Prevalence, predictors and correlates of insomnia in US army soldiers

Summary

The objective of this study was to investigate the rates, predictors and correlates of insomnia in a national sample of US Army soldiers. Data were gathered from the cross-sectional survey responses of the All-Army Study, of the Army Study to Assess Risk and Resilience in Service members. Participants were a representative sample of 21 499 US Army soldiers who responded to the All-Army Study self-administered questionnaire between 2011 and 2013. Insomnia was defined by selected DSM-5 criteria using the Brief Insomnia Questionnaire. The results highlight significant functional difficulties associated with insomnia among US soldiers, as well as insights into predictors of insomnia specific to this population. Insomnia was present in 22.76% of the sample. Predictors of insomnia status in logistic regression included greater number of current mental health disorders, less perceived open lines of communication with leadership, less unit member support and less education. Insomnia had global, negative associations with health, social functioning, support, morale, work performance and Army career intentions. The results provide the strongest evidence to-date that insomnia is common in a military population, and is associated with a wide array of negative factors in the domains of health, military readiness and intentions to remain in military careers.

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The impact of sleep deprivation on visual perspective taking

Summary

Total sleep deprivation (TSD) is known to alter cognitive processes. Surprisingly little attention has been paid to its impact on social cognition. Here, we investigated whether TSD alters levels-1 and -2 visual perspective-taking abilities, i.e. the capacity to infer (a) what can be seen and (b) how it is seen from another person's visual perspective, respectively. Participants completed levels-1 and -2 visual perspective-taking tasks after a night of sleep and after a night of TSD. In these tasks, participants had to take their own (self trials) or someone else's (other trials) visual perspective in trials where both perspectives were either the same (consistent trials) or different (inconsistent trials). An instruction preceding each trial indicated the perspective to take (i.e. the relevant perspective). Results show that TSD globally deteriorates social performance. In the level-1 task, TSD affects the selection of relevant over irrelevant perspectives. In the level-2 task, the effect of TSD cannot be unequivocally explained. This implies that visual perspective taking should be viewed as partially state-dependent, rather than a wholly static trait-like characteristic.

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Landscape opening and herding strategies: Carbon isotope analyses of herbivore bone collagen from the Neolithic and Bronze Age lakeshore site of Zurich-Mozartstrasse, Switzerland

Carbon isotope analysis (d13C) was performed on collagen extracted from 54 domestic cattle (Bos taurus) and 20 red deer (Cervus elaphus) bones from the Neolithic (3913-2586 BC) and Bronze Age (1950-950 cal. BC) layers of the lakeshore site Zurich-Mozartstrasse located in the lower Lake Zurich basin, Switzerland. We observed shifts in the d13C of both domestic cattle and red deer over two millennia. Mean d13C values of red deer changed from 24.1 ± 0.7‰ to 22.5 ± 0.3‰, while mean d13C values of domestic cattle showed minor changes from 22.7 ± 1.3‰ to 22.1 ± 0.3‰. Our data suggest that in the early 4th millennium BC the landscape was densely forested with red deer feeding in closed habitats and cattle grazing in more open landscapes. Forest was also a food resource for some young cattle as indicated by the lower d13C values of non-adult relative to adult animals. This points to a greater diversity of herding strategies and feeding techniques compared to the later periods. The landscape was still rather forested towards the mid-3rd millennium BC, with no obvious changes in the habitat use of the large herbivores. However, the carbon isotopes suggest a clearly reduced forest cover in the 2nd millennium BC with red deer using similar open feeding grounds as domestic cattle. Our study demonstrates that the stable carbon isotope composition of archeological bone material from large herbivores can provide integrative constraints on paleoenvironmental and vegetation changes, prehistoric animal management and land-use.

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Urinary potassium to urinary potassium plus sodium ratio can accurately identify hypovolemia in nephrotic syndrome: a provisional study

Abstract

There is evidence pointing to a decrease of the glomerular filtration rate (GFR) in a subgroup of nephrotic children, likely secondary to hypovolemia. The aim of this study is to validate the use of urinary potassium to the sum of potassium plus sodium ratio (UK/UK+UNa) as an indicator of hypovolemia in nephrotic syndrome, enabling detection of those patients who will benefit from albumin infusion. We prospectively studied 44 nephrotic children and compared different parameters to a control group (36 children). Renal perfusion and glomerular permeability were assessed by measuring clearance of para-aminohippurate and inulin. Vaso-active hormones and urinary sodium and potassium were also measured. Subjects were grouped into low, normal, and high GFR groups. In the low GFR group, significantly lower renal plasma flow (p = 0.01), filtration fraction (p = 0.01), and higher UK/UK+UNa (p = 0.03) ratio were noted. In addition, non-significant higher plasma renin activity (p = 0.11) and aldosteron (p = 0.09) were also seen in the low GFR group.

Conclusion: A subgroup of patients in nephrotic syndrome has a decrease in glomerular filtration, apparently related to hypovolemia which likely can be detected by a urinary potassium to potassium plus sodium ratio > 0.5–0.6 suggesting benefit of albumin infusion in this subgroup.

What is Known: • Volume status can be difficult to assess based on clinical parameters in nephrotic syndrome, and albumin infusion can be associated with development of pulmonary edema and fluid overload in these patients.

What is New: • Urinary potassium to the sum of urinary potassium plus sodium ratio can accurately detect hypovolemia in nephrotic syndrome and thus identify those children who would probably respond to albumin infusion.

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Oral and maxillofacial manifestations of chronic kidney disease - mineral and bone disorder: a multicentric retrospective study

Publication date: Available online 10 October 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Flávia Sirotheau Corrêa Pontes, Márcio Ajudarte Lopes, Lucas Lacerda de Souza, Diogo dos Santos da Mata Rezende, Alan Roger Santos-Silva, Jacks Jorge Junior, Wagner Gomes da Silva, Fábio Ramôa Pires, André Caroli Rocha, Wladimir Gushiken de Campos, Milena Coelho Fernandes Caldato, Regina Matsunaga Martin, Felipe Paiva Fonseca, Hélder Antônio Rebelo Pontes
ObjectiveTo describe the oral and maxillofacial manifestations of patients diagnosed with chronic kidney disease - mineral and bone disorders (CKD-MBD).Material and methodsOver a 13-year period, clinicopathological data of patients diagnosed with CKD-MBD who demonstrated oral and maxillofacial alterations were retrieved from the files of four Brazilian institutions. Data included clinical, radiographic, microscopic and biochemical findings, treatment employed and follow-up status.ResultsTwenty-one cases were identified, 13 cases as brown tumor of hyperparathyroidism (BTH) and 8 as osteitis fibrosa/renal osteodystrophy (OF/RO) (4 of them clinically consistent with Sagliker syndrome). The mean age was 32.7 years and the mandible was the most affected site (42.8%). OF/RO showed an ill defined "ground glass" radiographic appearance, and BTH well-defined radiolucent images. Biochemically, the following mean values were obtained: parathyroid hormone 1,511.07pg/ml, Calcium 9.25mg/dl, Phosphorus 5.19mg/dl, Alkaline phosphatase 941.55U/L, Urea 125.42mg/dL and Creatinine 7.14mg/dL. Treatment comprised vitamin D and calcium intake, parathyroidectomy, hemodialysis, renal transplantation and local surgery. During follow-up, 5 BTH patients were free of lesions, whereas 2 affected by OF/RO/Sagliker syndrome died.ConclusionsOral and maxillofacial manifestations of BTH and OF/RO are uncommon, but they can be associated with an important life threatening scenario.



