Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA).
Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane Review first published in 2010 and previously updated in 2014. To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) compared with non-surgical treatment in the management of children with PFAPA. The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL 2019, Issue 4); PubMed; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 15 October 2019. Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA. We used the standard methodological procedures expected by Cochrane. The primary outcomes were the proportion of children whose symptoms have completely resolved and complications of surgery (haemorrhage and number of days of postoperative pain). Secondary outcomes were: number of episodes of fever and the associated symptoms; severity of episodes; use of corticosteroids; absence or time off school; quality of life. We used GRADE to assess the certainty of the evidence for each outcome. Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias. One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months. Combining the trial results suggests that patients with PFAPA likely experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution) (moderate-certainty evidence). Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Surgery probably results in a large overall reduction in the average number of episodes over the total length of follow-up (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years (moderate-certainty evidence). Surgery also likely reduces severity, as indicated by the length of PFAPA symptoms during these episodes. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group (moderate-certainty evidence). The evidence suggests that the proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92) (low-certainty evidence). Other outcomes such as absence from school and quality of life were not measured or reported. The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate certainty (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.


Outcome of African-American compared to White-American patients with early-stage breast cancer, stratified by phenotype.
Breast cancer mortality rates are 39% higher in the African-American (AA) women compared to White-American (WA) women despite the advances in overall breast cancer screening and treatments. Several studies have undertaken to identify the factors leading to this disparity in United States with possible effects of lower socioeconomic status and underlying aggressive biology. A retrospective analysis was done using a prospectively maintained database of a metropolitan health system. Patients were selected based on diagnosis of early-stage breast cancer between 10/1998 and 02/2017, and included women over age of 18 with clinically node-negative disease. Patients were then stratified by phenotype confirmed by pathology and patient-identified race. A total of 2,298 women were identified in the cohort with 39% AA and 61% WA women. The overall mean age at the time of diagnosis for AA women was slightly younger at 60 years compared to 62 years for WA women (p = 0.003). Follow-up time was longer for the WA women at 95 months vs. 86 months in AA women. The overall 5-year survival was analyzed for the entire cohort, with the lowest survival occurring in patients with triple-negative breast cancer (TNBC). Phenotype distribution revealed a higher incidence of TNBC in AA women compared to WA women (AA 16% vs. WA 10%; p < 0.0001). AA women also had higher incidence of HER2 positive cancers (AA 16.8% vs. WA 15.3%; p < 0.0001). WA women had a significantly higher distribution of Non-TNBC/HER2-negative phenotype (AA 55% vs. WA 65%; p < 0.0001). Furthermore, a subgroup analysis was done for a sentinel lymph node (SLN) negative cohort that showed higher rates of grade 3 tumors in AA (AA 35% vs. WA 23%; p < 0.0001); and higher rates of grade 1 and grade 2 tumors in WA (30% vs. 21% and 44% vs. 40%). Despite higher grade tumors in AA women, five-year overall survival outcomes in SLN-negative cohort did not differ between AA and WA women when stratifying based on tumor subtype. Breast cancer survival disparities in AA and WA women with SLN-negative breast cancer are diminished when evaluated at early-stage cancers defined by SLN-negative tumors. Our evaluation suggests that when diagnosed early, phenotype does not contribute to racial survival outcomes. The lower survival rate in AA women with breast cancer may be attributed to later stage biology between the two races, or underlying socioeconomic disparities.


An Empirical Evaluation of Force Feedback in Body-Powered Prostheses.
Myoelectric prostheses have many advantages over body-powered prostheses, yet the absence of sensory feedback in myoelectric devices is one reason body-powered devices are often preferred by amputees. While considerable progress has been made in the mechanical design and control of myoelectric prostheses, research on haptic feedback has not had a similar impact. In this study, we seek to develop a fundamental understanding of the utility of force feedback and vision in the functional operation of a body-powered upper-limb prosthesis. Using a custom body-powered prosthesis in which force feedback can be conditionally removed, we asked N=10 non-amputee participants to identify objects based on stiffness in four separate conditions with and without visual and/or force feedback. Results indicate that the combination of visual and force feedback allows for the best accuracy, followed by force feedback only, then visual feedback only. In addition, combining force feedback with visual feedback does not significantly affect identification timing compared to visual feedback alone. These findings suggest that consideration should be given to the development of force feedback displays for myoelectric prostheses that function like a Bowden cable, coupling the amputee's control input to the resulting feedback.


Honey-Propolis-Engineered Collagen Peptides as Promising Wound-Healing Matrix in Mouse Model.
In this study, collagen hydrolysates (CHDs) were fabricated with honey-propolis wax (HPW), structurally modified as a sponge matrix, and experimentalized on wound healing in a mouse model. The scaffold was characterized by means of in vitro enzymatic degradation; in vitro HPW release; and in vivo wound-healing mouse model, wound-healing-specific RNA, transcripts, and protein markers. The functional activity of the HPW extracted from raw propolis was determined using total flavonoids, antioxidant scavenging assays, and anti-hemolytic principles. The results indicated that HPW had a high flavonoid content (20 μg/mL of wax) and antioxidant activities. The effective concentration (EC50) of HPW was estimated (28 mg/mL) and was then used in the subsequent in vivo experiments. Additionally, the dopped mixture of CHDs and HPW substantially enhanced the wound-healing process and regulated wound biochemical markers such as hexoseamine and melondialdehyde. CHDs- HPW upregulated the expression of growth factors including vascular endothelial growth factor (VEGF) (2.3-fold), fibroblast growth factor (FGF) and epidermal growth factor (EGF) (1.7-fold), and transforming growth factor-beta (TGF-β) (3.1-fold), indicating their potential capacity to perform wound re-epithelialization and the loading of ground tissue. Pro-inflammatory markers IL-1 β (51 pg/mL) and TNF-α (220 pg/mL) were significantly reduced in the CHD-HPW-treated wound. These interesting results were further confirmed using mRNA and protein growth factors from the wound, which enhanced the load of collagen-I in the wound site. In conclusion, CHDs-HPW exhibited a significant reduction in inflammation and inflammatory markers and helped to obtain a faster wound-healing process in a mouse model. The newly engineered biosponge could be developed as a promising therapeutic approach for the regeneration and repair of damaged human skin in the future.


BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib.
Olaparib (AZD-2281, Ku-0059436) is an orally bioavailable and well-tolerated poly(ADP-ribose) polymerase (PARP) inhibitor currently under investigation in patients with solid tumors. To study the clinical potential of olaparib as a single-agent for the treatment of acute myeloid leukemia (AML) patients, we analyzed the in vitro sensitivity of AML cell lines and primary blasts. Clinically achievable concentrations of olaparib were able to induce cell death in the majority of primary AML case samples (88%) and tested cell lines. At these concentrations, olaparib preferentially killed leukemic blasts sparing normal lymphocytes derived from the same patient and did not substantially affect the viability of normal bone marrow and CD34-enriched peripheral blood cells obtained from healthy donors. Most primary AML analyzed were characterized by low BRCA1 mRNA level and undetectable protein expression that likely contributed to explain their sensitivity to olaparib. Noteworthy, while PARP1 over-expression was detected in blasts not responsive to olaparib, phosphorylation of the histone H2AFX (γH2AX) was associated with drug sensitivity. As to genetic features of tested cases the highest sensitivity was shown by a patient carrying a 11q23 deletion. The high sensitivity of AML blasts and the identification of biomarkers potentially able to predict response and/or resistance may foster further investigation of olaparib monotherapy for AML patients unfit to conventional chemotherapy.


[Evaluation of effectiveness of whole-body cryotherapy in patients with tinnitus].
The aim of the study was evaluation of effectiveness of whole-body cryotherapy in patients with tinnitus. The research was carried out in 120 patients (aged 20-68) with tinnitus, divided into two groups: I--80 patients treated by cryotherapy and II--40 patients non treated. There were: 73 women and 47 men. Among patients of I group: 39 reported bilateral tinnitus, 20 reported right tinnitus, 15 reported left tinnitus and 6 reported tinnitus in head. Duration of the ailment took from 1 month to 23 years. The methods included: taking a history, otolaryngological physical examination, audiometry establishing level of tinnitus, medical consultation, X-ray examination of chest and cervical spine and CT of head. After examinations and additional consultations the patients were qualified for cryotherapy unless there were some contraindications. The patients underwent 10 procedures in two cycles with the weekend break. They were in cryochamber in temperature of -110 degrees C for 3 minutes. After cryotherapy they used kinesitherapy for 45 minutes. Intensity and troublesomeness of tinnitus was evaluated using self-assessment chart (point scale 0-100) and audiometry establishing level of tinnitus before and after treatment. The results indicates complete elimination of tinnitus in 4 patients, decrease in their intensity in 47 patients, maintenance of the ailment on the same level in 13 people and slightly increase of tinnitus in 16 patients. In audiometry we could observe in I group changes in frequency of tinnitus in 138 ears and changes in intensity of tinnitus in 91 ears. After treatment decrease of average hearing loss and average hearing damage were observed. Treatment of tinnitus may be effective by using whole-body cryotherapy.


