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The tick-borne multisystemic infection caused by Borrelia burgdorferi sensu lato , Lyme borreliosis, or Lyme disease, occurring in temperate regions of the northern hemisphere, continues to spread geographically with the expanding tick population. Despite the rising perceived risk of infection in the population, the clinical diagnosis of Borrelia infection is not always obvious and the most important laboratory test, antibody detection, has limited accuracy in diagnosing active disease. According to international guidelines, the primary serology test, which has a high sensitivity-low specificity, should, be verified using a high specificity confirmation test to improve the specificity. However, this enhancement in specificity comes at the cost of lower sensitivity. This two-step procedure is often omitted in everyday clinical practice. An optimal primary test would be one where no secondary tests for confirmation would be necessary. In the present study, the performance of a novel assay for quantitating IgG1-subclass antibodies to Borrelia C6-peptide was compared to a commercial reference assay of total IgG and IgM antibodies to Borrelia C6-peptide in the setting of a high endemic area for borreliosis. A derivation study on a retrospective clinical material was performed to compare the performance parameters and assess the discriminatory properties of the assays, followed by a prospective validation study. The IgG1-antibody assay achieved comparable summary performance parameters to those of the reference assay. The sensitivity was almost 100% while the specificity was about 50%. In a high-endemic setting, characterized by high background seropositivity of about 50% and disease prevalence of approximately 10%, antibody tests are unable to rule-in active Borrelia infection. The rule-out assessment of the methods revealed that of 1000 patients, 7 - 54 with negative results based on the reference method could have an active Borrelia infection. Such uncertainty was not found for the index test and may help improve the risk classification of patients., Competing Interests: DN, SO, and S-AC are partners in the Bimelix Laboratory. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nyman, Nordberg, Nyberg, Olausson, Carlströmer Berthen and Carlsson.)

Aim: The aim of this study was to investigate whether the choice reforms in healthcare in Stockholm county in 2008 and 2013 changed the sociodemographic user patterns of outpatient healthcare services for children., Methods: The study used regional data on healthcare use linked to sociodemographic data from national registers in the total population of children 0-15 years in the Stockholm county. Change in use of healthcare services was analysed in multiple linear regression in a difference in differences approach of socio-economic indicators., Results: The choice reform of 2013 increased children's overall use of specialised care by around 30% until 2017 while primary care use decreased by the same degree. The mean number of physician visits in specialised care for children with severe asthma increased from 3.9 to 5.2 per year. Overall, children in families with low maternal education, low disposable income and a non-Western background increased their use of specialised care more than children from families with a more privileged socio-economic situation., Conclusion: There was no indication that the choice reform in Stockholm county increased the social disparities in use of primary and specialised outpatient care for children, rather the opposite., (© 2023 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

The AxBioTick study was initiated to investigate the prevalence of ticks and tick-borne pathogens and their impact on antibody and clinical responses in tick-bitten individuals on the Aland Islands. This geographical area is hyperendemic for both Lyme borreliosis (LB) and Tick-borne encephalitis (TBE). Blood samples and ticks were collected from 100 tick-bitten volunteers. A total of 425 ticks was collected, all determined to Ixodes ricinus using molecular tools. Of them 20% contained Borrelia species, of which B. garinii and B. afzelii were most common. None contained the TBE virus (TBEV). Blood samples were drawn in conjunction with the tick bite, and eight weeks later. Sera were analyzed for Borrelia - and TBEV-specific antibodies using an ELISA and a semiquantitative antibody assay. In total 14% seroconverted in Borrelia C6IgG1, 3% in TBEV IgG, and 2% in TBEV IgM. Five participants developed clinical manifestations of LB. The high seroprevalence of both Borrelia (57%) and TBEV (52%) antibodies are likely attributed to the endemic status of the corresponding infections as well as the TBE vaccination program. Despite the similar prevalence of Borrelia spp. detected in ticks in other parts of Europe, the infection rate in this population is high. The AxBioTick study is continuing to investigate more participants and ticks for co-infections, and to characterize the dermal immune response following a tick bite.