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A guide for effective anatomical vascularization studies: useful ex vivo methods for both CT and MRI imaging before dissection

Abstract

The objective of this study was to develop a simple and useful injection protocol for imaging cadaveric vascularization and dissection. Mixtures of contrast agent and cast product should provide adequate contrast for two types of ex vivo imaging (MRI and CT) and should harden to allow gross dissection of the injected structures. We tested the most popular contrast agents and cast products, and selected the optimal mixture composition based on their availability and ease of use. All mixtures were first tested in vitro to adjust dilution parameters of each contrast agent and to fine-tune MR imaging acquisition sequences. Mixtures were then injected in 24 pig livers and one human pancreas for MR and computed tomography (CT) imaging before anatomical dissection. Colorized latex, gadobutrol and barite mixture met the above objective. Mixtures composed of copper sulfate (CuSO₄) gadoxetic acid (for MRI) and iodine (for CT) gave an inhomogeneous signal or extravasation of the contrast agent. Agar did not harden sufficiently for gross dissection but appears useful for CT and magnetic resonance imaging (MRI) studies without dissection. Silicone was very hard to inject but achieved the goals of the study. Resin is particularly difficult to use but could replace latex as an alternative for corrosion instead of dissection. This injection protocol allows CT and MRI images to be obtained of cadaveric vascularization and anatomical casts in the same anatomic specimen. Post-imaging processing software allow easy 3D reconstruction of complex anatomical structures using this technique. Applications are numerous, e.g. surgical training, teaching methods, postmortem anatomic studies, pathologic studies, and forensic diagnoses.

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The biorhythm of human skeletal growth

Abstract

Evidence of a periodic biorhythm is retained in tooth enamel in the form of Retzius lines. The periodicity of Retzius lines (RP) correlates with body mass and the scheduling of life history events when compared between some mammalian species. The correlation has led to the development of the inter-specific Havers–Halberg oscillation (HHO) hypothesis, which holds great potential for studying aspects of a fossil species biology from teeth. Yet, our understanding of if, or how, the HHO relates to human skeletal growth is limited. The goal here is to explore associations between the biorhythm and two hard tissues that form at different times during human ontogeny, within the context of the HHO. First, we investigate the relationship of RP to permanent molar enamel thickness and the underlying daily rate that ameloblasts secrete enamel during childhood. Following this, we develop preliminary research conducted on small samples of adult human bone by testing associations between RP, adult femoral length (as a proxy for attained adult stature) and cortical osteocyte lacunae density (as a proxy for the rate of osteocyte proliferation). Results reveal RP is positively correlated with enamel thickness, negatively correlated with femoral length, but weakly associated with the rate of enamel secretion and osteocyte proliferation. These new data imply that a slower biorhythm predicts thicker enamel for children but shorter stature for adults. Our results develop the intra-specific HHO hypothesis suggesting that there is a common underlying systemic biorhythm that has a role in the final products of human enamel and bone growth.

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A new approach to treat bone gaps after midfacial and zygomatic fractures with a collagen membrane

Abstract

Purpose

The aim of the study was to analyze the eligibility of resorbable collagen membrane in the treatment of midfacial fractures to prevent gap formation and subsequent cheek tissue retraction.

Material and methods

We included nine patients (six males, three females; mean age 51; range 20–73 years; mean bone gap size 8.03 × 13.12 mm) in a retrospective study design. The defect size was assessed by ultrasound.

Results

After a healing period of 4 to 55 weeks, treatment resulted in a significant reduction of gap size (residual mean bone gap size 6.14 × 7.32 mm).

Conclusions

Native resorbable collagen membrane is a promising tool to reduce the size of bony gap in midfacial defects.

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Association between weight gain during adjuvant chemotherapy for early-stage breast cancer and survival outcomes

Abstract

Obese and overweight women have an increased risk of breast cancer and worse outcomes at the time of diagnosis. Women tend to gain weight after breast cancer diagnosis and during chemotherapy for early-stage disease, which may in turn increase risk for worse outcomes. We examined if weight gained during adjuvant chemotherapy was associated with worse survival outcomes. We queried our database for data on patients who received adjuvant third-generation chemotherapy for early-stage breast cancer. Univariate and multivariate analyses by Cox regression were performed for survival outcomes across three categories according to BMI variation from start to end of chemotherapy: >0.5 kg/m² loss or gain and stable BMI (±0.5 kg/m²). We included 1998 patients in this study. Women over 50 years old and postmenopausal were more likely to lose weight during adjuvant chemotherapy, whereas women under 30 years old gained more weight (P < 0.001). At 1 year postchemotherapy, patients tended to return to their original weight (ρ = −0.3, P < 0.001). On multivariate analysis, BMI increase of >0.5 kg/m² compared to maintaining BMI was marginally associated with increased locoregional recurrence risk (HR: 2.53; 95% CI, 1.18–5.45; P = 0.017), adjusting for grade, stage, and radiation delivery. Weight variation during adjuvant chemotherapy for early-stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival.

Weight variation during adjuvant chemotherapy for early stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival.

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Targeting MTA1/HIF-1α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

Abstract

The metastasis-associated protein 1(MTA1)/histone deacetylase (HDAC) unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA1, could block prostate tumor progression in vivo. We generated and utilized a luciferase reporter in a prostate-specific Pten-null mouse model (Pb-Cre⁺; Pten^f/f; Rosa26^Luc/+) to evaluate the anticancer efficacy of Pter/SAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associated proangiogenic factors HIF-1α, VEGF, and IL-1β leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/HIF-1α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF-1α tumor-promoting signaling in PCa. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targeted therapies in PCa.

Utilization of dietary bioactive molecules as chemo-sensitizers is an emerging approach in developing combination strategies that can potentially provide more efficacy and less toxicity for anticancer treatments. Our study offers preclinical proof for combinatorial strategy using natural product, pterostilbene, with histone deacetylase inhibitor, SAHA, as a MTA1-targeted interventional therapy to abrogate prostate cancer. Changes in MTA1-associated proangiogenic factors in serum may be used as molecular response biomarkers for such therapy.

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The association between subjectively impaired sleep and symptoms of depression and anxiety in a frail elderly population

Abstract

Background

Most previous studies showed an association between sleep impairment in the elderly and symptoms of depression and anxiety. Majority of these studies were conducted in "strong", community-dwelling elderly.

Aim

To assess the association between subjective sleep impairment and its affective disturbances among frail elderly patients.

Methods

The retrospective study included patients 65 years old and above. Data included socio-demographic characteristics, the mini-mental state examination, the short anxiety screening test, the 15-item Geriatric Depression Scale, and the Patient Health Questionnaire. The patients were asked about sleep complaints.

Results

The study population consisted of 496 patients. The mean age was 83.7 ± 6.2 years, and only 7 (1.4%) did not report any sleep disturbance. After adjustment, depression symptoms were associated only with decreased overall sleep satisfaction (OR 2.62, 95% CI 1.18–5.81), while anxiety symptoms were associated with decreased overall sleep satisfaction (OR 3.17, 96% CI 1.71–5.88), difficulty falling asleep (OR 3.58, 95% CI 1.96–6.52), waking up during the night (OR 3.16, 95% CI 1.63–6.1), morning weakness (OR 2.68, 95% CI 1.44–5.0) and daytime drowsiness (OR 2.39, 95% CI 1.21–4.69).

Discussion

Sleep impairment is very prevalent among frail elderly and associated much more with anxiety than with depression.

Conclusion

The findings of the present study provide further evidence for the importance in taking a detailed history of sleep habits during the course of the geriatric assessment in frail elderly patients.

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Lesions Responsible for Delayed Oral Transit Time in Post-stroke Dysphagia

Abstract

Introduction

Some stroke patients show oral phase dysphagia, characterized by a markedly prolonged oral transit time that hinders oral feeding. The aim of this study was to clarify the clinical characteristics and lesions responsible for delayed swallowing.

Methods

We reviewed 90 patients with stroke. The oral processing time plus the postfaucial aggregation time required to swallow semisolid food was assessed. The patients were divided into two groups according to oral transit time, and we analyzed the differences in characteristics such as demographic factors, lesion factors, and cognitive function. Logistic regression analyses were performed to examine the predictors of delayed oral transit time. Lesion location and volume were measured on brain magnetic resonance images. We generated statistic maps of lesions related to delayed oral phase in swallowing using voxel-based lesion symptom mapping (VLSM).