1,25-dihydroxyvitamin D3-treated hypoparathyroidism: 35 patients years in 10 children.
Ten hormone-deficient hypoparathyroid children have been successfully treated with orally administered 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] within a dose range of 0.01--0.10 microgram/kg . day for a total of 35 patient yr. Resistance to 1,25-(OH)2D3 therapy was not observed. By monitoring the blood ionized calcium level (normal range, 4.05--5.14 mg/dl) at monthly intervals, 8 hypercalcemic and 10 hypocalcemic episodes were recognized during the entire treatment experience, though the patients were asymptomatic. In the former cases, cessation of treatment for 3 days resulted in normocalcemia; in the latter, half of the episodes were transient and related to intercurrent febrile illnesses. The remaining hypocalcemic occurrences responded to an increase in the dosage of 1,25-(OH)2D3. During 1,25-(OH)2D3 treatment, the mean ionized calcium level for individual patients ranged from 4.04--4.39 mg/dl. Urinary Ca excretion, expressed as a ratio of calcium to creatinine, ranged from 0.177--0.244. Twenty-four-hour mean levels of serum 1,25-(OH)2D did not correlate with the blood ionized calcium concentration in 4 patients who underwent sequential blood sampling every 1--2 h for a total of 59 time points (r = 0.05; P greater tha 0.10). To elucidate the temporal relationship between hormonal and mineral responses to exogenous PTH, we administered bovine PTH to four untreated hypoparathyroid children. Serum concentrations of PTH increased before the rise in ionized calcium, which in turn preceded the elevation in circulating 1,25-(OH)2D. This order was followed also in the fall in serum concentrations of these blood constituents to pre-PTH infusion values. These results indicate responsiveness of the l alpha-hydroxylase enzyme to exogenous PTH in hormone-deficient hypoparathyroid children.


Systems biology of the autophagy-lysosomal pathway.
The mechanisms of the control and activity of the autophagy-lysosomal protein degradation machinery are emerging as an important theme for neurodevelopment and neurodegeneration. However, the underlying regulatory and functional networks of known genes controlling autophagy and lysosomal function and their role in disease are relatively unexplored. We performed a systems biology-based integrative computational analysis to study the interactions between molecular components and to develop models for regulation and function of genes involved in autophagy and lysosomal function. Specifically, we analyzed transcriptional and microRNA-based post-transcriptional regulation of these genes and performed functional enrichment analyses to understand their involvement in nervous system-related diseases and phenotypes. Transcriptional regulatory network analysis showed that binding sites for transcription factors, SREBP1, USF, AP-1 and NFE2, are common among autophagy and lysosomal genes. MicroRNA enrichment analysis revealed miR-130, 98, 124, 204 and 142 as the putative post-transcriptional regulators of the autophagy-lysosomal pathway genes. Pathway enrichment analyses revealed that the mTOR and insulin signaling pathways are important in the regulation of genes involved in autophagy. In addition, we found that glycosaminoglycan and glycosphingolipid pathways also make a major contribution to lysosomal gene regulation. The analysis confirmed the known contribution of the autophagy-lysosomal genes to Alzheimer and Parkinson diseases and also revealed potential involvement in tuberous sclerosis, neuronal ceroidlipofuscinoses, sepsis and lung, liver and prostatic neoplasms. To further probe the impact of autophagy-lysosomal gene deficits on neurologically-linked phenotypes, we also mined the mouse knockout phenotype data for the autophagylysosomal genes and found them to be highly predictive of nervous system dysfunction. Overall this study demonstrates the utility of systems biology-based approaches for understanding the autophagy-lysosomal pathways and gaining additional insights into the potential impact of defects in these complex biological processes.


The characteristics of acute aortic dissection among young Chinese patients: a comparison between Marfan syndrome and non-Marfan syndrome patients.
Aortic dissection (AoD) is one of the most common catastrophes involving the aorta. Nevertheless, early diagnosis remains to be a challenge in the Emergency Department (ED), particularly in young individuals. In this study, we attempted to identify the characteristics of acute AoD among young individuals, particular in patients with Marfan syndrome. This was an retrospective chart-review study conducted in a tertiary referring hospital. The hospital database was queried for the combination of AoD and patients under age of 40 years. The medical charts were reviewed to obtain demographic data, clinical data and laboratory characteristics by using a standardized data collection sheet. A comparison between Marfan syndrome and non-Marfan syndrome patients was performed. During the 10-years period, 18 of 344 patients with acute AoD were younger than 40 years-old. Patients with Marfan syndrome developed acute AoD at a younger age than patients without Marfan syndrome. The mean diastolic blood pressure was significantly lower in patients with Marfan syndrome upon presenting to the ED than those without. Patients with Marfan syndrome had trends toward higher risk of development of type A AoD, increased recurrence rate and higher mortality rate than those without. However, statistical significance was not present. ED physicians should have high alert to acute AoD in young patients presenting with severe unexplained chest and back pain, particularly in those patients with a history of heart diseases, hypertension, and Marfan syndrome or featuring Marfanoid habitus. Acute coronary syndrome, unexplained abdominal symptoms, and sudden cardiac arrest could be the initial manifestation of AoD in young patients. A low threshold to perform enhanced computed tomography may facilitate early diagnosis and timely treatment in this patient population.


The trigeminocervical complex and migraine: current concepts and synthesis.
Neurones in the trigeminocervical complex are the major relay neurones for nociceptive afferent input from the meninges and cervical structures; therefore, they are the neural substrates of head pain. This review highlights the importance of two basic mechanisms in headache physiology: convergence of nociceptive afferents and sensitization of trigeminocervical neurones. These physiologic findings have clinical correlates such as hypersensitivity and spread and referral of pain frequently seen in patients with primary headache, such as migraine. Special reference is made to the influence of structures from the upper cervical spine in generating and contributing to migraine headaches. The pathophysiology and functional relevance of these basic mechanisms to headaches is discussed in the context of recent experimental findings with regard to pain processing.


Comprehensive transcriptome analysis provides new insights into nutritional strategies and phylogenetic relationships of chrysophytes.
Chrysophytes are protist model species in ecology and ecophysiology and important grazers of bacteria-sized microorganisms and primary producers. However, they have not yet been investigated in detail at the molecular level, and no genomic and only little transcriptomic information is available. Chrysophytes exhibit different trophic modes: while phototrophic chrysophytes perform only photosynthesis, mixotrophs can gain carbon from bacterial food as well as from photosynthesis, and heterotrophs solely feed on bacteria-sized microorganisms. Recent phylogenies and megasystematics demonstrate an immense complexity of eukaryotic diversity with numerous transitions between phototrophic and heterotrophic organisms. The question we aim to answer is how the diverse nutritional strategies, accompanied or brought about by a reduction of the plasmid and size reduction in heterotrophic strains, affect physiology and molecular processes. We sequenced the mRNA of 18 chrysophyte strains on the Illumina HiSeq platform and analysed the transcriptomes to determine relations between the trophic mode (mixotrophic vs. heterotrophic) and gene expression. We observed an enrichment of genes for photosynthesis, porphyrin and chlorophyll metabolism for phototrophic and mixotrophic strains that can perform photosynthesis. Genes involved in nutrient absorption, environmental information processing and various transporters (e.g., monosaccharide, peptide, lipid transporters) were present or highly expressed only in heterotrophic strains that have to sense, digest and absorb bacterial food. We furthermore present a transcriptome-based alignment-free phylogeny construction approach using transcripts assembled from short reads to determine the evolutionary relationships between the strains and the possible influence of nutritional strategies on the reconstructed phylogeny. We discuss the resulting phylogenies in comparison to those from established approaches based on ribosomal RNA and orthologous genes. Finally, we make functionally annotated reference transcriptomes of each strain available to the community, significantly enhancing publicly available data on Chrysophyceae. Our study is the first comprehensive transcriptomic characterisation of a diverse set of Chrysophyceaen strains. In addition, we showcase the possibility of inferring phylogenies from assembled transcriptomes using an alignment-free approach. The raw and functionally annotated data we provide will prove beneficial for further examination of the diversity within this taxon. Our molecular characterisation of different trophic modes presents a first such example.


Effect of acute kidney injury on long-term mortality in patients with ST-segment elevation myocardial infarction complicated by cardiogenic shock who underwent primary percutaneous coronary intervention in a high-volume tertiary center.
Acute kidney injury (AKI) is a reflection of both renal and cardiac reserve in patients with ST-segment elevation myocardial infarction (STEMI), but there is a lack of evidence related to the effect of AKI on long-term mortality in patients with STEMI. This study was an investigation of the prognostic value of AKI for long-term mortality in patients with STEMI complicated by cardiogenic shock (CS) and primary percutaneous coronary intervention (PPCI). This retrospective analysis evaluated the long-term prognostic impact of AKI on 492 patients with STEMI complicated by CS who were treated with PPCI. AKI was defined as ≥0.3mg/dL increase in serum creatinine within 48 hours or a ≥50% increase in serum creatinine in 7 days, or a reduction in urine output (documented oliguria of less than 0.5mL/kg per hour >6 hours. Patients were grouped according to the incidence of AKI and long-term mortality was compared. Cox regression analysis was used to determine independent prognostic factors of long-term mortality. In Cox regression analysis, the age- and sex- adjusted hazard ratios (HRs) were higher for all-cause mortality in patients with AKI. [HR: 4.556; 95% confidence interval: (CI) 2.370-8.759]. After adjustment for confounding variables, the relative risk was greater for patients with AKI in comparison with patients without AKI (HR: 2.207; 95% CI: 1.150-4.739). Age (HR: 1.060, 95% CI: 1.027-1.094; p<0.001), left ventricular ejection fraction (HR: 0.952, 95% CI: 0.916-0.989; p=0.012), blood urea nitrogen level (HR: 1.019, 95% CI: 1.005-1.034; p=0.010), and AKI (HR: 2.244, 95% CI: 1.077-4.676; p=0.031) were found to be independent factors to determine long-term mortality. The results of this study demonstrated that AKI was an independent prognostic factor for long-term mortality among patients with STEMI complicated by CS and treated with PPCI.