In order to help talented athletes to combine sport and education, different forms of Dual Career Support (DCS) have been developed in many countries. The effectiveness of these support systems have been debated. Most studies have investigated young athletes in the beginning of their careers, less is known about athletes who reached the highest levels. Therefore, the aim of this study was to explore the extent to which former Swedish world-class athletes have attended dual career sport programs at upper secondary school. A retrospective design was used with 274 former world-class athletes who answered a questionnaire. In order to investigate whether there was a relationship between attending a dual career sport school and athletic characteristics, as well as post career educational and employment outcomes, a series of Chi-square tests were conducted. The main results show that more than half of the athletes did not take part in any DCS. These results indicate that DCS in Sweden is not a decisive factor for success in sports as intended. Half of all participants, regardless of whether they studied at DCS, have studied at university, and all participants had a job at the time of data collection. The majority also consider that their financial situation has improved after their sports career., Competing Interests: The authors declare that the research was conducted in the absence of any commercial of financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nyberg, Wagnsson, Gustafsson and Stråhlman.)

Study Question: Can use of a commercially available time-lapse algorithm for Day 5 blastocyst selection improve pregnancy rates compared with morphology alone?, Summary Answer: The use of a time-lapse selection model to choose blastocysts for fresh single embryo transfer on Day 5 did not improve ongoing pregnancy rate compared to morphology alone., What Is Known Already: Evidence from time-lapse monitoring suggests correlations between timing of key developmental events and embryo viability. No good quality evidence exists to support improved pregnancy rates following time-lapse selection., Study Design, Size, Duration: A prospective multicenter randomized controlled trial including 776 randomized patients was performed between 2018 and 2021. Patients with at least two good quality blastocysts on Day 5 were allocated by a computer randomization program in a proportion of 1:1 into either the control group, whereby single blastocysts were selected for transfer by morphology alone, or the intervention group whereby final selection was decided by a commercially available time-lapse model. The embryologists at the time of blastocyst morphological scoring were blinded to which study group the patients would be randomized, and the physician and patients were blind to which group they were allocated until after the primary outcome was known. The primary outcome was number of ongoing pregnancies in the two groups., Participants/materials, Setting, Methods: From 10 Nordic IVF clinics, 776 patients with a minimum of two good quality blastocysts on Day 5 (D5) were randomized into one of the two study groups. A commercial time-lapse model decided the final selection of blastocysts for 387 patients in the intervention (time-lapse) group, and blastocysts with the highest morphological score were transferred for 389 patients in the control group. Only single embryo transfers in fresh cycles were performed., Main Results and the Role of Chance: In the full analysis set, the ongoing pregnancy rate for the time-lapse group was 47.4% (175/369) and 48.1% (181/376) in the control group. No statistically significant difference was found between the two groups: mean difference -0.7% (95% CI -8.2, 6.7, P = 0.90). Pregnancy rate (60.2% versus 59.0%, mean difference 1.1%, 95% CI -6.2, 8.4, P = 0.81) and early pregnancy loss (21.2% versus 18.5%, mean difference 2.7%, 95% CI -5.2, 10.6, P = 0.55) were the same for the time-lapse and the control group. Subgroup analyses showed that patient and treatment characteristics did not significantly affect the commercial time-lapse model D5 performance. In the time-lapse group, the choice of best blastocyst changed on 42% of occasions (154/369, 95% CI 36.9, 47.2) after the algorithm was applied, and this rate was similar for most treatment clinics., Limitations, Reasons for Caution: During 2020, the patient recruitment rate slowed down at participating clinics owing to coronavirus disease-19 restrictions, so the target sample size was not achieved as planned and it was decided to stop the trial prematurely. The study only investigated embryo selection at the blastocyst stage on D5 in fresh IVF transfer cycles. In addition, only blastocysts of good morphological quality were considered for transfer, limiting the number of embryos for selection in both groups: also, it could be argued that this manual preselection of blastocysts limits the theoretical selection power of time-lapse, as well as restricting the results mainly to a good prognosis patient group. Most patients were aimed for blastocyst stage transfer when a minimum of five zygotes were available for extended culture. Finally, the primary clinical outcome evaluated was pregnancy to only 6-8 weeks., Wider Implications of the Findings: The study suggests that time-lapse selection with a commercially available time-lapse model does not increase chance of ongoing pregnancy after single blastocyst transfer on Day 5 compared to morphology alone., Study Funding/competing Interest(s): The study was financed by a grant from the Swedish state under the ALF-agreement between the Swedish government and the county councils (ALFGBG-723141). Vitrolife supported the study with embryo culture dishes and culture media. During the study period, T.H. changed his employment from Livio AB to Vitrolife AB. All other authors have no conflicts of interests to disclose., Trial Registration Number: ClinicalTrials.gov registration number NCT03445923., Trial Registration Date: 26 February 2018., Date of First Patient’s Enrolment: 11 June 2018., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A good working view is critical for safe and successful endovascular treatment of cerebral aneurysms. In a few cases, endovascular treatment of cerebral aneurysms may be challenging due to difficulty in obtaining a proper working view. In this report of 6 cases, we described the advantage of using a distal intracranial catheter (DIC) to achieve better visualization of cerebral aneurysms hidden by a parent artery or its branches. Between September 2017 and January 2021, we treated 390 aneurysms with endovascular techniques. In 6 cases in which it was difficult to obtain a proper working view, the DIC was placed distally close to the aneurysm in order to remove the parent artery projection from the working view and obtain better visualization of the aneurysm. Clinical and procedural outcomes and complications were evaluated. The position of the DIC was above the internal carotid artery siphon in the 6 cases. All aneurysms were successfully embolized. Raymond-Roy class 1 occlusion was achieved in all 4 unruptured aneurysms, while the result was class 2 in the 2 ruptured aneurysms. Placement of the DIC was atraumatic without dissections or significant catheter-induced vasospasm in all patients. Transient dysphasia was seen in 2 cases and transient aphasia in 1. Using this technique, we have found it possible to better visualize the aneurysm sac or neck and thereby treat cases we otherwise would have considered untreatable.