Results

The group of patients who showed delayed oral transit time had significantly low cognitive function. Also, in a regression model, delayed oral phase was predicted with low K-MMSE (Korean version of the Mini Mental Status Exam). Using VLSM, we found the lesion location to be associated with delayed oral phase after adjusting for K-MMSE score. Although these results did not reach statistical significance, they showed the lesion pattern with predominant distribution in the left frontal lobe.

Conclusion

Delayed oral phase in post-stroke patients was not negligible clinically. Patients' cognitive impairments affect the oral transit time. When adjusting it, we found a trend that the lesion responsible for delayed oral phase was located in the left frontal lobe, though the association did not reach significance. The delay might be related to praxis function.

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A Significant Association of Malnutrition with Dysphagia in Acute Patients

Abstract

Dysphagia and malnutrition seem to be associated, but little research in detail has been reported. We aimed to clarify the association between dysphagia and malnutrition by adopting accurate diagnosis and mathematical evaluation of dysphagia using videofluorography and nutritional assessment calculated by a well-established nutritional risk index. We conducted a retrospective analysis of 165 enrolled patients who were admitted to our hospital for acute diseases and underwent videofluorography on suspicion of dysphagia in the year 2016. We diagnosed high-risk dysphagia in patients with 8-point penetration–aspiration scale (PAS) score over 4. We used the geriatric nutritional risk index (GNRI) as a nutritional assessment tool. A GNRI score less than 91.2 corresponds to malnutrition. The median age of 165 enrolled patients was 76.0, and the number of female patients was 53. The mean GNRI was 81.2, and 134 patients (81.2%) had malnutrition. The number of the patients with a diagnosis of high-risk dysphagia was 54 (32.7%). The GNRI of patients with high-risk dysphagia was significantly less than that of patients without (mean value 77.7 ± 10.5 vs. 83.0 ± 10.5, P = 0.003). GNRI < 91.2 was independently and significantly associated with high-risk dysphagia (OR 3.094; CI 1.057–9.058; P = 0.039). Based on the current study, the authors propose evaluating nutritional status to predict dysphagia risk of patients in the acute phase.

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Assessment of a closed wash system developed for processing living donor femoral heads

Abstract

NHS Blood and Transplant Tissue and Eye Services (TES) and Scottish National Blood Transfusion Services Tissues and Cells Directorate (TCD) currently bank whole, frozen femoral head bone from living donors who are undergoing primary hip replacement surgery. When required, the bone is issued to a surgeon still frozen on dry ice (− 79 °C). Consequently, the femoral head bone is not processed, is not sterilised and at the time of issue, it contains donor blood, bone marrow and associated cells. We have previously shown that, cut, shaped and washed bone from deceased donors can be processed to remove up to 99.9% of blood, bone marrow and associated cells (Eagle et al. 2015). However, cut and shaped bone is not suitable for some orthopaedic procedures and some orthopaedic surgeons do not wish to use irradiated bone; therefore in this report, a method has been developed in which whole femoral heads can be washed to remove donor blood and bone marrow components. Processing results in excess of 99% bone marrow component removal—soluble protein, haemoglobin and DNA; the procedure is performed inside a closed system, thereby eliminating the need for terminal sterilisation by irradiation. In addition, uniaxial testing demonstrated no difference in compressive strength between washed and unwashed bone. We suggest that this washed bone may be capable of improving incorporation after grafting without disturbing biomechanical properties of the graft.

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Doc: Bogus dentist's behaviour not normal

KUALA LUMPUR: The behaviour of bogus dentist Nur Farahanis Ezatty Adli, who did not show any remorse and instead thanked her critics for making her famous, has baffled many, with an expert saying that her actions were "not normal". Universiti Malaya Medical Centre Assoc Prof in psychological medicine Datin Dr Sharmilla Kanaga sundram said Nur Farahanis' behaviour was not normal for someone who had committed a serious offence as she did not show remorse or take the offence seriously.

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Systematic Identification of Mycobacterium tuberculosis Effectors Reveals that BfrB Suppresses Innate Immunity [Research]

Mycobacterium tuberculosis (Mtb) has evolved multiple strategies to counter the human immune system. The effectors of Mtb play important roles in the interactions with the host. However, due to the lack of highly efficient strategies, there are only a handful of known Mtb effectors, thus hampering our understanding of Mtb pathogenesis. In this study, we probed Mtb proteome microarray with biotinylated whole-cell lysates of human macrophages, identifying 27 Mtb membrane proteins and secreted proteins that bind to macrophage proteins. Combining GST pull-down with mass spectroscopy then enabled the specific identification of all binders. We refer to this proteome microarray-based strategy as SOPHIE (Systematic unlOcking of Pathogen and Host Interacting Effectors). Detailed investigation of a novel effector identified here, the iron storage protein BfrB (Rv3841), revealed that BfrB inhibits NF-B-dependent transcription through binding and reducing the nuclear abundance of the ribosomal protein S3 (RPS3), which is a functional subunit of NF-B. The importance of this interaction was evidenced by the promotion of survival in macrophages of the mycobacteria, Mycobacterium smegmatis, by overexpression of BfrB. Thus, beyond demonstrating the power of SOPHIE in the discovery of novel effectors of human pathogens, we expect that the set of Mtb effectors identified in this work will greatly facilitate the understanding of the pathogenesis of Mtb in particular, possibly leading to additional potential molecular targets in the battle against tuberculosis.

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Cold agglutinins in a patient undergoing normothermic cardiac operation with warm cardioplegia

Cold agglutinins are autoantibodies that agglutinate red blood cells at low temperatures, leading to haemagglutination and haemolysis. They are generally of no clinical significance. However, when people with cold agglutinins undergo cardiac operation with hypothermia and cold cardioplegia, they can experience complications. Thus, different perioperative management is required for such patients. We describe a 74-year-old man with cold agglutinins incidentally detected on the preoperative screening test. He had never experienced any complications or developed a haematological disease. Since cold agglutinins were incidentally detected on the preoperative test, a special strategy was used to manage the temperature of cardiopulmonary bypass (CPB) and cardioplegia. He successfully underwent normothermic cardiac operation with warm cardioplegia. A continuous retrograde hyperkalaemic infusion and intermittent antegrade infusion of warm cardioplegia with normothermic CPB is one of the best methods to avoid hypothermia and excessive activity and metabolism of the heart, and to provide a suitable operative field.

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Early sonographic detection of a succenturiate placenta after IVF in a 42-year-old woman with multiple comorbidities

We present a case of a 42-year-old woman with a pregnancy resulting from in vitro fertilisation and a medical history including two spontaneous abortions, hypercoagulable state and other comorbidities. At 13 4/7 weeks' gestation, during research ultrasonography, the patient was noted to have an anterior succenturiate placental lobe. Following an episode of vaginal bleeding at 21 6/7 weeks, she was diagnosed with a low-lying posterior placental lobe. Velamentous cord insertion, placenta previa and vasa previa were excluded at that time. After elective induction for advanced maternal age at 39 0/7 weeks, arrest of labour and chorioamnionitis resulted in a primary low transverse caesarean section and delivery of a healthy girl at 39 3/7 weeks. Gross examination of the placenta showed an irregular, singleton placenta with an attached succenturiate lobe and a marginally inserting umbilical cord. Both lobes were connected by two vessels.

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Knotted urethral catheter: an unusual complication in adults

Knotting of feeding tubes or urinary catheters has been reported as a rare complication in paediatrics when draining the bladder. This is caused by inserting thin flexible tubes too far in, allowing it to coil. We present a case of a 70-year-old woman who was catheterised during a routine spinal surgery, and the catheter coiled and balloon failed to deflate requiring a cystostopic approach to puncture the balloon and remove it. Awareness of this complication in female catheterisation and education on length of catheter insertion is important to avoid this.