Panic disorder, autonomic nervous system and dissociation - changes during therapy.
Alarming somatic symptoms and in particular the cardiovascular symptoms, are the characteristic features of panic attacks. Increased cardiac mortality and morbidity have been proposed in these patients. Power spectral analysis of electrocardiogram R-R intervals is known to be a particularly successful tool in the detection of autonomic instabilities in various clinical disorders. Heart rate variability (HRV) has been found to be the outcome of rapidly reacting cardiovascular control systems. The aim of our study is to measure very low frequency band (VLF), low frequency band (LF) and high frequency band (HF) components of R-R interval during orthostatic experiment in patients with panic disorder before and after treatment and compares it with healthy controls. We assessed heart rate variability in 19 patients with panic disorder before and after 6-weeks treatment with antidepressants combined with cognitive behavioral therapy (CBT) and in 18 healthy controls. Diagnosis was done according to the ICD-10 research diagnostic criteria confirmed with MINI (MINI international neuropsychiatric interview). Patients were treated with CBT and psychotropics. They were regularly every week assessed using CGI (Clinical Global Impression), BAI (Beck Anxiety Inventory) and BDI (Beck Depression Inventory). Heart rate variability was assessed during 3 positions (1st - 5 min supine; 2nd - 5 min standing; 3rd - 5 min supine) before and after the treatment. Power spectra were computed for very low frequency - VLF (0.0033-0.04 Hz), low-frequency - LF (0.04-0.15 Hz) and high frequency - HF (0.15-0.40 Hz) bands using fast Fourier transformation. Nineteen panic disorder patients resistant to pharmacological treatment entered a 6-week open-label treatment study with combination of SSRI and CBT. The combination of CBT and pharmacotherapy proved to be an effective treatment in these patients. The patients significantly improved during the study period in all rating scales. There were highly statistical significant differences between panic patients and control group in all components of power spectral analysis in 2nd (VLF, LF and H in standing) and in two component of 3rd (LF and HF in supine) positions. There was also a statistically significant difference between these two groups in LF/HF ratio in standing position (2nd). During therapy there was a tendency increasing values in all three positions in components of HRV power spectra, but HF in 1st supine position was the only component where the increase reached the level os statistical significance. These findings demonstrate a lower autonomic activity in panic disorder patients measured during the changes of postural position in comparison with healthy controls and tendency to increase this autonomic power during the treatment.


Perspectives on Quality of Life in Glaucoma.
Chronic diseases are invariably associated with decreased functioning ability of the individual in one form or the other depending upon the system/organ involved. Disability consequent to the disease is the major factor affecting the patient's physical and psychosocial well-being; in other words, the 'Quality of Life (QOL)'. Besides the disease itself, the treatment and its consequences are also major determinants of QOL of the patients. Globally, glaucoma, which is emerging as one of the leading causes of blindness, is one such chronic ophthalmic disease characterized by a progressive loss of visual function and a potential to cause irreversible blindness, if not treated at an early stage. Patients of glaucoma need to take lifelong medications in order to keep their intraocular pressure within limits. It's impact on the daily life of patients cannot be overexpressed and compounded by the fact that it remains asymptomatic for a considerable time after the disease has set in; has led to new imperatives in diagnosis, treatment and epidemiological and outcome studies. Assessment of the debilitating effect of glaucoma and side effects of its treatment on the emotional and physical QOL of the patient is therefore an important criterion for arriving at the treatment regimen. An extensive literature search was done on Pubmed Central, Pubmed and Google Scholar using the keywords 'glaucoma', 'quality of life in glaucoma', 'management in POAG' and 'QOL assessment tools'. Various tools available for the assessment of QOL, and their advantages and limitations have been reviewed in this article.


Myometrium Invasion, Tumour Size and Lymphovascular Invasion as a Prognostic Factor in Dissemination of Pelvic Lymphatics at Endometrial Carcinoma.
The aim of this work is to show the importance of the depth of myometrium invasion, tumour size and lymphovascular invasion as prognostic factors in dissemination of lymphatic nodes at endometrial carcinoma (CE). In the period from 2010 to 2015 at the University Clinic for Gynecology and Obstetrics in Banja Luka, 221 endometrial cancer surgeries were done (laparatomy 184-83%, laparascopy 37-16,74%). Patients who had uterus bleeding in peri/postmenopause or those whose endometrium thickness was bigger than 5 mm which was established by ultrasound, or those who had in their cavum uteri pathological (PH) diagnosis, underwent fractional curettage (FC) or hysteroscopy in order to obtain pathohistological endometrium diagnosis. Substances which were removed by fractional curettage, biopsy or by surgery were sent to patohystological analysis. We analysed the following factors: age (5 groups), histological grade (G) of tumour, depth of myometrial invasion (DIM), whether it is more or less than 50%, the size of the tumour (if it is bigger or smaller than 2 cm), positive or negative lymphovascular invasion (LVI), positive or negative pelvic lymph nodes (PLN). Within histological type the endometrioid type CE 166 (75,11%) was most dominant. Adenocarcinoma of endometrium was present 25 (11,31%), serous CE 11 (4,97%) and clear cell KE 2 (0,90%). Dominant population with CE was over 60 years old 127 (57,46) of female patients. At G3 where DIM was <50% positive PLN were present 2 (3.92%), whereas if DIM was>50%, 6 (26,73%) patients with positive PLN were registred. Tumour size < 2 cm was found with 57 (25,79%) female patients with positive PLN 8 (14,03%), while 164 (74,20%) patients had tumours > 2 cm who had 21 (12,80) PLN metastases. At G1 when tumour was <2 cm, positive PLN had 3 patients (5,88), while when tumour was >2 cm, positive PLN were found at 6 patients (9,69%). At G3 whose size was <2 cm, positive PLN were found at 2 patients (16,66%), but when tumour was >2 cm, PLN metastases were more frequent, 6 (25,00%). Negative LVI was found with 168 patients (76,01%) whose PLN were positive 16 (9,52%), while positive LIV was with 53 patients (23,99%) of whom 14 had PLN metastases (26,41%). At G1 two patients had positive PLN (2,32%) with negative LVI, while with positive LVI, positive PLN were found at 3 patients (11,11%). At G3 having negative LVI positive PLN were found with 6 patients (24,00%), while if LIV was positive, the number of positive PLN were 6 (54,54%). With low risk for lymphatic spread (DIM less than 50%, tumour size smaller than 2 cm and lack of LVI at G1 CE) we also encounter low metastasis rate of PLN. Diagnoses of this kind have an aim to lower the number of pelvic lymphadenectomies. With patients who have a high risk of lymphatic spread (myometrium invasion >50%, tumour size > 2cm, LVI present at G2 and G3) metastasis rate of PLN is high, therefore it is necessary to perform pelvic and paraaortic lymphadenectomy which lowers the mortality rate for more than 50% and at the same time patients get an absolute chance of 5-year survival period.


Spatial-temporal patterns of malaria incidence in Uganda using HMIS data from 2015 to 2019.
As global progress to reduce malaria transmission continues, it is increasingly important to track changes in malaria incidence rather than prevalence. Risk estimates for Africa have largely underutilized available health management information systems (HMIS) data to monitor trends. This study uses national HMIS data, together with environmental and geographical data, to assess spatial-temporal patterns of malaria incidence at facility catchment level in Uganda, over a recent 5-year period. Data reported by 3446 health facilities in Uganda, between July 2015 and September 2019, was analysed. To assess the geographic accessibility of the health facilities network, AccessMod was employed to determine a three-hour cost-distance catchment around each facility. Using confirmed malaria cases and total catchment population by facility, an ecological Bayesian conditional autoregressive spatial-temporal Poisson model was fitted to generate monthly posterior incidence rate estimates, adjusted for caregiver education, rainfall, land surface temperature, night-time light (an indicator of urbanicity), and vegetation index. An estimated 38.8 million (95% Credible Interval [CI]: 37.9-40.9) confirmed cases of malaria occurred over the period, with a national mean monthly incidence rate of 20.4 (95% CI: 19.9-21.5) cases per 1000, ranging from 8.9 (95% CI: 8.7-9.4) to 36.6 (95% CI: 35.7-38.5) across the study period. Strong seasonality was observed, with June-July experiencing highest peaks and February-March the lowest peaks. There was also considerable geographic heterogeneity in incidence, with health facility catchment relative risk during peak transmission months ranging from 0 to 50.5 (95% CI: 49.0-50.8) times higher than national average. Both districts and health facility catchments showed significant positive spatial autocorrelation; health facility catchments had global Moran's I = 0.3 (p < 0.001) and districts Moran's I = 0.4 (p < 0.001). Notably, significant clusters of high-risk health facility catchments were concentrated in Acholi, West Nile, Karamoja, and East Central - Busoga regions. Findings showed clear countrywide spatial-temporal patterns with clustering of malaria risk across districts and health facility catchments within high risk regions, which can facilitate targeting of interventions to those areas at highest risk. Moreover, despite high and perennial transmission, seasonality for malaria incidence highlights the potential for optimal and timely implementation of targeted interventions.


Polarization-independent holographic gratings based on azo-dye-doped polymer-dispersed liquid-crystal films.
We demonstrate polarization-independent holographic gratings (PIHGs) based on azo-dye-doped polymer-dispersed liquid crystal films. The PIHGs are recorded by irradiation under an intensity-modulated interference field, generated by two linearly polarized green optical beams, and by simultaneously applying a suitable AC voltage to the sample. The photoexcited azo dyes are adsorbed onto the UV-cured polymer film with their long axes parallel to the normal of the substrate. When the applied voltage is switched off, the PIHGs are generated with periodic modulation of liquid-crystal structures with transparently homeotropic and randomly scattered alignments. Additionally, the generated PIHGs can be completely switched off by an applied voltage.


Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells.
The tumor cell-derived hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) into proangiogenic fragments that support tumor progression. Although HYAL-1 is a critical determinant of tumor progression and a marker for cancer diagnosis and metastasis prediction, it has not been evaluated as a target for cancer therapy. Similarly, sulfated hyaluronic acid (sHA) has not been evaluated for biological activity, although it is an HAase inhibitor. In this study, we show that sHA is a potent inhibitor of prostate cancer. sHA blocked the proliferation, motility, and invasion of LNCaP, LNCaP-AI, DU145, and LAPC-4 prostate cancer cells, and induced caspase-8-dependent apoptosis associated with downregulation of Bcl-2 and phospho-Bad. sHA inhibited Akt signaling including androgen receptor (AR) phosphorylation, AR activity, nuclear factor κB (NFκB) activation, and VEGF expression. These effects were traced to a blockade in complex formation between phosphoinositide 3-kinase (PI3K) and HA receptors and to a transcriptional downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition. Angiogenic HA fragments or overexpression of myristoylated Akt or HA receptors blunted these effects of sHA, implicating a feedback loop between HA receptors and PI3K/Akt signaling in the mechanism of action. In an animal model, sHA strongly inhibited LNCaP-AI prostate tumor growth without causing weight loss or apparent serum-organ toxicity. Inhibition of tumor growth was accompanied by a significant decrease in tumor angiogenesis and an increase in apoptosis index. Taken together, our findings offer mechanistic insights into the tumor-associated HA-HAase system and a preclinical proof-of-concept of the safety and efficacy of sHA to control prostate cancer growth and progression.


Sodium Is Not Essential for High Bioactivity of Glasses.
This study aims to demonstrate that excellent bioactivity of glass can be achieved without the presence of an alkali metal component in glass composition. In vitro bioactivity of two sodium-free glasses based on the quaternary system SiO2-P2O5-CaO-CaF2 with 0 and 4.5 mol% CaF2 content was investigated and compared with the sodium containing glasses with equivalent amount of CaF2. The formation of apatite after immersion in Tris buffer was followed by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), 31P and 19F solid state MAS-NMR. The dissolution study was completed by ion release measurements in Tris buffer. The results show that sodium free bioactive glasses formed apatite at 3 hours of immersion in Tris buffer, which is as fast as the corresponding sodium containing composition. This signifies that sodium is not an essential component in bioactive glasses and it is possible to make equally degradable bioactive glasses with or without sodium. The results presented here also emphasize the central role of the glass compositions design which is based on understanding of structural role of components and/or predicting the network connectivity of glasses.


Three-dimensional numerical simulation and experimental investigation of boundary-driven streaming in surface acoustic wave microfluidics.
Acoustic streaming has been widely used in microfluidics to manipulate various micro-/nano-objects. In this work, acoustic streaming activated by interdigital transducers (IDT) immersed in highly viscous oil is studied numerically and experimentally. In particular, we developed a modeling strategy termed the "slip velocity method" that enables a 3D simulation of surface acoustic wave microfluidics in a large domain (4 × 4 × 2 mm3) and at a high frequency (23.9 MHz). The experimental and numerical results both show that on top of the oil, all the acoustic streamlines converge at two horizontal stagnation points above the two symmetric sides of the IDT. At these two stagnation points, water droplets floating on the oil can be trapped. Based on these characteristics of the acoustic streaming field, we designed a surface acoustic wave microfluidic device with an integrated IDT array fabricated on a 128°YX LiNbO3 substrate to perform programmable, contactless droplet manipulation. By activating IDTs accordingly, the water droplets on the oil can be moved to the corresponding traps. With its excellent capability for manipulating droplets in a highly programmable, controllable manner, our surface acoustic wave microfluidic devices are valuable for on-chip contactless sample handling and chemical reactions.


The traumatised chronic pain patient-Prevalence of posttraumatic stress disorder - PTSD and pain sensitisation in two Scandinavian samples referred for pain rehabilitation.
Introduction Correctly identifying chronic pain patients with posttraumatic stress disorder (PTSD) is important because the comorbidity of a chronic pain condition and PTSD is found to compromise treatment success. In addition, the existence of PTSD is associated with pain sensitisation, elevated levels of pain, and disability. Furthermore, the diagnostic criteria for PTSD has changed dramatically in the last two decades which has had a profound impact on the reported prevalence rates of PTSD in chronic pain samples. To our knowledge, no study has employed the DSM-IV criteria for estimating the prevalence of PTSD in chronic pain patients referred consecutively for multidisciplinary pain rehabilitation. Aim The aim of the present study was to assess the prevalence of significant traumatic stressors and PTSD in chronic pain patients referred consecutively to multidisciplinary pain rehabilitation. We wanted to investigate whether specific pain diagnoses were more related to PTSD than others. Moreover, we investigated the possible association of altered sensory processing (hypersensitivity or hyposensitivity) and PTSD. Methods Data were collected from two Scandinavian multidisciplinary pain centres (Denmark and Finland). All patients referred consecutively were assessed for PTSD and sensitisation at admission. A total of 432 patients were assessed, of which 304 (DK, N =220, female n = 144; FIN, N=84, female n = 44) were admitted and consented to participate. All patients had to be diagnosed with a non-malign chronic pain condition lasting for at least 6 months (median = 6.0 years). The Harvard Trauma Questionnaire was employed to measure PTSD symptoms, using the DSM-IV criteria. To measure altered sensory processing, anaesthetists performed quantitative sensory testing on admission. Patients were asked to report if cold, brush, and pinprick mechanical stimulation resulted in decreased or increased sensation or pain. Results stimulation resulted in decreased or increased sensation or pain. A high prevalence of PTSD was found in both consecutive samples. Using the DSM-IV criteria, 23% fulfilled the criteria for a possible PTSD diagnosis. There were no gender differences in PTSD. The three most reported traumatic events: traffic accidents, serious illness personally or in the family, and the actual loss of someone, were reported as the primary traumatic events by almost 50% of those with PTSD. No particular pain diagnosis was significantly related to PTSD. However, hypersensitivity to cold and hyposensitivity to brush were significantly associated with PTSD. Discussion The prevalence of PTSD in the present study was 23%. Earlier studies finding a lower prevalence rate of PTSD may reflect the use of older diagnostic criteria for PTSD or other estimates, for instance PTSD symptom cut-off scores. Conclusion The study emphasised the importance of screening all chronic pain patients for PTSD at admission for pain rehabilitation, using up to date diagnostic tools. Implications Untreated PTSD may exacerbate or maintain the pain condition and negatively affect outcome of pain rehabilitation.


Cyanine-like dyes with large bond-length alternation.
Herein, the synthesis and properties of alkyne-bridged carbocations, which are analogous in structure to cyanine dyes, are reported. An alkene-bridged dye, linked at the third position of the indole, was also synthesized as a reference compound. These new carbocations are stable under ambient conditions, allowing characterization by UV/Vis and NMR ((1)H and (13)C) spectroscopies. These techniques revealed a large degree of delocalization of the positive charge, similar to a previously reported porphyrin carbocation. The linear and nonlinear optical properties are compared with cyanine dyes and triarylmethyl cations, to investigate the effects of the bond-length alternation and the overall molecular geometry. The value of Re(γ), the real part of the third-order microscopic polarizability, of -1.3×10(-33) esu for the alkyne-linked cation is comparable to that of a cyanine dye of similar length. Nondegenerate two-photon absorption spectra showed that the alkene-bridged dye exhibited characteristics of cyanines, whereas the alkyne-bridged dye is reminiscent of octupolar chromophores, such as the triarylmethyl carbocation brilliant green. Such attributes were confirmed and rationalized by quantum chemical calculations.


Asbestos fibres in the lungs of an American mechanic who drilled, riveted, and ground brake linings: a case report and discussion.
In North America and Europe, the use of asbestos in friction products was discontinued before the end of the 20th century. In the developing world, the use of asbestos-containing friction products continues. In 2010, Cely-Garcia and colleagues (Cely-Garcia et al., 2012) sampled three brake repair shops located in Bogota, Colombia. Both asbestos and non-asbestos containing brake linings were sold separately or attached to a shoe. When brake linings are sold separated from the shoe, they must be manipulated to attach them to the shoe before installation. The process starts with the removal of the old brake shoe from the vehicle's brake drum. If the existing brake shoe is to be reused, the old lining needs to be removed and the old shoe must be ground to prepare it for a new lining. Riveting requires drilling holes in the linings and shoes and before installing rivets, the lining must be countersunk. The borders of the lining are bevelled. On some occasions, the entire exposed surface of the lining is ground to make it thinner. Once attached to the shoe, the edges of brake linings may extend beyond the shoe. In this case, it is necessary to cut or grind the edges to match the lining to the shoe before bevelling or grinding. The authors reported that 'the sampling results indicate that the brake mechanics sampled are exposed to extremely high asbestos concentrations (i.e. based on transmission electron microscopy counts), suggesting that this occupational group could be at excess risk of asbestos-related diseases'.