Aim of the Study: The aim of this study was to evaluate our results regarding treatment options, complications, and outcomes in patients with non-saccular aneurysms of cerebral arteries belonging to type 1 and type 4 according to Mizutani's classification., Methods: A total of 26 aneurysms in 26 patients were treated between 2014 and 2019. There were 13 males (mean age 42.77 ± 11.73 years) and 13 females (mean age 50.84 ± 9.37 years). In 23 cases the onset was haemorrhagic and in three cases non-haemorrhagic. A combination of conventional stents and coils was used in 10 cases, conventional stents and flow diverters in three cases, flow diverters and coils in five cases, and flow diverters only were used in eight cases. Radiological results of treatment were assessed after eight months and clinical after one year., Results: In 24 patients, aneurysms were occluded at the end of the follow-up period. An iatrogenic dissection and two haemorrhagic complications were registered. In three cases, parent arteries were occluded due to re-growth of the aneurysm, which caused middle cerebral artery infarction in one case. A favourable clinical outcome was registered in 19, patients, and non-favourable in five. Two patients died in the early postoperative period due to extensive damage to the brain parenchyma caused by initial bleeding., Conclusion: Our results indicate that treatment of type 1 and type 4 non-saccular aneurysms with various combination of stents and flow diverters, with or without coils, is promising, although very challenging and technically demanding.

Neutrophils operate as part of the innate defence in the skin and may eliminate the Borrelia spirochaete via phagocytosis, oxidative bursts, and hydrolytic enzymes. However, their importance in Lyme neuroborreliosis (LNB) is unclear. Neutrophil extracellular trap (NET) formation, which is associated with the production of reactive oxygen species, involves the extrusion of the neutrophil DNA to form traps that incapacitate bacteria and immobilise viruses. Meanwhile, NET formation has recently been studied in pneumococcal meningitis, the role of NETs in other central nervous system (CNS) infections has previously not been studied. Here, cerebrospinal fluid (CSF) samples from clinically well-characterised children ( N = 111) and adults ( N = 64) with LNB and other CNS infections were analysed for NETs (DNA/myeloperoxidase complexes) and elastase activity. NETs were detected more frequently in the children than the adults ( p = 0.01). NET presence was associated with higher CSF levels of CXCL1 ( p < 0.001), CXCL6 ( p = 0.007), CXCL8 ( p = 0.003), CXCL10 ( p < 0.001), MMP-9 ( p = 0.002), TNF ( p = 0.02), IL-6 ( p < 0.001), and IL-17A ( p = 0.03). NETs were associated with fever ( p = 0.002) and correlated with polynuclear pleocytosis (r s = 0.53, p < 0.0001). We show that neutrophil activation and active NET formation occur in the CSF samples of children and adults with CNS infections, mainly caused by Borrelia and neurotropic viruses. The role of NETs in the early phase of viral/bacterial CNS infections warrants further investigation.