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Double PCL sign on sagittal MRI of the knee

Description

A 24-year-old male presented with left knee pain and swelling after a fall six weeks earlier playing football. Clinical examination revealed an antalgic gait and a moderate left knee effusion with tenderness along the medial joint line. Anterior drawer and Lachman tests were positive, suggesting an anterior cruciate ligament (ACL) injury. An MRI scan performed shortly after the injury revealed a large joint effusion and significant acute bone oedema involving the medial tibial condyle. While the posterior cruciate ligament (PCL) was intact, the ACL was elongated and suspicious for an intrasubstance tear. A bucket-handle tear of the medial meniscus was observed with the free fragment seen within the intercondylar notch. This gave rise to the double PCL sign on sagittal view. The patient underwent arthroscopic ACL reconstruction with a hamstring graft, and the medial meniscus was excised as it was unrepairable.

The 'double PCL' sign refers to the...

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Fulminant Bacillus cereus septicaemia with multiple organ ischaemic/haemorrhagic complications in a patient undergoing chemotherapy for acute myelogenous leukaemia

Bacillus cereus is a Gram-positive spore-forming rod widely found in the environment and is thought to be a frequent source of contamination. This micro-organism is reportedly a significant pathogenic agent among immunocompromised individuals. Furthermore, multiple cases of fulminant septicaemia have been reported among individuals receiving chemotherapy for acute myelogenous leukaemia. In some cases, B. cereus septicaemia was associated with multiple haemorrhages. We, herein, describe a patient with an extremely acute course of B. cereus septicaemia characterised by haemorrhage and infarction of multiple organs, which led to his death. Our findings suggest that delayed treatment of B. cereus in patients with haematologic malignancies undergoing chemotherapy may result in extremely poor outcomes; thus, immediate empirical treatment with vancomycin should be considered.

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Sleeve lobectomy for lung cancer

Abstract

Considerable progress has been made in the field of lung cancer surgery since the first sleeve lobectomy was performed 70 years ago. Technology has advanced significantly and a multitude of lung cancer treatments and diagnostic tests is now available. These advancements have led to improved surgical treatments and understanding of this disease. Historically, pneumonectomy was considered the procedure of choice for central or locally advanced non-small cell lung cancer (NSCLC). Sleeve lobectomy was conceived only as an alternative for patients with limited cardiopulmonary reserve. However, the advantages of bronchoplastic resections for NSCLC have long been established (Thomas et al. J R Coll Surg Edinb. 1956;1:169–186; Allison et al. Ann R Coll Surg. 1954; 25:20–22; Thomas et al. Thorax. 1960;15:9–11; Weisel et al. J Thorac Cardiovasc Surg. 1979;78(6):839–849; Jensik et al. J Thorac Cardiovasc Surg. 1972;64(3):400–412. Many reliable studies have published convincing results over the years demonstrating superior outcomes over pneumonectomy when sleeve lobectomy is extended to patients with normal cardiopulmonary reserve (Gaissert et al. Thorac Cardiovasc Surg. 111(5):948–953, 1996). Not only does sleeve lobectomy surgery preserve lung function, but literature over the years has clearly shown this procedure to be associated with comparable morbidity, decreased mortality, and favorable long-term survival and enhanced quality of life (Weisel et al. J Thorac Cardiovasc Surg. 1979;78:839–849; Jensik et al. J Thorac Cardiovasc Surg. 1972;64:400–412, Ferguson et al. Ann Thorac Surg. 2003;76:1782–1788). In this review, we highlight patient selection factors and current indications for considering sleeve lobectomy. In addition, we describe our sleeve lobectomy surgical techniques and review post-operative management strategies and potential associated complications. We also discuss the long-term outcomes, recurrence, and survival rates associated with sleeve lobectomy in more recently available published series.

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Ethnic and population differences in the genetic predisposition to human obesity

Summary

Obesity rates have escalated to the point of a global pandemic with varying prevalence across ethnic groups. These differences are partially explained by lifestyle factors in addition to genetic predisposition to obesity. This review provides a comprehensive examination of the ethnic differences in the genetic architecture of obesity. Using examples from evolution, heritability, admixture, monogenic and polygenic studies of obesity, we provide explanations for ethnic differences in the prevalence of obesity. The debate over definitions of race and ethnicity, the advantages and limitations of multi-ethnic studies and future directions of research are also discussed. Multi-ethnic studies have great potential to provide a better understanding of ethnic differences in the prevalence of obesity that may result in more targeted and personalized obesity treatments.

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Enhancement of BLM-DNA2-Mediated Long-Range DNA End Resection by CtIP

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): James M. Daley, Judit Jimenez-Sainz, Weibin Wang, Adam S. Miller, Xiaoyu Xue, Kevin A. Nguyen, Ryan B. Jensen, Patrick Sung
DNA double-strand break repair by homologous recombination entails the resection of DNA ends to reveal ssDNA tails, which are used to invade a homologous DNA template. CtIP and its yeast ortholog Sae2 regulate the nuclease activity of MRE11 in the initial stage of resection. Deletion of CtIP in the mouse or SAE2 in yeast engenders a more severe phenotype than MRE11 nuclease inactivation, indicative of a broader role of CtIP/Sae2. Here, we provide biochemical evidence that CtIP promotes long-range resection via the BLM-DNA2 pathway. Specifically, CtIP interacts with BLM and enhances its helicase activity, and it enhances DNA cleavage by DNA2. Thus, CtIP influences multiple aspects of end resection beyond MRE11 regulation.

Graphical abstract

Teaser

Biochemical analysis by Daley et al. shows that CtIP not only functions as a cofactor for the MRN complex but also stimulates long-range resection by BLM-DNA2-RPA. CtIP interacts with BLM and enhances its helicase activity, and it upregulates the DNA flap cleavage activity of DNA2.


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Homeostatic Presynaptic Plasticity Is Specifically Regulated by P/Q-type Ca2+ Channels at Mammalian Hippocampal Synapses

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Alexander F. Jeans, Fran C. van Heusden, Bashayer Al-Mubarak, Zahid Padamsey, Nigel J. Emptage
Voltage-dependent Ca²⁺ channels (VGCC) represent the principal source of Ca²⁺ ions driving evoked neurotransmitter release at presynaptic boutons. In mammals, presynaptic Ca²⁺ influx is mediated mainly via P/Q-type and N-type VGCC, which differ in their properties. Changes in their relative contributions tune neurotransmission both during development and in Hebbian plasticity. However, whether this represents a functional motif also present in other forms of activity-dependent regulation is unknown. Here, we study the role of VGCC in homeostatic plasticity (HSP) in mammalian hippocampal neurons using optical techniques. We find that changes in evoked Ca²⁺ currents specifically through P/Q-type, but not N-type, VGCC mediate bidirectional homeostatic regulation of both neurotransmitter release efficacy and the size of the major synaptic vesicle pools. Selective dependence of HSP on P/Q-type VGCC in mammalian terminals has important implications for phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.

Graphical abstract

Teaser

Jeans at al. show that both basal neurotransmission and synaptic vesicle pool sizes are specifically regulated by the presynaptic P/Q-type voltage-gated Ca²⁺ channel during HSP at mammalian hippocampal synapses. This may shed light on mechanisms underlying phenotypes associated with P/Q-type channelopathies, including migraine and epilepsy.


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Functional Plasticity of Odor Representations during Motherhood

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Amit Vinograd, Yael Fuchs-Shlomai, Merav Stern, Diptendu Mukherjee, Yuan Gao, Ami Citri, Ian Davison, Adi Mizrahi
Motherhood is accompanied by new behaviors aimed at ensuring the wellbeing of the offspring. Olfaction plays a key role in guiding maternal behaviors during this transition. We studied functional changes in the main olfactory bulb (OB) of mothers in mice. Using in vivo two-photon calcium imaging, we studied the sensory representation of odors by mitral cells (MCs). We show that MC responses to monomolecular odors become sparser and weaker in mothers. In contrast, responses to biologically relevant odors are spared from sparsening or strengthen. MC responses to mixtures and to a range of concentrations suggest that these differences between odor responses cannot be accounted for by mixture suppressive effects or gain control mechanisms. In vitro whole-cell recordings show an increase in inhibitory synaptic drive onto MCs. The increase of inhibitory tone may contribute to the general decrease in responsiveness and concomitant enhanced representation of specific odors.