Parasites of an Arctic scavenger; the wolverine (Gulo gulo).
Parasites are fundamental components within all ecosystems, shaping interaction webs, host population dynamics and behaviour. Despite this, baseline data is lacking to understand the parasite ecology of many Arctic species, including the wolverine (Gulo gulo), a top Arctic predator and scavenger. Here, we combined traditional count methods (i.e. adult helminth recovery, where taxonomy was confirmed by molecular identification) with 18S rRNA high-throughput sequencing to document the wolverine parasite community. Further, we investigated whether the abundance of parasites detected using traditional methods were associated with host metadata, latitude, and longitude (ranging from the northern limit of the boreal forest to the low Arctic and Arctic tundra in Nunavut, Canada). Adult parasites in intestinal contents were identified as Baylisascaris devosi in 72% (n = 39) of wolverines and Taenia spp. in 22% (n = 12), of which specimens from 2 wolverines were identified as T. twitchelli based on COX1 sequence. 18S rRNA high-throughput sequencing on DNA extracted from faeces detected additional parasites, including a pseudophyllid cestode (Diplogonoporus spp. or Diphyllobothrium spp.), two metastrongyloid lungworms (Angiostrongylus spp. or Aelurostrongylus spp., and Crenosoma spp.), an ascarid nematode (Ascaris spp. or Toxocara spp.), a Trichinella spp. nematode, and the protozoan Sarcocystis spp., though each at a prevalence less than 13% (n = 7). The abundance of B. devosi significantly decreased with latitude (slope = -0.68; R2 = 0.17; P = 0.004), suggesting a northerly limit in distribution. We describe B. devosi and T. twitchelli in Canadian wolverines for the first time since 1978, and extend the recorded geographic distribution of these parasites ca 2000 km to the East and into the tundra ecosystem. Our findings illustrate the value of molecular methods in support of traditional methods, encouraging additional work to improve the advancement of molecular screening for parasites.


Phase II trail of didemnin B in previously treated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group (ECOG) Study.
Patients with non-Hodgkin's lymphoma (NHL) who fail initial therapy have a poor prognosis. We conducted a phase II study to determine the efficacy and toxicity of didemnin B, a non-myelosuppressive marine compound, in patients with NHL who relapsed or progressed after receiving one or two previous chemotherapy regimens. Fifty-one eligible patients were registered on this phase II study. Twenty-nine patients had intermediate or high grade (IG/HG) disease and 22 patients had low grade (LG) disease. Twenty-five patients received didemnin B at a dose of 6.3 mg/m2 and the remainder received 5.6 mg/m2, administered intravenously every 28 days. The patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and biopsy-proven relapsed disease. Objective responses were observed in two (7%) patients (one complete remission [CR] and one partial remission [PR]) with IG/HG disease and five (23%) patients (one CR and four PR) with LG disease. Patients with IG/HG disease had a median time to treatment failure (TTF) of 1.6 months and a median survival of 8.0 months. In contrast, the group with LG disease had a median TTF of 4.6 months and a median survival of 2.7 years. There were five grade V, 12 grade IV, and 57 grade III toxicities. Didemnin B appears to have modest activity in low grade NHL. However, the drug has considerable toxicity in this population of patients.


Analysis of rear-end crash potential and driver contributing factors based on car-following driving simulation.
The purpose of the study was to investigate the factors associating the car-following behavior, which could lead to rear-end crash potential. The safe distance in this study was when the traffic flow was in an asymptotic stability state. Traffic flow observation was conducted to observe how vehicle characteristics associating car-following behavior. However, it was not possible to determine the driver characteristics and their driving habits using the traffic flow observation alone. Therefore, a driving simulation and questionnaires were used in combination to investigate how driving characteristics were associate with car-following behavior. From the two observation methods, several factors were found to significantly associate the rear-end crash potential including vehicle types, traveling lanes, the purposes of vehicle usage, age, income, the number of driving hours per week, stress, and anger or aggressive behavior. The traffic flow observation indicated that among the different types of vehicles, sedan/hatchback cars were more likely to be involved in rear-end crashes than others type of vehicles. Vehicles using the high-speed lane typically drove closer to each other and had a higher chance of rear-end collisions. The observation of driver characteristics showed that younger and high-income drivers were more likely to drive with less gap, resulting in higher possibilities of a rear-accident. Despite being in a normal emotional state, drivers with high frequency of stress, anger or aggression while driving had shorter headway distances and were more likely to cause rear-end collisions.


Lipid localization in bacterial cells through curvature-mediated microphase separation.
Although many proteins are known to localize in bacterial cells, for the most part our understanding of how such localization takes place is limited. Recent evidence that the phospholipid cardiolipin localizes to the poles of rod-shaped bacteria suggests that targeting of some proteins may rely on the heterogeneous distribution of membrane lipids. Membrane curvature has been proposed as a factor in the polar localization of high-intrinsic-curvature lipids, but the small size of lipids compared to the dimensions of the cell means that single molecules cannot stably localize. At the other extreme, phase separation of the membrane energetically favors a single domain of such lipids at one pole. We have proposed a physical mechanism in which osmotic pinning of the membrane to the cell wall naturally produces microphase separation, i.e., lipid domains of finite size, whose aggregate sensitivity to cell curvature can support spontaneous and stable localization to both poles. Here, we demonstrate that variations in the strength of pinning of the membrane to the cell wall can also act as a strong localization mechanism, in agreement with observations of cardiolipin relocalization from the poles to the septum during sporulation in the bacterium Bacillus subtilis. In addition, we rigorously determine the relationship between localization and the domain-size distribution including the effects of entropy, and quantify the strength of domain-domain interactions. Our model predicts a critical concentration of cardiolipin below which domains will not form and hence polar localization will not take place. This observation is consistent with recent experiments showing that in Escherichia coli cells with reduced cardiolipin concentrations, cardiolipin and the osmoregulatory protein ProP fail to localize to the poles.


The neural substrates and timing of top-down processes during coarse-to-fine categorization of visual scenes: a combined fMRI and ERP study.
Spatial frequencies in an image influence visual analysis across a distributed, hierarchically organized brain network. Low spatial frequency (LSF) information may rapidly reach high-order areas to allow an initial coarse parsing of the visual scene, which could then be "retroinjected" through feedback into lower level visual areas to guide finer analysis on the basis of high spatial frequency (HSF). To test this "coarse-to-fine" processing scheme and to identify its neural substrates in the human brain, we presented sequences of two spatial-frequency-filtered scenes in rapid succession (LSF followed by HSF or vice versa) during fMRI and ERPs in the same participants. We show that for low-to-high sequences (but not for high-to-low sequences), LSF produces a first increase of activity in prefrontal and temporo-parietal areas, followed by enhanced responses to HSF in primary visual cortex. This pattern is consistent with retroactive influences on low-level areas that process HSF after initial activation of higher order areas by LSF.


A reentry study on the use of bovine porous bone mineral, GTR, and platelet-rich plasma in the regenerative treatment of intrabony defects in humans.
This study compared the clinical effectiveness of a combination therapy consisting of bovine porous bone mineral (BPBM), guided tissue regeneration (GTR), and platelet-rich plasma (PRP) in the regeneration of periodontal intrabony defects in humans. Twenty-eight paired intrabony defects were surgically treated using a split-mouth design. Defects were treated with BPBM, GTR, and PRP (experimental), or with open-flap debridement (control). Clinical parameters evaluated included changes in attachment level, pocket depth, and defect fill as revealed by reentry at 6 months. Preoperative pocket depths, attachment levels, and transoperative bone measurements were similar for the two groups. Postsurgical measurements taken at 6 months revealed that both treatment modalities significantly decreased pocket depth and increased clinical attachment and defect fill compared to baseline. The differences between the experimental and control groups were 2.22+/-0.39 mm on buccal and 2.12+/-0.34 mm on lingual sites for pocket depth, 3.05+/-0.51 mm on buccal and 2.88+/-0.46 mm on lingual sites for gain in clinical attachment, and 3.46+/-0.96 mm on buccal and 3.42+/-0.02 mm on lingual sites for defect fill. These differences between groups were statistically significant in favor of the experimental defects. The combined therapy was also clinically more effective than open-flap debridement. The superiority of the experimental group could not be attributed solely to the surgical intervention and was likely a result of the BPBM/GTR/ PRP application. Combining BPBM, GTR, and PRP was an effective modality of regenerative treatment for intrabony defects in patients with advanced periodontitis.


Algae separation from urban landscape water using a high density microbubble layer enhanced by micro-flocculation.
Eutrophication of raw water results in outbreaks of algae, which hinders conventional water treatment. In this study, high density microbubble layers combined with micro-flocculation was adopted to remove algae from urban landscape water, and the effects of pressure, hydraulic loading, microbubble layer height and flocculation dosage on the removal efficiency for algae were studied. The greatest removal efficiency for algae, chemical oxygen demand, nitrogen and phosphorus was obtained at 0.42 MPa with hydraulic loading at 5 m/h and a flocculation dosage of 4 mg/L using a microbubble layer with a height of 130 cm. Moreover, the size, clearance distance and concentration of microbubbles were found to be affected by pressure and the height of the microbubble layer. Based on the study, this method was an alternative for algae separation from urban landscape water and water purification.


Mass balance of the Antarctic Ice Sheet from 1992 to 2017.
The Antarctic Ice Sheet is an important indicator of climate change and driver of sea-level rise. Here we combine satellite observations of its changing volume, flow and gravitational attraction with modelling of its surface mass balance to show that it lost 2,720 ± 1,390 billion tonnes of ice between 1992 and 2017, which corresponds to an increase in mean sea level of 7.6 ± 3.9 millimetres (errors are one standard deviation). Over this period, ocean-driven melting has caused rates of ice loss from West Antarctica to increase from 53 ± 29 billion to 159 ± 26 billion tonnes per year; ice-shelf collapse has increased the rate of ice loss from the Antarctic Peninsula from 7 ± 13 billion to 33 ± 16 billion tonnes per year. We find large variations in and among model estimates of surface mass balance and glacial isostatic adjustment for East Antarctica, with its average rate of mass gain over the period 1992-2017 (5 ± 46 billion tonnes per year) being the least certain.