Background: Patients with subarachnoid hemorrhage often have impaired consciousness and cannot regulate nutritional intakes themselves. Previous studies have demonstrated elevated energy expenditure in the acute phase, but it is not known whether the energy demand is constant during the first week after onset of the disease. In this study, we performed daily measurements of energy expenditure with indirect calorimetry during the first 7 days after aneurysmal subarachnoid hemorrhage in mechanically ventilated patients. Methods: Metabolic measurements were performed daily with indirect calorimetry in 26 patients with aneurysmal subarachnoid hemorrhage. All patients were intubated and mechanically ventilated. The measured value was compared to the predicted values from the Harris-Benedict equation and the Penn State University 1998 equation. Urinary nitrogen excretion was measured daily. Results: There was a significant increase in energy expenditure during days 2-3 compared to days 5-6. The Harris-Benedict equation underestimated metabolic demand. The Penn State 1998 equation was closer to the measured values, but still underestimated caloric need. Urinary nitrogen excretion increased throughout the first week from initially low values. Conclusions: There is a dynamic course in energy expenditure in patients with aneurysmal subarachnoid hemorrhage, with increasing metabolic demand during the first week of the disease. Indirect calorimetry could be used more often to help provide an adequate amount of energy.

Aim of the Study: To present our experience in the treatment of iatrogenic dissections of extracranial internal carotid and vertebral arteries with the Neuroform Atlas stent., Materials and Methods: Between January 2017 and February 2018 we treated iatrogenic dissections of three internal carotid arteries and three vertebral arteries. These iatrogenic dissections occurred during the endovascular treatment of ruptured and unruptured intracranial aneurysms. The indication for stenting was haemodynamically significant, flow-limiting dissection with threatening flow arrest. In all six cases, the dissections were treated by placement of Neuroform Atlas stents in the dissected segments of internal carotid or vertebral arteries. Deployment of the stent was followed by the usual dual antiplatelet regimen., Results: Single or multiple Neuroform Atlas stents were deployed without any technical difficulties, and blood flow was restored immediately after placement of the stents in all six cases. Midterm follow-up (6-8 months) showed complete reconstruction of the shape and lumen of all treated arteries, with negligible intimal hyperplasia., Conclusion: Our results indicate that a favourable outcome can be achieved by treating iatrogenic dissections of extracranial internal carotid and vertebral arteries with the Neuroform Atlas stent.

Introduction: In patients with severe illness, such as aneurysmal subarachnoid hemorrhage (SAH), a physiologic stress response is triggered. This includes activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The aim of this study was to investigate the very early responses of these systems., Methods: A porcine animal model of aneurysmal SAH was used. In this model, blood is injected slowly to the basal cisterns above the anterior skull base until the cerebral perfusion pressure is 0 mm Hg. Sampling was done from blood and urine at -10, +15, +75 and +135 minutes from time of induction of SAH. Analyses of adrenocorticotropic hormone (ACTH), cortisol, aldosterone, catecholamines and chromogranin-A were performed., Results: Plasma ACTH, serum cortisol and plasma aldosterone increased in the samples following induction of SAH, and started to decline after 75 minutes. Urine cortisol also increased after SAH. Urine catecholamines and their metabolites were found to increase after SAH. Many samples were however below detection level, not allowing for statistical analysis. Plasma chromogranin-A peaked at 15 minutes after SAH, and thereafter decreased., Conclusions: The endocrine stress response after aneurysmal SAH was found to start within 15 minutes in the HPA axis with early peak values of ACTH, cortisol and aldosterone. The fact that the concentrations of the HPA axis hormones decreased 135 minutes after SAH may suggest that a similar pattern exists in SAH patients, thus making it difficult to catch these early peak values. There were also indications of early activation of the sympathetic nervous system, but the small number of valid samples made interpretation difficult.