Graphical abstract

Teaser

Motherhood is associated with changes in neural circuits that affect how the mother senses her surroundings. Vinograd et al. show that the olfactory bulb is a locus of plasticity. Output neurons of the bulb have elevated inhibition, and odor coding of natural odors is improved.


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Uncoupling of Metabolic Health from Longevity through Genetic Alteration of Adipose Tissue Lipid-Binding Proteins

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Khanichi N. Charles, Min-Dian Li, Feyza Engin, Ana Paula Arruda, Karen Inouye, Gökhan S. Hotamisligil
Deterioration of metabolic health is a hallmark of aging and generally assumed to be detrimental to longevity. Exposure to a high-calorie diet impairs metabolism and accelerates aging; conversely, calorie restriction (CR) prevents age-related metabolic diseases and extends lifespan. However, it is unclear whether preservation of metabolic health is sufficient to extend lifespan. We utilized a genetic mouse model lacking Fabp4/5 that confers protection against metabolic diseases and shares molecular and lipidomic features with CR to address this question. Fabp-deficient mice exhibit extended metabolic healthspan, with protection against insulin resistance and glucose intolerance, inflammation, deterioration of adipose tissue integrity, and fatty liver disease. Surprisingly, however, Fabp-deficient mice did not exhibit any extension of lifespan. These data indicate that extension of metabolic healthspan in the absence of CR can be uncoupled from lifespan, indicating the potential for independent drivers of these pathways, at least in laboratory mice.

Graphical abstract

Teaser

Deterioration of metabolic health is a hallmark of aging and generally thought to be detrimental to longevity. Charles et al. utilize FABP-deficient mice as a model to demonstrate that the preservation of metabolic health in this model persists throughout life, even under metabolic stress, but does not increase longevity.


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A Specific ChREBP and PPARα Cross-Talk Is Required for the Glucose-Mediated FGF21 Response

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Alison Iroz, Alexandra Montagner, Fadila Benhamed, Françoise Levavasseur, Arnaud Polizzi, Elodie Anthony, Marion Régnier, Edwin Fouché, Céline Lukowicz, Michèle Cauzac, Emilie Tournier, Marcio Do-Cruzeiro, Martine Daujat-Chavanieu, Sabine Gerbal-Chalouin, Véronique Fauveau, Solenne Marmier, Anne-Françoise Burnol, Sandra Guilmeau, Yannick Lippi, Jean Girard, Walter Wahli, Renaud Dentin, Hervé Guillou, Catherine Postic
While the physiological benefits of the fibroblast growth factor 21 (FGF21) hepatokine are documented in response to fasting, little information is available on Fgf21 regulation in a glucose-overload context. We report that peroxisome-proliferator-activated receptor α (PPARα), a nuclear receptor of the fasting response, is required with the carbohydrate-sensitive transcription factor carbohydrate-responsive element-binding protein (ChREBP) to balance FGF21 glucose response. Microarray analysis indicated that only a few hepatic genes respond to fasting and glucose similarly to Fgf21. Glucose-challenged Chrebp^−/− mice exhibit a marked reduction in FGF21 production, a decrease that was rescued by re-expression of an active ChREBP isoform in the liver of Chrebp^−/− mice. Unexpectedly, carbohydrate challenge of hepatic Pparα knockout mice also demonstrated a PPARα-dependent glucose response for Fgf21 that was associated with an increased sucrose preference. This blunted response was due to decreased Fgf21 promoter accessibility and diminished ChREBP binding onto Fgf21 carbohydrate-responsive element (ChoRE) in hepatocytes lacking PPARα. Our study reports that PPARα is required for the ChREBP-induced glucose response of FGF21.

Graphical abstract

Teaser

FGF21 is a hepatokine with beneficial metabolic effects, including control of sucrose preference. Iroz et al. demonstrate that Fgf21 is a unique hepatic gene inducible by both fasting and glucose signals and that the transcription factors PPARα and ChREBP both regulate the endocrine control of sugar intake by hepatic FGF21.


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Differential Regulation of Lipoprotein and Hepatitis C Virus Secretion by Rab1b

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Constantin N. Takacs, Ursula Andreo, Viet Loan Dao Thi, Xianfang Wu, Caroline E. Gleason, Michelle S. Itano, Gabriella S. Spitz-Becker, Rachel L. Belote, Brenna R. Hedin, Margaret A. Scull, Charles M. Rice, Sanford M. Simon
Secretory cells produce diverse cargoes, yet how they regulate concomitant secretory traffic remains insufficiently explored. Rab GTPases control intracellular vesicular transport. To map secretion pathways, we generated a library of lentivirus-expressed dominant-negative Rab mutants and used it in a large-scale screen to identify regulators of hepatic lipoprotein secretion. We identified several candidate pathways, including those mediated by Rab11 and Rab8. Surprisingly, inhibition of Rab1b, the major regulator of transport from the endoplasmic reticulum to the Golgi, differently affected the secretion of the very-low-density lipoprotein components ApoE and ApoB100, despite their final association on mature secreted lipoprotein particles. Since hepatitis C virus (HCV) incorporates ApoE and ApoB100 into its virus particle, we also investigated infectious HCV secretion and show that its regulation by Rab1b mirrors that of ApoB100. These observations reveal differential regulation of hepatocyte secretion by Rab1b and advance our understanding of lipoprotein assembly and lipoprotein and HCV secretion.

Graphical abstract

Teaser

Takacs et al. show that Rab1b, a major regulator of transport from the endoplasmic reticulum to the Golgi, differentially controls the secretion of lipoprotein components ApoE and ApoB100 and infectious hepatitis C virus particles.


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Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Natalia Edison, Yael Curtz, Nicole Paland, Dana Mamriev, Nicolas Chorubczyk, Tali Haviv-Reingewertz, Nir Kfir, David Morgenstern, Meital Kupervaser, Juliana Kagan, Hyoung Tae Kim, Sarit Larisch
We describe a mechanism by which the anti-apoptotic B cell lymphoma 2 (Bcl-2) protein is downregulated to induce apoptosis. ARTS (Sept4_i2) is a tumor suppressor protein that promotes cell death through specifically antagonizing XIAP (X-linked inhibitor of apoptosis). ARTS and Bcl-2 reside at the outer mitochondrial membrane in living cells. Upon apoptotic induction, ARTS brings XIAP and Bcl-2 into a ternary complex, allowing XIAP to promote ubiquitylation and degradation of Bcl-2. ARTS binding to Bcl-2 involves the BH3 domain of Bcl-2. Lysine 17 in Bcl-2 serves as the main acceptor for ubiquitylation, and a Bcl-2 K17A mutant has increased stability and is more potent in protection against apoptosis. Bcl-2 ubiquitylation is reduced in both XIAP- and Sept4/ARTS-deficient MEFs, demonstrating that XIAP serves as an E3 ligase for Bcl-2 and that ARTS is essential for this process. Collectively, these results suggest a distinct model for the regulation of Bcl-2 by ARTS-mediated degradation.

Graphical abstract

Teaser

Many cancers avoid cell death (apoptosis) by expressing high levels of apoptosis inhibitors, such as Bcl-2. Thus, Bcl-2 is a major target for cancer therapy. Edison et al. describe a mechanism by which the ARTS protein promotes proteasome-mediated degradation of Bcl-2 and thereby stimulates cell death.