Detection of gonioscopically occludable angles and primary angle closure glaucoma by estimation of limbal chamber depth in Asians: modified grading scheme.
To evaluate the performance of limbal chamber depth estimation as a means of detecting occludable drainage angles and primary angle closure, with or without glaucoma, in an east Asian population, and determine whether an augmented grading scheme would enhance test performance. A two phase, cross sectional, community based study was conducted on rural and urban areas of Hövsgöl and Omnögobi provinces, Mongolia. 1800 subjects aged 40 to 93 years were selected and 1717 (95%) of these were examined. Depth of the anterior chamber at the temporal limbus was graded as a percentage fraction of peripheral corneal thickness. An "occludable" angle was one in which the trabecular meshwork was seen in less than 90 degrees of the angle circumference by gonioscopy. Primary angle closure (PAC) was diagnosed in subjects with an occludable angle and either raised pressure or peripheral anterior synechiae. PAC with glaucoma (PACG) was diagnosed in cases with an occludable angle combined with glaucomatous optic neuropathy and consistent visual morbidity. Occludable angles were identified in 140 subjects, 28 of these had PACG. The 15% grade (equivalent to the traditional "grade 1") yielded sensitivity and specificity of 84% and 86% respectively for the detection of occludable angles. The 5% grade gave sensitivity of 91% and specificity of 93% for the detection of PACG. The interobserver agreement for this augmented grading scheme was good (weighted kappa 0.76). The traditional limbal chamber depth grading scheme offers good performance for detecting occludable drainage angles in this population. The augmented scheme gives enhanced performance in detection of established PACG. The augmented scheme has potential for good interobserver agreement.


Impact of cancer surgery slowdowns on patient survival during the COVID-19 pandemic: a microsimulation modelling study.
With the declaration of the global pandemic, surgical slowdowns were instituted to conserve health care resources for anticipated surges in patients with COVID-19. The long-term implications on survival of these slowdowns for patients with cancer in Canada is unknown. We constructed a microsimulation model based on real-world population data on cancer care from Ontario, Canada, from 2019 and 2020. Our model estimated wait times for cancer surgery over a 6-month period during the pandemic by simulating a slowdown in operating room capacity (60% operating room resources in month 1, 70% in month 2, 85% in months 3-6), as compared with simulated prepandemic conditions with 100% resources. We used incremental differences in simulated wait times to model survival using per-day hazard ratios for risk of death. Primary outcomes included life-years lost per patient and per cancer population. We conducted scenario analyses to evaluate alternative, hypothetical scenarios of different levels of surgical slowdowns on risk of death. The simulated model population comprised 22 799 patients waiting for cancer surgery before the pandemic and 20 177 patients during the pandemic. Mean wait time to surgery prepandemic was 25 days and during the pandemic was 32 days. Excess wait time led to 0.01-0.07 life-years lost per patient across cancer sites, translating to 843 (95% credible interval 646-950) life-years lost among patients with cancer in Ontario. Pandemic-related slowdowns of cancer surgeries were projected to result in decreased long-term survival for many patients with cancer. Measures to preserve surgical resources and health care capacity for affected patients are critical to mitigate unintended consequences.


Liver damage induced by bile duct ligation affects CYP isoenzymes differently in rats.
We examined the influence of liver damage induced by bile duct ligation on the activity and the expression of hepatic cytochrome P450 (CYP) 1A, 2B, 2C6, 2C11, 2E1 and 3A2 in male Sprague-Dawley rats. In the ligation group, testosterone 2 alpha-, 16 alpha-, and 6 beta-hydroxylase activities were severely decreased, whereas ethoxyresorufin O-deethylase and progesterone 21-hydroxylase activities relatively remained. Pentoxyresorufin O-deethylase and chlorzoxazone 6-hydroxylase activities were reduced to approximately one thirds those of control. The protein contents of these isoenzymes expressed in hepatic microsomes of the ligation group were decreased to 45%, 32%, 79%, 13%, 58%, and 23% of control for CYP1A, 2B, 2C6, 2C11, 2E1 and 3A2, respectively. The rank order of magnitude of the influence of bile duct ligation on CYP isoenzymes, assessed by the reduction in the enzyme activity and the protein content, corresponded with each other except CYP1A. The reduction of the enzyme activities significantly correlated with the reduction in the protein contents of different isoenzymes. These results suggested that bile duct ligation affected CYP isoenzyme activities and contents with different extent.


Increased frequency of CD16+ monocytes and the presence of activated dendritic cells in salivary glands in primary Sjögren syndrome.
In the salivary glands of patients with primary Sjögren Syndrome (pSjS) an accumulation of dendritic cells (DCs) is seen, which is thought to play a role in stimulating local inflammation. Aberrancies in subsets of monocytes, generally considered the blood precursors for DCs, may play a role in this accumulation of DCs. This study is aimed at determining the level of mature CD14lowCD16+ monocytes in pSjS and their contribution to the accumulation of DCs in pSjS. Levels of mature and immature monocytes in patients with pSjS (n = 19) and controls (n = 15) were analysed by flow cytometry. The reverse transmigration system was used for generation of DCs generated from monocyte subsets. The phenotype of DCs in pSjS salivary glands was analysed using immunohistochemistry. In vivo tracking of monocyte subsets was performed in a mouse model. Increased levels of mature CD14lowCD16+ monocytes were found in patients with pSjS (mean (SD) 14.5 (5.5)% vs 11.4 (3.4)%). These cells showed normal expression of chemokine receptor and adhesion molecules. Mature monocytes partly developed into DC-lysosome-associated membrane glycoprotein (LAMP)+ (19.6 (7.5)%) and CD83+ (16 (9)%) DCs, markers also expressed by DCs in pSjS salivary glands. Monocyte tracking in the non-obese diabetic (NOD) mouse showed that the homologue population of mature mouse monocytes migrated to the salivary glands, and preferentially developed into CD11c+ DCs in vivo. Mature monocytes are increased in pSjS and patient and mouse data support a model where this mature monocyte subset migrates to the salivary glands and develops into DCs.


Interrogation of fiber Bragg-grating resonators by polarization-spectroscopy laser-frequency locking.
We report on an optically-based technique that provides an efficient way to track static and dynamic strain by locking the frequency of a diode laser to a fiber Bragg-grating Fabry-Pérot cavity. For this purpose, a suitable optical frequency discriminator is generated exploiting the fiber natural birefringence and that resulting from the gratings inscription process. In our scheme, a polarization analyzer detects dispersive-shaped signals centered on the cavity resonances without need for additional optical elements in the resonator or any laser-modulation technique. This method prevents degradation of the resonator quality and maintains the configuration relatively simple, demonstrating static and dynamic mechanical sensing below the picostrain level.


On-chip two-octave supercontinuum generation by enhancing self-steepening of optical pulses.
Dramatic advances in supercontinuum generation have been made recently using photonic crystal fibers, but it is quite challenging to obtain an octave-spanning supercontinuum on a chip, partially because of strong dispersion in high-index-contrast nonlinear integrated waveguides. We show by simulation that extremely flat and low dispersion can be achieved in silicon nitride slot waveguides over a wavelength band of 500 nm. Different from most of previously reported supercontinua that were generated either by higher-order soliton fission in anomalous dispersion regime or by self-phase modulation in normal dispersion regime, a two-octave supercontinuum from 630 to 2650 nm (360 THz in total) can be generated by enhancing self-steepening in pulse propagation in nearly zero dispersion regime, when an optical shock as short as 3 fs is formed.


Riboflavin carrier protein: a serum and tissue marker for breast carcinoma.
We have earlier shown that the estrogen-modulated riboflavin carrier protein (RCP) first isolated from the chicken egg is evolutionarily conserved in mammals and is elaborated by lactating mammary gland as demonstrated with rat mammary epithelial cells in culture and confirmed by isolation of the vitamin carrier from bovine milk. In view of several earlier reports that many milk proteins as well as other estrogen-inducible proteins are up-regulated and secreted into circulation in animal models and in women with neoplastic breast disease, we analyzed serum RCP levels in a double-blind study using a specific radioimmunoassay in pre- and post-menopausal women with clinically diagnosed breast cancer at early and advanced stages of the disease and compared these levels with those in normal age-matched control volunteers. Our data reveal that the serum RCP levels in cycling breast cancer patients are 3- to 4-fold higher (p < 0.01) than those in their normal counterparts. This difference in circulatory RCP levels between cancer patients and their age-matched normal counterparts is further magnified to 9- to 11-fold (p < 0.005) at the post-menopausal stage. In addition, there seems to be a good correlation between rising RCP levels and disease progression, since significantly higher RCP concentrations (p < 0.005) are encountered in patients with advanced metastasizing breast cancer versus those with early disease. Using specific monoclonal antibodies, RCP could be localized immunohistochemically in the cytoplasm of invading neoplastic cells of lobular and ductal carcinomas of the breast, indicating that the malignant cells are probably the source of the elevated serum RCP levels in breast cancer. These findings suggest that measurement of circulatory RCP and the immunohistochemical staining pattern of RCP in biopsy specimens could be exploited as an additional marker in diagnosis/prognosis of breast cancer in women.


Modulation of Rac localization and function by dynamin.
The GTPase dynamin controls a variety of endocytic pathways, participates in the formation of phagosomes, podosomal adhesions, and invadopodia, and in regulation of the cytoskeleton and apoptosis. Rac, a member of the Rho family of small GTPases, controls formation of lamellipodia and focal complexes, which are critical in cell migration and phagocytosis. We now show that disruption of dynamin(-2) function alters Rac localization and inhibits cell spreading and lamellipodia formation even though Rac is activated. Dominant-negative K44A dynamin(-2) inhibited cell spreading and lamellipodia formation on fibronectin without blocking cell adhesion; dynamin(-2) depletion by specific small interfering RNA inhibited lamellipodia in a similar manner. Dyn2(K44A) induced Rac mislocalization away from cell edges, into abnormal dorsal ruffles, and led to increased total Rac activity. Fluorescence resonance energy transfer imaging of Rac activity confirmed its predominant localization to aberrant dorsal ruffles in the presence of dominant-negative dyn2(K44A). Dyn2(K44A) induced the accumulation of tubulated structures bearing membrane-bound Rac-GFP. Constitutively active but not wild-type GFP-Rac was found on macropinosomes and Rac-dependent, platelet-derived growth factor-induced macropinocytosis was abolished by Dyn2(K44A) expression. These data suggest an indispensable role of dynamin in Rac trafficking to allow for lamellipodia formation and cell spreading.