Juvenile nasal angiofibroma (JNA) is a hypervascularised, benign, but locally aggressive tumour that grows in the posterior, upper part of the nasal cavity and invades surrounding anatomical structures. The treatment of choice is surgical removal, but complete resection of the tumour can be hampered because of profuse perioperative bleeding. Preoperative embolisation of the tumour has been proposed as an effective method for prevention of perioperative bleeding, thereby shortening of the time of the operation. In this report of five cases, we describe successful preoperative devascularisation of the tumour by applying a modified method of direct intratumoural injection of the liquid embolic agent Onyx combined with protection of the internal carotid artery. The control of bleeding during the embolisation and occlusion of the maxillary or sphenopalatine artery was achieved by using a bi-luminal balloon catheter. Such use of the dual-lumen catheter in treatment of JNA has not been reported so far in the medical literature., (© The Author(s) 2015.)

Background: Aneurysmal subarachnoid hemorrhage (SAH) may produce cerebral ischemia and systemic responses including stress. To study immediate cerebral and systemic changes in response to aneurysm rupture, animal models are needed., Objective: To study early cerebral energy changes in an animal model., Methods: Experimental SAH was induced in 11 pigs by autologous blood injection to the anterior skull base, with simultaneous control of intracranial and cerebral perfusion pressures. Intracerebral microdialysis was used to monitor concentrations of glucose, pyruvate and lactate., Results: In nine of the pigs, a pattern of transient ischemia was produced, with a dramatic reduction of cerebral perfusion pressure soon after blood injection, associated with a quick glucose and pyruvate decrease. This was followed by a lactate increase and a delayed pyruvate increase, producing a marked but short elevation of the lactate/pyruvate ratio. Glucose, pyruvate, lactate and lactate/pyruvate ratio thereafter returned toward baseline. The two remaining pigs had a more severe metabolic reaction with glucose and pyruvate rapidly decreasing to undetectable levels while lactate increased and remained elevated, suggesting persisting ischemia., Conclusion: The animal model simulates the conditions of SAH not only by deposition of blood in the basal cisterns, but also creating the transient global ischemic impact of aneurysmal SAH. The metabolic cerebral changes suggest immediate transient substrate failure followed by hypermetabolism of glucose upon reperfusion. The model has features that resemble spontaneous bleeding, and is suitable for future research of the early cerebral and systemic responses to SAH that are difficult to study in humans.

Sibling configuration, including birth order, or the number, age, and sex of siblings is associated with parental resource allocation between children and is thus associated with a person's well-being. Little is known about the association between specific types of siblings and adult health outcomes. Here we test several hypotheses about sibling composition (number of older brothers, older sisters, younger sisters, younger brothers) and adult blood pressure in a foraging-farming society of native Amazonians in Bolivia (Tsimane'). We collected data in 2007 from 374 adults (16-60years of age) from 196 households in 13 villages. Household random-effects multiple regressions were run using systolic (SBP) or diastolic blood pressure (DBP) as outcomes; covariates included the four sibling categories and control variables (e.g., sex, age, education, body mass index [BMI]). Mean SBP and DBP were 114 (SD=14) and 66 (SD=11)mmHg. The prevalence of hypertension was 5.08%. Having an additional younger brother bore a small (3.3-5.9%) positive association with both SBP and DBP, with the effect weakening as people aged. Having an additional younger sister was associated with a small (3.8%) increase in SBP among women, with the magnitude shrinking as people aged. In a large family, the number of younger brothers may exert an impact on an individual's blood pressure., (Copyright © 2012 Elsevier B.V. All rights reserved.)