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Covalent Modifications of Histone H3K9 Promote Binding of CHD3

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Adam H. Tencer, Khan L. Cox, Luo Di, Joseph B. Bridgers, Jie Lyu, Xiaodong Wang, Jennifer K. Sims, Tyler M. Weaver, Hillary F. Allen, Yi Zhang, Jovylyn Gatchalian, Michael A. Darcy, Matthew D. Gibson, Jinzen Ikebe, Wei Li, Paul A. Wade, Jeffrey J. Hayes, Brian D. Strahl, Hidetoshi Kono, Michael G. Poirier, Catherine A. Musselman, Tatiana G. Kutateladze
Chromatin remodeling is required for genome function and is facilitated by ATP-dependent complexes, such as nucleosome remodeling and deacetylase (NuRD). Among its core components is the chromodomain helicase DNA binding protein 3 (CHD3) whose functional significance is not well established. Here, we show that CHD3 co-localizes with the other NuRD subunits, including HDAC1, near the H3K9ac-enriched promoters of the NuRD target genes. The tandem PHD fingers of CHD3 bind histone H3 tails and posttranslational modifications that increase hydrophobicity of H3K9—methylation or acetylation (H3K9me3 or H3K9ac)—enhance this interaction. Binding of CHD3 PHDs promotes H3K9Cme3-nucleosome unwrapping in vitro and perturbs the pericentric heterochromatin structure in vivo. Methylation or acetylation of H3K9 uniquely alleviates the intra-nucleosomal interaction of histone H3 tails, increasing H3K9 accessibility. Collectively, our data suggest that the targeting of covalently modified H3K9 by CHD3 might be essential in diverse functions of NuRD.

Graphical abstract

Teaser

Tencer et al. find that CHD3 co-localizes with the other subunits of the NuRD complex and H3K9ac at NuRD target genes. The authors further demonstrate that the PHD fingers of CHD3 associate with histone H3 tails, and this association is augmented through methylation or acetylation of H3K9.


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Activation of the p53 Transcriptional Program Sensitizes Cancer Cells to Cdk7 Inhibitors

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Sampada Kalan, Ramon Amat, Miriam Merzel Schachter, Nicholas Kwiatkowski, Brian J. Abraham, Yanke Liang, Tinghu Zhang, Calla M. Olson, Stéphane Larochelle, Richard A. Young, Nathanael S. Gray, Robert P. Fisher
Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer-derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here, we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7^as inhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1, or the more selective YKL-1-116. The effects were allele specific; a CDK7^as mutation conferred both sensitivity to bulky adenine analogs and resistance to covalent inhibitors. Non-transformed colon epithelial cells were resistant to these combinations, as were cancer-derived cells with p53-inactivating mutations. Apoptosis was dependent on death receptor DR5, a p53 transcriptional target whose expression was refractory to Cdk7 inhibition. Therefore, p53 activation induces transcriptional dependency to sensitize cancer cells to Cdk7 inhibition.

Graphical abstract

Teaser

Kalan et al. find that activation of the p53 tumor suppressor protein in human colon cancer-derived cells can induce transcriptional dependency on Cdk7, analogous to constitutive dependencies described in other tumors driven by oncogenic transcription factors. This work provides a proof of concept for combining p53-activating agents with Cdk7 inhibitors to elicit synthetic lethality.


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Erasure of Tet-Oxidized 5-Methylcytosine by a SRAP Nuclease

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Soo-Mi Kweon, Bing Zhu, Yibu Chen, L. Aravind, Shuang-Yong Xu, Douglas E. Feldman
Enzymatic oxidation of 5-methylcytosine (5mC) in DNA by the Tet dioxygenases reprograms genome function in embryogenesis and postnatal development. Tet-oxidized derivatives of 5mC such as 5-hydroxymethylcytosine (5hmC) act as transient intermediates in DNA demethylation or persist as durable marks, yet how these alternative fates are specified at individual CpGs is not understood. Here, we report that the SOS response-associated peptidase (SRAP) domain protein Srap1, the mammalian ortholog of an ancient protein superfamily associated with DNA damage response operons in bacteria, binds to Tet-oxidized forms of 5mC in DNA and catalyzes turnover of these bases to unmodified cytosine by an autopeptidase-coupled nuclease. Biallelic inactivation of murine Srap1 causes embryonic sublethality associated with widespread accumulation of ectopic 5hmC. These findings establish a function for a class of DNA base modification-selective nucleases and position Srap1 as a determinant of 5mC demethylation trajectories during mammalian embryonic development.

Graphical abstract

Teaser

Kweon et al. uncover a function for the SRAP domain, which couples autoproteolytic cleavage to activation of a nuclease selective for DNA containing Tet-oxidized derivatives of 5-methylcytosine. These findings reveal a mechanism for targeted erasure of DNA methylation via the stepwise enzymatic actions of Tet and SRAP.


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Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Sagar R. Shah, Justin M. David, Nathaniel D. Tippens, Ahmed Mohyeldin, Juan C. Martinez-Gutierrez, Sara Ganaha, Paula Schiapparelli, Duane H. Hamilton, Claudia Palena, Andre Levchenko, Alfredo Quiñones-Hinojosa
Molecular factors that define stem cell identity have recently emerged as oncogenic drivers. For instance, brachyury, a key developmental transcriptional factor, is also implicated in carcinogenesis, most notably of chordoma, through mechanisms that remain elusive. Here, we show that brachyury is a crucial regulator of stemness in chordoma and in more common aggressive cancers. Furthermore, this effect of brachyury is mediated by control of synthesis and stability of Yes-associated protein (YAP), a key regulator of tissue growth and homeostasis, providing an unexpected mechanism of control of YAP expression. We further demonstrate that the brachyury-YAP regulatory pathway is associated with tumor aggressiveness. These results elucidate a mechanism of controlling both tumor stemness and aggressiveness through regulatory coupling of two developmental factors.

Graphical abstract

Teaser

Malignant neoplasms exhibit uninhibited and dysregulated growth coupled with acquisition of stem-like properties that are integral to the development and progression of disease. Shah et al. demonstrate a critical role of brachyury in regulating stemness and growth by activating YAP through direct transcriptional and post-transcriptional mechanisms in various cancers.


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Human Organ Chip Models Recapitulate Orthotopic Lung Cancer Growth, Therapeutic Responses, and Tumor Dormancy In Vitro

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Bryan A. Hassell, Girija Goyal, Esak Lee, Alexandra Sontheimer-Phelps, Oren Levy, Christopher S. Chen, Donald E. Ingber
Here, we show that microfluidic organ-on-a-chip (organ chip) cell culture technology can be used to create in vitro human orthotopic models of non-small-cell lung cancer (NSCLC) that recapitulate organ microenvironment-specific cancer growth, tumor dormancy, and responses to tyrosine kinase inhibitor (TKI) therapy observed in human patients in vivo. Use of the mechanical actuation functionalities of this technology revealed a previously unknown sensitivity of lung cancer cell growth, invasion, and TKI therapeutic responses to physical cues associated with breathing motions, which appear to be mediated by changes in signaling through epidermal growth factor receptor (EGFR) and MET protein kinase. These findings might help to explain the high level of resistance to therapy in cancer patients with minimal residual disease in regions of the lung that remain functionally aerated and mobile, in addition to providing an experimental model to study cancer persister cells and mechanisms of tumor dormancy in vitro.

Graphical abstract

Teaser

Hassell et al. demonstrate that, when human lung cancer cells are grown within organ-on-a-chip culture devices that mimic lung structure and function, tumor cells recapitulate tumor growth and invasion patterns, as well as responses to therapy, observed in human patients. They also discover that breathing motions influence these responses.