Targeting γ-herpesvirus 68 Bcl-2-mediated down-regulation of autophagy.
γ-herpesviruses (γHVs) are common human pathogens that encode homologs of the anti-apoptotic cellular Bcl-2 proteins, which are critical to viral reactivation and oncogenic transformation. The murine γHV68 provides a tractable in vivo model for understanding general features of these important human pathogens. Bcl-XL, a cellular Bcl-2 homolog, and the murine γHV68 Bcl-2 homolog, M11, both bind to a BH3 domain within the key autophagy effector Beclin 1 with comparable affinities, resulting in the down-regulation of Beclin 1-mediated autophagy. Despite this similarity, differences in residues lining the binding site of M11 and Bcl-XL dictate varying affinities for the different BH3 domain-containing proteins. Here we delineate Beclin 1 differential specificity determinants for binding to M11 or Bcl-XL by quantifying autophagy levels in cells expressing different Beclin 1 mutants and either M11 or Bcl-XL, and we show that a G120E/D121A Beclin 1 mutant selectively prevents down-regulation of Beclin 1-mediated autophagy by Bcl-XL, but not by M11. We use isothermal titration calorimetry to identify a Beclin 1 BH3 domain-derived peptide that selectively binds to M11, but not to Bcl-XL. The x-ray crystal structure of this peptide bound to M11 reveals the mechanism by which the M11 BH3 domain-binding groove accommodates this M11-specific peptide. This information was used to develop a cell-permeable peptide inhibitor that selectively inhibits M11-mediated, but not Bcl-XL-mediated, down-regulation of autophagy.


The influence of combined oral contraceptives containing drospirenone on hypothalamic-pituitary-adrenocortical axis activity and glucocorticoid receptor expression and function in women with polycystic ovary syndrome.
Most women with PCOS have increased adrenal androgen production, enhanced peripheral metabolism of cortisol and elevation in urinary excretion of its metabolites. Increased cortisol clearance in PCOS is followed by a compensatory overdrive of the hypothalamic-pituitary-adrenocortical (HPA) axis. We hypothesized that oral contraceptives containing ethinylestradiol and drospirenone (EE-DRSP) could modulate glucocorticoid receptor (GR) expression and function and thus affect HPA axis activity in PCOS patients. We analyzed 12 women with PCOS (age 24.17±4.88 years; body mass index 22.05±3.97 kg/m²) treated for 12 months with EE-DRSP and 20 BMI matched controls. In all subjects testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone binding globulin (SHBG), cortisol (basal and after dexamethasone), concentrations of GR protein, phospo-GR211 protein, number of GR per cell (B(max) and its equilibrium dissociation constant (K(D)) were measured. Before treatment, increased concentrations of testosterone and DHEAS (p<0.001, respectively), unaltered basal cortisol and an increased sensitivity (p<0.05) of the HPA axis to dexamethasone were observed in PCOS women in comparison to controls. After treatment, testosterone (p<0.01), DHEAS (p<0.05) and cortisol suppression after dexamethasone (p<0.01) were decreased in PCOS women. There were no changes in GR protein concentration, GR phosphorylation nor in the receptor functional parameters B(max) and K(D) in women with PCOS before and after the therapy, and in comparison to controls. Prolonged treatment with EE-DRSP in PCOS women decreased serum androgens and increased cortisol in the presence of decreased sensitivity of the HPA axis and did not exert changes in GR expression and function.


PinX1 is up-regulated and associated with poor patients' survival in gliomas.
PinX1, a conserved nuclear protein, could maintain telomere integrity and plays an important role in regulating telomerase activity. It has been reported that the expression of PinX1 is down-regulated in some cancer and associated with cancer prognosis. However, the value of PinX1 in gliomas has not been studied. In this study, two independent retrospective gliomas cohorts with the corresponding gliomas tissue microarrays (TMAs) were established to detect the expression level of PinX1 and the correlation of PinX1 expression with the clinicopathological features and the patients' survival. Compared with non-cancerous brain tissues, PinX1 protein levels were remarkably up-regulated in gliomas (P = 0.001), and further increased from benign gliomas tissues to malignant gliomas tissues (P = 0.090). Moreover, high PinX1 expression was significantly positively associated with gliomas WHO grade in the training set (P = 0.019) and the validation set (P = 0.037). High PinX1 expression significantly correlated with a worse 5-year overall (P = 0.016) and disease-specific survival (P = 0.026). Simultaneously, the multivariate COX regression analysis showed that PinX1 was an independent unfavorable prognostic factor for 5-year overall survival (hazard ratio (HR) = 2.078, P = 0.015) and disease-specific survival (HR = 2.429, P = 0.012) after adjusting with age, sex and WHO grade in gliomas. In conclusion, PinX1 expression may serve as a prognostic and predictive biomarker for gliomas.


Risk for HIV-1 infection associated with a common CXCL12 (SDF1) polymorphism and CXCR4 variation in an African population.
CXC chemokine ligand 12 (CXCL12), or stromal cell-derived factor 1 (SDF1), is the only known natural ligand for the HIV-1 coreceptor, CXC chemokine receptor 4 (CXCR4). A single nucleotide polymorphism (SNP) in the CXCL12 gene (SDF1-3'A) has been associated with disease progression to AIDS in some studies, but not others. Mutations in the CXCR4 gene are generally rare and have not been implicated in HIV-1/AIDS pathogenesis. This study analyzed the SDF1-3'A SNP and performed mutation screening for polymorphic markers in the CXCR4 gene to determine the presence or absence of significant associations with susceptibility to HIV-1 infection. The study consisted of 257 HIV-1-seropositive patients and 113 HIV-1-seronegative controls representing a sub-Saharan African population belonging to the Xhosa ethnic group of South Africa. The SDF1-3'A SNP was associated with an increased risk for HIV-1 infection (P = 0.0319) whereas no significant association was observed between the occurrence of the SDF1-3'A SNP and increased or decreased plasma levels of CXCL12. Comprehensive mutation analysis of the CXCR4 gene confirmed a high degree of genetic conservation within the coding region of this ancient population.


Inhibition of mammary tumorigenesis in the C3(1)/SV40 mouse model by green tea.
Previous studies show inhibitory effects of green tea in chemically induced mammary tumors or human tumor explants, but not in spontaneous tumor models that are more representative of human breast cancer. The C3(1)/SV40 mouse model is particularly suited for breast cancer prevention studies because it produces spontaneous ductal adenocarcinomas and a predictable time course for mammary tumorigenesis through a multistage progression similar to that occurring in humans. We therefore used this model to test the chemoprotective effects of green tea. Administration of 0.5% Polyphenon E (Poly E) (a standardized preparation of green tea extract) in drinking water delayed tumor onset and suppressed tumor growth by 40%, compared to tap water-fed animals, with no adverse side effects. Histological analysis of mammary glands showed that green tea slowed the progression of ductal lesions to advanced mammary intraepithelial neoplasias and suppressed tumor invasiveness. Green tea inhibited the proliferation of ductal epithelial cells and tumors and, overall, disrupted post-pubertal ductal growth. Immunohistochemical analyses also demonstrated that green tea inhibited angiogenesis through a decrease in both ductal epithelial and stromal VEGF expression and a decrease in intratumoral microvascular density. Our data strongly support the potential use of green tea as a breast cancer chemopreventive agent.


Fixed drug eruption to ingested propolis.
Fixed drug eruptions (FDEs) are a unique type of drug allergy in which skin lesions recur in the same location after each ingestion of the offending agent. More than 100 drugs have been implicated in causing FDEs. More recently, herbal medications and food additives have been implicated. Propolis is an important contact allergen, but has not previously been reported to cause FDE. We present the case of a patient with a 1-year history of a recurrent lesion on the shaft of his penis. He tested strongly positive to propolis and had been using a herbal supplement. A trial off this supplement was initiated, and his penile lesion cleared. The patient then rechallenged himself with his powder and developed the same reaction, biopsy-proven to be consistent with FDE. This case illustrates the utility of systemic (rechallenge) and topical (patch-testing) testing to identify the causative agent. It is interesting to note that our patient developed a reaction at the site of the patch test for propolis itself, rather than at the former reaction site. Our patient also illustrates the necessity of considering new causes for FDE when typical lesions are present.


Transmission of rhinovirus in the Utah BIG-LoVE families: Consequences of age and household structure.
Common cold viruses create significant health and financial burdens, and understanding key loci of transmission would help focus control strategies. This study (1) examines factors that influence when individuals transition from a negative to positive test (acquisition) or a positive to negative test (loss) of rhinovirus (HRV) and other respiratory tract viruses in 26 households followed weekly for one year, (2) investigates evidence for intrahousehold and interhousehold transmission and the characteristics of individuals implicated in transmission, and (3) builds data-based simulation models to identify factors that most strongly affect patterns of prevalence. We detected HRV, coronavirus, paramyxovirus, influenza and bocavirus with the FilmArray polymerase chain reaction (PCR) platform (BioFire Diagnostics, LLC). We used logistic regression to find covariates affecting acquisition or loss of HRV including demographic characteristics of individuals, their household, their current infection status, and prevalence within their household and across the population. We apply generalized linear mixed models to test robustness of results. Acquisition of HRV was less probable in older individuals and those infected with a coronavirus, and higher with a higher proportion of other household members infected. Loss of HRV is reduced with a higher proportion of other household members infected. Within households, only children and symptomatic individuals show evidence for transmission, while between households only a higher number of infected older children (ages 5-19) increases the probability of acquisition. Coronaviruses, paramyxoviruses and bocavirus also show evidence of intrahousehold transmission. Simulations show that age-dependent susceptibility and transmission have the largest effects on mean HRV prevalence. Children are most likely to acquire and most likely to transmit HRV both within and between households, with infectiousness concentrated in symptomatic children. Simulations predict that the spread of HRV and other respiratory tract viruses can be reduced but not eliminated by practices within the home.