This paper examines three morphological indicators measuring obesity among a native Amazonian population of foragers-farmers in Bolivia (Tsimane') and estimates the associations between them and standard covariates of obesity (e.g., socioeconomic status [SES]). We collected annual data from 350 non-pregnant women and 385 men ≥20 years of age from all 311 households in 13 villages during five consecutive years (2002-2006). We used three indicators to measure obesity: body-mass index (BMI), waist circumference (WC), and body fat using bioelectrical impedance analysis (BF-BIA). We ran separate individual random-effect panel multiple regressions for women and men with wealth, acculturation, health, and household food availability as key covariates, and controlled for village and year fixed effects and village×year interaction effects. Although BMI increases by a statistically significant annual growth rate of 0.64% among women and 0.37% among men over the five years, the increase does not yield significant biological meanings. Neither do we find consistent and biologically meaningful covariates associated with adult obesity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

FAK (focal adhesion kinase) and IGF-1R (insulin-like growth factor receptor-1) directly interact with each other and thereby activate crucial signaling pathways that benefit cancer cells. Inhibition of FAK and IGF-1R function has been shown to significantly decrease cancer cell proliferation and increase sensitivity to chemotherapy and radiation treatment. As a novel approach in human melanoma, we evaluated the effect of a small-molecule compound that disrupts the protein interaction of FAK and IGF-1R. Previously, using virtual screening and functional testing, we identified a lead compound (INT2-31) that targets the known FAK-IGF-1R protein interaction site. We studied the ability of this compound to disrupt FAK-IGF-1R protein interactions, inhibit downstream signaling, decrease human melanoma cell proliferation, alter cell cycle progression, induce apoptosis and decrease tumor growth in vivo. INT2-31 blocked the interaction of FAK and IGF-1R in vitro and in vivo in melanoma cells and tumor xenografts through precluding the activation of IRS-1, leading to reduced phosphorylation of AKT upon IGF-1 stimulation. As a result, INT2-31 significantly inhibited cell proliferation and viability (range 0.05-10 μM). More importantly, 15 mg/kg of INT2-31 given for 21 d via intraperitoneal injection disrupted the interaction of FAK and IGF-1R and effectively decreased phosphorylation of tumor AKT, resulting in significant melanoma tumor regression in vivo. Our data suggest that the FAK-IGF-1R protein interaction is an important target, and disruption of this interaction with a novel small molecule (INT2-31) has potential anti-neoplastic therapeutic effects in human melanoma.

The aim of this prospective study was to investigate the diagnostic performance of Borrelia (Bb)-induced interferon (IFN)-γ secretion detected by ELISPOT modified to be feasible for clinical laboratories as a supplementary test to the laboratory diagnosis of Lyme neuroborreliosis (LNB) in an endemic setting. Between 2002 and 2004, patients with symptoms of suspected clinical LNB were included in a study conducted on the Åland islands in the Finnish archipelago, which is a hyper-endemic area for Lyme borreliosis (LB). Fourteen patients with confirmed LNB and 103 patients with non-LNB were included, and the numbers of spontaneous and Bb-induced IFN-γ-secreting cells were assayed by the ELISPOT test. The ELISPOT assay showed a weak diagnostic performance with a sensitivity of 36% and a specificity of 82%. The findings in this study show that this ELISPOT-assay modified to be feasible in clinical routine laboratories is not useful as a supplementary diagnostic tool in the laboratory diagnosis of patients with clinically suspected LNB.

Background: Evolutionary theory suggests that natural selection favors the evolution of cognitive abilities which allow humans to use facial cues to assess traits of others. The use of facial and somatic cues by humans has been studied mainly in western industrialized countries, leaving unanswered whether results are valid across cultures., Methodology/principal Findings: Our objectives were to test (i) if previous finding about raters' ability to get accurate information about an individual by looking at his facial photograph held in low-income non western rural societies and (ii) whether women and men differ in this ability. To answer the questions we did a study during July-August 2007 among the Tsimane', a native Amazonian society of foragers-farmers in Bolivia. We asked 40 females and 40 males 16-25 years of age to rate four traits in 93 facial photographs of other Tsimane' males. The four traits were based on sexual selection theory, and included health, dominance, knowledge, and sociability. The rating scale for each trait ranged from one (least) to four (most). The average rating for each trait was calculated for each individual in the photograph and regressed against objective measures of the trait from the person in the photograph. We found that (i) female Tsimane' raters were able to assess facial cues related to health, dominance, and knowledge and (ii) male Tsimane' raters were able to assess facial cues related to dominance, knowledge, and sociability., Conclusions/significance: Our results support the existence of a human ability to identify objective traits from facial cues, as suggested by evolutionary theory.