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Self-Organized Cerebral Organoids with Human-Specific Features Predict Effective Drugs to Combat Zika Virus Infection

Publication date: 10 October 2017
Source:Cell Reports, Volume 21, Issue 2
Author(s): Momoko Watanabe, Jessie E. Buth, Neda Vishlaghi, Luis de la Torre-Ubieta, Jiannis Taxidis, Baljit S. Khakh, Giovanni Coppola, Caroline A. Pearson, Ken Yamauchi, Danyang Gong, Xinghong Dai, Robert Damoiseaux, Roghiyh Aliyari, Simone Liebscher, Katja Schenke-Layland, Christine Caneda, Eric J. Huang, Ye Zhang, Genhong Cheng, Daniel H. Geschwind, Peyman Golshani, Ren Sun, Bennett G. Novitch
The human cerebral cortex possesses distinct structural and functional features that are not found in the lower species traditionally used to model brain development and disease. Accordingly, considerable attention has been placed on the development of methods to direct pluripotent stem cells to form human brain-like structures termed organoids. However, many organoid differentiation protocols are inefficient and display marked variability in their ability to recapitulate the three-dimensional architecture and course of neurogenesis in the developing human brain. Here, we describe optimized organoid culture methods that efficiently and reliably produce cortical and basal ganglia structures similar to those in the human fetal brain in vivo. Neurons within the organoids are functional and exhibit network-like activities. We further demonstrate the utility of this organoid system for modeling the teratogenic effects of Zika virus on the developing brain and identifying more susceptibility receptors and therapeutic compounds that can mitigate its destructive actions.

Graphical abstract

Teaser

Cerebral organoids recapitulate many aspects of human corticogenesis and are a useful platform for modeling neurodevelopmental mechanisms and diseases. Watanabe et al. describe enhanced organoid methods and model ZIKV pathology. More susceptibility receptors for ZIKV are identified, and differential effects of various compounds to mitigate ZIKV-induced cytopathy are demonstrated.


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Effects of 445-nm Diode Laser-Assisted Debonding of Self-Ligating Ceramic Brackets on Shear Bond Strength

Photomedicine and Laser Surgery , Vol. 0, No. 0.


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Firearm Projectile in the Maxillary Tuberosity Located by Adjunctive Examination of Wide-Field Optical Fluorescence

Photomedicine and Laser Surgery , Vol. 0, No. 0.


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Targeting Aging with Functional Food: Pasta with Opuntia Single-Arm Pilot Study

Rejuvenation Research , Vol. 0, No. 0.


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Gastrointestinal perforation related to lenvatinib, an anti-angiogenic inhibitor that targets multiple receptor tyrosine kinases, in a patient with metastatic thyroid cancer

Summary

Lenvatinib, a novel potent multikinase inhibitor, was approved for the treatment of radioiodine-refractory differentiated thyroid cancer based on results from phase III trial (SELECT study). Thyroid cancer is a diverse disease that includes anaplastic thyroid cancer (ATC), which the most aggressive form of the disease, although it accounts for <2% of all thyroid cancers. Current treatments for ATC have limited efficacy. We report the case of a woman with recurrent well-differentiated papillary carcinoma of the thyroid that had transformed into ATC who developed a perforation of the small intestine secondary to a marked effect of lenvatinib. She received lenvatinib (24 mg once a day) at only two doses during two weeks due to pleurodesis with talc for malignant pleural effusion. Eventually, she developed peritonitis due to the perforation and died of sepsis. However, an autopsy revealed marked efficacy of lenvatinib for ATC at a metastatic site in the small intestine despite limited exposure to the drug. Here, we report on our experience with lenvatinib treatment and gastrointestinal perforation concerning anti-angiogenic therapy.

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Mechanisms and implications of ADAR-mediated RNA editing in cancer

Publication date: 28 December 2017
Source:Cancer Letters, Volume 411
Author(s): Chen Wang, Jun Zou, Xiangyi Ma, Edward Wang, Guang Peng
Adenosine deaminases acting on RNA (ADARs) are enzymes that catalyze the conversion of adenosine (A) to inosine (I) in double-stranded RNAs. Inosine exhibits similar properties as guanosine. As a result, A-to-I editing has a great impact on edited RNAs, not only affecting the base pairing properties, but also altering codons after translation. A-to-I editing are known to mediate and diversify transcripts. However, the overall biological effect of ADARs are still largely unknown. Aberrant ADAR activity and editing dysregulation are present in a variety of cancers, including hepatocellular carcinoma, chronic myelogenous leukemia, glioblastoma and melanoma. ADAR-mediated A-to-I editing can influence uncontrolled nucleotide changes, resulting in susceptibility of cells to developmental defects and potential carcinogenicity. A deeper understanding of the biological function of ADARs may provide mechanistic insights in the development of new cancer therapy. Here, we discuss recent advances in research on ADAR in detail including the structure and function of ADARs, the biochemistry of ADAR-mediated RNA editing, and the relevance of ADAR proteins in cancer.



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HSP90 inhibitor (NVP-AUY922) enhances the anti-cancer effect of BCL-2 inhibitor (ABT-737) in small cell lung cancer expressing BCL-2

Publication date: 28 December 2017
Source:Cancer Letters, Volume 411
Author(s): Hannah Yang, Mi-Hee Lee, Intae Park, Hanwool Jeon, Junyoung Choi, Seyoung Seo, Sang-We Kim, Gou Young Koh, Kang-Seo Park, Dae Ho Lee
Small cell lung cancer (SCLC) cannot be efficiently controlled using existing chemotherapy and radiotherapy approaches, indicating the need for new therapeutic strategies. Although ABT-737, a B-cell lymphoma-2 (BCL-2) inhibitor, exerts anticancer effects against BCL-2-expressing SCLC, monotherapy with ABT-737 is associated with limited clinical activity because of the development of resistance and toxicity. Here, we examined whether combination therapy with ABT-737 and heat shock protein 90 (HSP90) inhibitor NVP-AUY922 exerted synergistic anticancer effects on SCLC. We found that the combination of ABT-737 and NVP-AUY922 synergistically induced the apoptosis of BCL-2-expressing SCLC cells. NVP-AUY922 downregulated the expression of AKT and ERK, which activate MCL-1 to induce resistance against ABT-737. The synergistic effect was also partly due to blocking NF-κB activation, which induces anti-apoptosis protein expressions. However, interestingly, targeting BCL-2 and MCL-1 or BCL2 and NF-κB did not induce the cytotoxicity. In conclusion, our study showed that combination of BCL2 inhibitor with HSP90 inhibitor increased activity in in vitro and in vivo study in only BCL-2 expressing SCLC compared to either single BCL2 inhibitor or HSP inhibitor. The enhanced activity might be led by blocking several apoptotic pathways simultaneously rather than a specific pathway.



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Integrating T cell metabolism in cancer immunotherapy

Publication date: 28 December 2017
Source:Cancer Letters, Volume 411
Author(s): Erica Dugnani, Valentina Pasquale, Carlotta Bordignon, Adriana Canu, Lorenzo Piemonti, Paolo Monti
Activation and maintenance of the T cell response occurs concurrently with metabolic reprogramming. This ensures the T cell response is supported by sufficient energy and substrates necessary for cell survival, growth and proliferation. Different metabolic programs are associated with differentiation into different cell subsets, effector function and development of long-lasting memory. This provides an opportunity to improve the T cell response through manipulation of metabolism, which is instrumental to ameliorate the current protocols for cancer immunotherapy. Using drugs and molecules targeting selective metabolic pathways it is now possible to generate T cells that can mount a durable and stable anti-tumor response. On the other hand, cancer cells can take advantage of the metabolic requirements of T cells to evade the immune response. In this brief review we discuss recent findings of T cell metabolism in quiescence and activation, how the tumor microenvironment can affect T cell metabolism, and how T cell metabolism can be manipulated to improve the T cell response to tumors.



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Pharmacological evidence for the bone-autonomous contribution of the NFκB/β-catenin axis to breast cancer related osteolysis

Publication date: 1 December 2017
Source:Cancer Letters, Volume 410
Author(s): Silvia Marino, Ryan T. Bishop, John G. Logan, Patrick Mollat, Aymen I. Idris
The NFκB signaling pathway is implicated in breast cancer and bone metastasis. However, the bone-autonomous contribution of NFκB to breast cancer-induced osteolysis is poorly understood. Here, we report that pretreatment of osteoblasts with the sesquiterpene lactone Parthenolide (PTN), a verified NFκB inhibitor, prior to exposure to conditioned medium from human and mouse breast cancer cell lines enhanced osteoblast differentiation and reduced osteoblast ability to stimulate osteoclastogenesis. PTN prevented breast cancer-induced osteoclast formation and reduced the ability of breast cancer cells to prolong osteoclast survival and to inhibit osteoclast apoptosis. In vivo, administration of PTN in immuno-competent mice reduced osteolytic bone loss and skeletal tumour growth following injection of the syngeneic 4T1-BT1 cells and reduced local osteolysis caused by conditioned medium from human and mouse osteotropic breast cancer cell lines. Mechanistic studies revealed that NFκB inhibition by PTN in osteoblasts and osteoclasts was accompanied by a significant increase in β-catenin activation and expression. Collectively, these results raise the possibility that combined targeting of NFκB and β-catenin signalling in the tumour microenvironment may be of value in the treatment of breast cancer related osteolysis.



