasma membrane. Phosphorylated ReP1-NCXSQ can stimulate the exchanger in the absence of ATP. Experiments with proteoliposomes proved that this up-regulation can take place just with the lipid membrane and the exchanger protein. The structure of ReP1-NCXSQ predicted from the amino acid sequence has been confirmed by X-ray crystal analysis; it has a "barrel" formed by ten beta sheets and two alpha helices, with a lipid coordinated by hydrogen bonds with Arg 126 and Tyr 128.


Normal values of real-time 3-dimensional echocardiographic parameters in a healthy Japanese population: the JAMP-3D Study.
The recently developed real-time 3-dimensional echocardiography (RT3DE) is a promising imaging method to quantify cardiac chamber volumes and their functions in clinical practice. However, normal reference values of RT3DE parameters have not been fully investigated in a large, healthy Japanese population. This study consisted of 410 healthy subjects aged from 20 to 69 years who had a RT3DE at one of the 23 collaborating institutions. All subjects had no history of cardiac disease and no risk factors. The mean values in men and women were as follows: 50 ± 12 ml/m(2) and 46 ± 9 ml/m(2) for left ventricular (LV) end-diastolic volume index, 19 ± 5 ml/m(2) and 17 ± 4 ml/m(2) for end-systolic volume index, 61 ± 4% and 63 ± 4% for ejection fraction, 64 ± 1 2 g/m(2) and 56 ± 11 g/m(2) for mass index, 23 ± 6 ml/m(2) and 24 ± 6 ml/m(2) for left atrial (LA) maximum volume index, 10 ± 3 ml/m(2) and 10 ± 3 ml/m(2) for minimum volume index, and 58 ± 6% and 58 ± 6% for percent volume change. LV sizes decreased with age, whereas LV mass index did not change. LA sizes slightly increased with age. This multicenter investigation determined normal reference values for LV and LA sizes, and their functional parameters on RT3DE in a large, healthy Japanese population. The results of the present study support the use of RT3DE for the diagnosis and management of cardiovascular disease.


Effects of web-based electrocardiography simulation on strategies and learning styles.
To identify the association between the use of web simulation electrocardiography and the learning approaches, strategies and styles of nursing degree students. A descriptive and correlational design with a one-group pretest-posttest measurement was used. The study sample included 246 students in a Basic and Advanced Cardiac Life Support nursing class of nursing degree. No significant differences between genders were found in any dimension of learning styles and approaches to learning. After the introduction of web simulation electrocardiography, significant differences were found in some item scores of learning styles: theorist (p < 0.040), pragmatic (p < 0.010) and approaches to learning. The use of a web electrocardiogram (ECG) simulation is associated with the development of active and reflexive learning styles, improving motivation and a deep approach in nursing students.


Prospective assessment of the hepatic perfusion index in patients with colorectal cancer.
This prospective study was designed to test the hypothesis that abnormal liver blood flow is related to poor prognosis in patients with colorectal cancer. The hepatic perfusion index (HPI), measured by dynamic hepatic scintigraphy, was assessed in 202 patients with colorectal cancer. Assessment for overt hepatic metastasis included liver palpation at laparotomy and perioperative computed tomography (CT). Follow-up at a dedicated clinic included regular abdominal ultrasonography and CT. The HPI was abnormal (greater than 0.37) in 92 (88 per cent) of 105 patients with overt liver metastases. Of 89 patients with no evidence of overt metastases or residual tumour after primary resection, 52 had an abnormal and 37 a normal HPI. At a median follow-up of 39 (range 13-76) months, 25 of 38 patients with recurrence had an abnormal HPI. Some 31 of 45 patients who died had an abnormal HPI. The HPI predicted overall recurrence (P=0.04, log rank test). Multivariate analysis showed the HPI was independent of Dukes stage for predicting disease-free survival (P=0.04, relative risk 1.94 (95 per cent confidence interval (c.i.) 1.03-3.67)) but this just failed to attain significance for overall survival (P=0.055, relative hazard 1.88 (95 per cent c.i. 1.00-3.58)). The HPI predicts a poor outcome in patients with colorectal cancer and may be useful in patient selection for adjuvant chemotherapy.