Neuroblastoma is the most common extracranial solid tumor of childhood. Focal adhesion kinase (FAK) is an intracellular kinase that regulates both cellular adhesion and apoptosis. FAK is overexpressed in a number of human tumors including neuroblastoma. Previously, we have shown that the MYCN oncogene, the primary adverse prognostic indicator in neuroblastoma, regulates the expression of FAK in neuroblastoma. In this study, we have examined the effects of FAK inhibition upon neuroblastoma using a small molecule [1,2,4,5-benzenetetraamine tetrahydrochloride (Y15)] to inhibit FAK expression and the phosphorylation of FAK at the Y397 site. Utilizing both non-isogenic and isogenic MYCN(+)/MYCN(-) neuroblastoma cell lines, we found that Y15 effectively diminished phosphorylation of the Y397 site of FAK. Treatment with Y15 resulted in increased detachment, decreased cell viability and increased apoptosis in the neuroblastoma cell lines. We also found that the cell lines with higher MYCN are more sensitive to Y15 treatment than their MYCN negative counterparts. In addition, we have shown that treatment with Y15 in vivo leads to less tumor growth in nude mouse xenograft models, again with the greatest effects seen in MYCN(+) tumor xenografts. The results of the current study suggest that FAK and phosphorylation at the Y397 site plays a role in neuroblastoma cell survival, and that the FAK Y397 phosphorylation site is a potential therapeutic target for this childhood tumor.

Among adults of industrial nations, growth stunting (<-2 SD height Z score) is associated with worse indicators of adult well-being (e.g., income). Does adult stunting also inflict private costs in traditional societies? Adult stunting penalties or height premiums might only emerge when traditional societies modernize. Here we estimate the association between adult stunting and indicators of adult well-being using data from a panel study in progress among the Tsimane', a foraging-farming society of native Amazonians in Bolivia. Subjects included 248 women and 255 men >or=age 22 measured annually during 5 consecutive years (2002-2006). Nine outcomes (wealth, monetary income, illness, access to credit, mirth, schooling, math skills, plant knowledge, forest clearance) were regressed separately against a stunting dummy variable and a wide range of control variables. We found no significant association between any of the indicators of own well-being and adult stunting. Additional analysis showed that stunting bore an association only with poorer mid-arm muscle area. Height premiums and stunting penalties, though evident and marked in modern societies, might not be common in all traditional societies., (Copyright 2009 Elsevier B.V. All rights reserved.)

The basic concept of conditionally replicating adenoviruses (CRAD) as oncolytic agents is that progenies generated from each round of infection will disperse, infect and kill new cancer cells. However, CRAD has only inhibited, but not eradicated tumor growth in xenograft tumor therapy, and CRAD therapy has had only marginal clinical benefit to cancer patients. Here, we found that CRAD propagation and cancer cell survival co-existed for long periods of time when infection was initiated at low multiplicity of infection (MOI), and cancer cell killing was inefficient and slow compared to the assumed cell killing effect upon infection at high MOI. Excessive production of fiber molecules from initial CRAD infection of only 1 to 2% cancer cells and their release prior to the viral particle itself caused a tropism-specific receptor masking in both infected and non-infected bystander cells. Consequently, the non-infected bystander cells were inefficiently bound and infected by CRAD progenies. Further, fiber overproduction with concomitant restriction of adenovirus spread was observed in xenograft cancer therapy models. Besides the CAR-binding Ad4, Ad5, and Ad37, infection with CD46-binding Ad35 and Ad11 also caused receptor masking. Fiber overproduction and its resulting receptor masking thus play a key role in limiting CRAD functionality, but potentially promote adenovirus and host cell co-existence. These findings also give important clues for understanding mechanisms underlying the natural infection course of various adenoviruses.

Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that is overexpressed in many types of tumors, including pancreatic cancer, and plays an important role in cell adhesion and survival signaling. Pancreatic cancer is a lethal disease and is very resistant to chemotherapy, and FAK has been shown recently to assist in tumor cell survival. Therefore, FAK is an excellent potential target for anti-cancer therapy. We identified a novel small molecule inhibitor (1,2,4,5-Benzenetetraamine tetrahydrochloride, that we called Y15) targeting the main autophosphorylation site of FAK and hypothesized that it would be an effective treatment strategy against human pancreatic cancer. Y15 specifically blocked phosphorylation of Y397-FAK and total phosphorylation of FAK. It directly inhibited FAK autophosphorylation in a dose- and time-dependent manner. Furthermore, Y15 increased pancreatic cancer cell detachment and inhibited cell adhesion in a dose-dependent manner. Y15 effectively caused human pancreatic tumor regression in vivo, when administered alone and its effects were synergistic with gemcitabine chemotherapy. This was accompanied by a decrease in Y397-phosphorylation of FAK in the tumors treated with Y15. Thus, targeting the Y397 site of FAK in pancreatic cancer with the small molecule inhibitor, 1,2,4,5-Benzenetetraamine tetrahydrochloride, is a potentially effective treatment strategy in this deadly disease.

Most adenoviruses bind directly to the coxsackie and adenovirus receptor (CAR) on target cells in vitro, but recent research has shown that adenoviruses can also use soluble components in body fluids for indirect binding to target cells. These mechanisms have been identified upon addressing the questions of how to de- and retarget adenovirus-based vectors for human gene and cancer therapy, but the newly identified mechanisms also suggest that the role of body fluids and their components may also be of importance for natural, primary infections. Here we demonstrate that plasma, saliva, and tear fluid promote binding and infection of adenovirus type 5 (Ad5) in respiratory and ocular epithelial cells, which corresponds to the natural tropism of most adenoviruses, and that plasma promotes infection by Ad31. By using a set of binding and infection experiments, we also found that Ad5 and Ad31 require coagulation factors IX (FIX) or X (FX) or just FIX, respectively, for efficient binding and infection. The concentrations of these factors that were required for maximum binding were 1/100th of the physiological concentrations. Preincubation of virions with heparin or pretreatment of cells with heparinase I indicated that the role of cell surface heparan sulfate during FIX- and FX-mediated adenovirus binding and infection is mechanistically serotype specific. We conclude that the use of coagulation factors by adenoviruses may be of importance not only for the liver tropism seen when administering adenovirus vectors to the circulation but also during primary infections by wild-type viruses of their natural target cell types.

Previously we have shown that gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter restricting the pubertal increase in LHRH release in juvenile monkeys, and that interfering with GABA synthesis with an antisense oligodeoxynucleotide (AS) for glutamic acid decarboxylase (GAD67) mRNA results in an increase in LHRH release in prepubertal monkeys. GAD67 is a catalytic enzyme that synthesizes GABA from glutamate. To further clarify the role of GABA in puberty, we examined whether the inhibition of LHRH release by GABA continues after the onset of puberty and whether input from glutamatergic neurons plays any role in the onset of puberty when GABA inhibition declines, using a push-pull perfusion method. In Study I, the effects of the AS GAD67 mRNA on LHRH release in pubertal monkeys (34.3 +/- 1.5 months of age, n = 8) were examined, and the results were compared with those in prepubertal monkeys (18.5 +/- 0.4 months, n = 12). Direct infusion of AS GAD67 (1 microM) into the stalk-median eminence (S-ME) for 5 h stimulated LHRH release in both prepubertal and pubertal monkeys. However, the increase in LHRH release in pubertal monkeys was significantly (P < 0.01) smaller than that in prepubertal monkeys. Infusion of a scrambled oligo as a control was without effect in either group. In Study II, to examine the possibility that an increase in glutamate tone after the reduction of an inhibitory GABA tone contributes to the AS GAD67-induced LHRH increase, the effects of the NMDA receptor blocker MK801 (5 microM) on LHRH release were tested in monkeys treated with AS GAD67. MK801 infusion into the S-ME during the treatment of AS GAD67 (1 microM) suppressed the AS GAD67-induced LHRH release in both age groups. MK801 alone did not cause any significant effect in either group. The data are interpreted to mean that GABA continues to suppress LHRH release after the onset of puberty, although the degree of suppression is weakened considerably after the onset of puberty, and that the increased LHRH release after AS GAD67 treatment may be partly due to an increase in glutamate tone mediated by NMDA receptors, as well as due to the decrease in GABA release following the decrease in GAD synthesis. Taken together, the present results suggest that GAD may play an important role in the onset and progress of puberty in nonhuman primates.