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Fundraiser for Syrian refugee to practice dentistry in Norwich

Anas, a refugee who fled Syria in 2015, is raising funds to help him convert his dentistry qualification into one which is recognised in the UK. Before leaving his home after being targetted by conflict sides in Syria, who were aiming at medical proffesionals, Anas studied at the University of Damascus.

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Effect of desiccant system on thin layer drying kinetics of corn

Abstract

Drying is one of the most important post-harvest processes for reducing the moisture content of agricultural products and improving their performance has obvious benefits. Most dryers are convective type in which hot air is used for reduction of product moisture content. Effect of adding a desiccant unit to a re-circulating convective dryer on thin layer drying kinetics of corn kernels is reported here. The influence of the desiccant unit, drying temperature and flow rate on drying time, moisture diffusivity coefficient and reactivation energy were investigated. The experiments were conducted at air temperatures of 50, 60 and 70 °C and flow rates of 1, 1.4 and 1.8 kg/min with and without the desiccant unit. Results showed that the use of the desiccant wheel decreased drying time by 9.75% and increased drying rate by 7.85%. Application of a Logarithmic model for fitting the data, while being simple, resulted in good statistical indexes (R² and RMSE). Moisture diffusivity coefficient was obtained to be in the 3.47258 × 10⁻¹¹ to 8.18826 × 10⁻¹¹ m²/s range, while activation energy varied between 14.2931 and 17.6770 kJ/mol on the average. Therefore, utilization of the desiccant unit accelerates moisture extraction from corn samples.

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The role of cognitive reserve in cognitive aging: what we can learn from Parkinson’s disease

Abstract

Parkinson's disease (PD) typically occurs in elderly people and some degree of cognitive impairment is usually present. Cognitive reserve (CR) theory was proposed to explain the discrepancy between the degree of brain pathologies and clinical manifestations. We administered a comprehensive neuropsychological battery to 35 non-demented participants affected by PD. All participants underwent also the Cognitive Reserve Index questionnaire and the Brief Intelligence Test as proxies for CR. Relationships between CR and cognitive performance were investigated by linear regression analyses, adjusting for significant confounding factors. At linear regression analyses, higher CR scores were independently associated with a better performance on Word Fluency (p ≤ 0.04) and Digit Span (backward) (p ≤ 0.02); no associations were observed between CR and other cognitive tests. Our data provide empirical support to the relation between CR and cognitive impairment in PD. In particular, this study suggests that CR may have greater effects on the cognitive areas mostly affected in PD as executive functions.

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Hypoxic volume evaluated by 18F-fluoromisonidazole positron emission tomography (FMISO-PET) may be a prognostic factor in patients with oral squamous cell carcinoma: preliminary analyses

This study evaluated the relationships between these PET parameters and 5-year survival in OSCC patients. Twenty-three patients (age 42 –84 years; 15 male, eight female) with OSCC underwent FMISO- and 18F-fluoro-2-deoxyglucose (FDG)-PET computed tomography before surgery. (Source: International Journal of Oral and Maxillofacial Surgery)

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The trajectory of positive psychological change in a head and neck cancer population

A stressful event may be sufficient to challenge a strongly held set of assumptions about the world and the self. In some people this may lead to post-traumatic stress disorder (PTSD) and in others to positive psychological change (PPC), whereby a person 's reactions to the challenge are beneficial. Little research has investigated PPC in people who have had head and neck cancer (HNC). The aim of this study was to identify demographic, clinical, and psychological factors associated with PPC over time. (Source: International Journal of Oral and Maxillofacial Surgery)

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SPECT bone scintigraphy for the assessment of condylar growth activity in mandibular asymmetry: is it accurate?

The comparison of serial radiographs and clinical photographs is considered the current accepted standard for the diagnosis of active condylar hyperplasia in patients with facial asymmetry. Single photon emission computed tomography (SPECT) has recently been proposed as an alternative method. SPECT can be interpreted using three reported methods absolute difference in uptake, uptake ratio, and relative uptake. SPECT findings were compared to those from serial comparisons of radiographs and clinical photographs taken at the time of SPECT and a year later; the sensitivities and specificities were determined. (Source: International Journal of Oral and Maxillofacial Surgery)

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Intrasinusal locking technique: a novel use of the ring block technique at sinus perforations for simultaneous implant placement

Ten patients who underwent sinus lift surgery with simultaneous implant placement using the intrasinusal locking technique were evaluated retrospectively. All patients were scheduled for sinus floor elevation procedures with simultaneous implant placement. Schneiderian membrane perforation occurred during the lifting procedure, and conventional methods failed to repair the perforation. Therefore, an autogenous bone ring was placed at the base of the maxillary sinus and was locked to the alveolar crest with a dental implant. (Source: International Journal of Oral and Maxillofacial Surgery)

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Erythrokeratoderma - a manifestation associated with multiple types of ichthyoses with different gene defects

Erythrokeratoderma (OMIM #133200) refers to a group of closely related disorders of cornification manifesting with hyperkeratotic, often transient and migratory, erythematous figurate plaques with sharply demarcated borders that typically develop in early childhood with or without palmoplantar involvement.¹ Erythrokeratodermas have been historically classified into the two main categories: (a) erythrokeratodermia variabilis et progressiva (EKVP, also known as erythrokeratoderma figurata variabilis and Mendes da Costa disease), and (b) progressive symmetric erythrokeratoderma (PSEK, also known as Gottron syndrome).

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The optimal regimen of brentuximab vedotin for CD30+ cutaneous lymphoma: Are we there yet?

Brentuximab vedotin (BV) is an anti-CD30 antibody–drug conjugate that is approved for refractory Hodgkin lymphoma and systemic anaplastic large-cell lymphoma. In the ALCANZA trial, the proportion of CD30+ cutaneous T-cell lymphoma (CTCL) patients achieving an objective response lasting at least 4 months was 56.3% with BV versus 12.5% with conventional therapy (oral methotrexate or bexarotene), and progression-free survival, complete response rate and improvement in symptom burden were significantly improved.¹ As in previous studies, 1.8 mg/kg dose was administered every 3 weeks in this study.^1,2 We routinely use this regimen that has been well studied in clinical trials, starting with 1.8 mg/kg and decrease to 1.2 mg/kg if needed. The safety profile for BV is similar to conventional therapies and although peripheral neuropathy occurs in 67%, it usually resolves or improves after cessation or completion of treatment.¹

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Sperm counts, testicular cancers, and the environment

A recent meta-analysis by Levine and colleagues1 showing significant declines in sperm counts among men in the Western world caught considerable media attention.2 The Levine study followed a similar...

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Comparison of postoperative outcomes among patients treated by male and female surgeons: a population based matched cohort study

Objective To examine the effect of surgeon sex on postoperative outcomes of patients undergoing common surgical procedures.Design Population based, retrospective, matched cohort study from 2007 to...

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#ILookLikeASurgeon: embracing diversity to improve patient outcomes

Over the two years since it began1 #ILookLikeASurgeon, an online campaign celebrating women in surgery, has been included in over 150 000 tweets by over 35 000 users, making nearly a billion...

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Improving patient outcomes after surgery

Factors associated with variation in outcome after surgery have been a topic of major interest for the past 20 years. By far the most explored is the relation between case volume and outcome....

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