Life and Leisure Activities following Stroke or Transient Ischaemic Attack (TIA): An Observational, Multi-Centre, 6-Month Follow-Up Study.
To examine changes in leisure participation following stroke/transient ischaemic attack (TIA) and explore its relationship to modifiable and non-modifiable participant characteristics. An observational study design with self-report questionnaires collected at two time points (baseline and 6-months). The study was conducted across 21 hospital sites in England, Wales, and Northern Ireland. Participants were aged 18+ and had experienced a first or recurrent stroke or TIA and had a post-stroke/TIA modified Rankin score (mRS) of ≤3. Research practitioners at each site approached potential participants. Individuals who agreed to participate completed a baseline questionnaire whilst an inpatient or at a first post-stroke/TIA clinic appointment. A follow-up questionnaire was posted to participants with a freepost return envelope. Two questionnaires were developed that collected demographic information, pre-stroke/TIA mRS, social circumstances (e.g., employment situation) and incorporated the shortened Nottingham Leisure Questionnaire (sNLQ). The study recruited eligible participants (N = 3295); 2000 participants returned questionnaires at follow-up. Data showed three participant variables were significant predictors of engagement in leisure activities post-stroke/TIA: age, sex, and deprivation decile. There was an overall decline in the number and variety of leisure activities, with an average loss of 2.2 activities following stroke/TIA. Only one activity, "exercise/fitness" saw an increase in engagement from baseline to follow-up; watching TV remained stable, whilst participation in all other activities reduced between 10% and 40% with an average activity engagement reduction of 22%. Some groups experienced a greater reduction in activities than others-notably older participants, female participants, and those living in a low socioeconomic area. researchregistry4607. 1. This is the largest-ever study to survey life and leisure activity engagement following stroke/TIA. 2. Survey responses were self-reported retrospectively and, therefore, may have been misreported, or misremembered. 3. Despite the large cohort, there were few participants, and so respondents, from ethnic minority groups.


Neurofeedback intervention in fibromyalgia syndrome; a randomized, controlled, rater blind clinical trial.
We designed a randomized, rater blind study to assess the efficacy of EEG Biofeedback (Neurofeedback-NFB) in patients with fibromyalgia syndrome (FMS). Eighteen patients received twenty sessions of NFB-sensory motor rhythm (SMR) treatment (NFB group) during 4 weeks, and eighteen patients were given 10 mg per day escitalopram treatment (control group) for 8 weeks. Visual Analog Scales for pain and fatigue, Hamilton and Beck Depression and Anxiety Inventory Scales, Fibromyalgia Impact Questionnaire and Short Form 36 were used as outcome measures which were applied at baseline and 2nd, 4th, 8th, 16th, 24th weeks. Mean amplitudes of EEG rhythms (delta, theta, alpha, SMR, beta1 and beta2) and theta/SMR ratio were also measured in NFB group. All post-treatment measurements showed significant improvements in both of the groups (for all parameters p < 0.05). NFB group displayed greater benefits than controls (for all parameters p < 0.05). Therapeutic efficacy of NFB was found to begin at 2nd week and reached to a maximum effect at 4th week. On the other hand, the improvements in SSRI treatment were also detected to begin at 2nd week but reached to a maximum effect at 8th week. No statistically significant changes were noted regarding mean amplitudes of EEG rhythms (p > 0.05 for all). However, theta/SMR ratio showed a significant decrease at 4th week compared to baseline in the NFB group (p < 0.05). These data support the efficacy of NFB as a treatment for pain, psychological symptoms and impaired quality of life associated with fibromyalgia.


[Decision-making concerning guardianship--who is the "person that no longer has the capacity to make decisions regarding personal matters"?].
Appointment of a guardian is a complicated and important process, when necessary. It is a paternalistic intervention in the life of an individual, which aims to protect those who require that protection. Appointment of a guardian significantly impedes the rights and autonomy of the individual and should therefore remain a last resort. Alternatively, not appointing a guardian for one who needs protection could potentially expose that person to financial or physical harm, exploitation and neglect. The law allows for appointment of a guardian for a person that no longer has the capacity to make decisions regarding some or all of his/her personal matters. The law and the ruling have not defined who is considered a person that no longer has the capacity to make decisions. The criteria for financial capacity should include whether or not the patient knows the extent of his property, his income, expenses, and demonstrates ability to make logical decisions concerning these issues? The criteria for personal capacity [physical wellbeing] should include whether or not the patient can independently take care of his personal needs and care for himself in terms of: nutrition, housing, clothing, general security, and a safe living environment? We suggest that the expert opinion should specifically relate to the issues of guardianship for physical wellbeing and/or property and should provide the following: 1) Reason: What is the disorder/diagnosis that the patient suffers from? 2) Cognitive impairment: What cognitive impairment results from the patient's illness? 3) Functional impairment: What functional impairments resulting from illness affect the life of the patient?


Evidence of non-tandemly repeated rDNAs and their intragenomic heterogeneity in Rhizophagus irregularis.
Arbuscular mycorrhizal fungus (AMF) species are some of the most widespread symbionts of land plants. Our much improved reference genome assembly of a model AMF, Rhizophagus irregularis DAOM-181602 (total contigs = 210), facilitated a discovery of repetitive elements with unusual characteristics. R. irregularis has only ten or 11 copies of complete 45S rDNAs, whereas the general eukaryotic genome has tens to thousands of rDNA copies. R. irregularis rDNAs are highly heterogeneous and lack a tandem repeat structure. These findings provide evidence for the hypothesis that rDNA heterogeneity depends on the lack of tandem repeat structures. RNA-Seq analysis confirmed that all rDNA variants are actively transcribed. Observed rDNA/rRNA polymorphisms may modulate translation by using different ribosomes depending on biotic and abiotic interactions. The non-tandem repeat structure and intragenomic heterogeneity of AMF rDNA/rRNA may facilitate successful adaptation to various environmental conditions, increasing host compatibility of these symbiotic fungi.


Amplification and expression of EGFR and ERBB2 in Wilms tumor.
Wilms tumor is one of the most common solid tumors in children. We evaluated expression and amplification of a number of genes and their prognostic significance in 45 patients with Wilms tumor, using tissue microarray technology. The expression of EGFR, ERBB2, MDM2, CCND1, MLH1, MSH2, TP53, and ABCB1 (alias MDR1) was studied by immunohistochemistry. Amplification of the EGFR, ERBB2, MDM2, CCND1, CTTN (previously EMS1), RAF1, MYC, FGF3 (previously INT2), WNT1, GLI1, CDK4, and NCOA3 (alias AIB1) genes was assessed by fluorescence in situ hybridization. Expression of EGFR was seen in 17 of the 45 cases (38%) but was not associated with gene amplification. The ERBB2 gene was neither overexpressed nor amplified in any case. Tissue microarray and immunohistochemistry analyses for ERBB2 in whole-tumor sections were also negative in all cases. Strong p53 reactivity was noted in blastemal cells in two cases with an unfavorable outcome. ABCB1 reactivity was seen in five cases with favorable histology and outcome. Only one case showed nuclear cyclin D1 positivity. All tumors showed MLH1 and MSH2 expression. All examined genes showed normal copy numbers. Unfavorable histology correlated with poor prognosis (P=0.03). There was no significant association between gene expression and prognosis. Overexpression of the EGFR gene in many Wilms tumor cases warrants further study to determine the therapeutic benefit of EGFR inhibitors in combination with other therapies in Wilms tumor patients.


Genetics of type III Bartter syndrome in Spain, proposed diagnostic algorithm.
The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC-Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families.


Interleukin 10 modulation of pathogenic Th17 cells during fatal alphavirus encephalomyelitis.
Mosquito-borne alphaviruses are important causes of epidemic encephalomyelitis. Neuronal cell death during fatal alphavirus encephalomyelitis is immune-mediated; however, the types of cells involved and their regulation have not been determined. We show that the virus-induced inflammatory response was accompanied by production of the regulatory cytokine IL-10, and in the absence of IL-10, paralytic disease occurred earlier and mice died faster. To determine the reason for accelerated disease in the absence of IL-10, immune responses in the CNS of IL-10(-/-) and wild-type (WT) mice were compared. There were no differences in the amounts of brain inflammation or peak virus replication; however, IL-10(-/-) animals had accelerated and increased infiltration of CD4(+)IL-17A(+) and CD4(+)IL-17A(+)IFNγ(+) cells compared with WT animals. Th17 cells infiltrating the brain demonstrated a pathogenic phenotype with the expression of the transcription factor, Tbet, and the production of granzyme B, IL-22, and GM-CSF, with greater production of GM-CSF in IL-10(-/-) mice. Therefore, in fatal alphavirus encephalomyelitis, pathogenic Th17 cells enter the CNS at the onset of neurologic disease and, in the absence of IL-10, appear earlier, develop into Th1/Th17 cells more often, and have greater production of GM-CSF. This study demonstrates a role for pathogenic Th17 cells in fatal viral encephalitis.


Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice.
Familial hemiplegic migraine type 1, a monogenic migraine variant with aura, is linked to gain-of-function mutations in the CACNA1A gene encoding Ca(V)2.1 channels. The S218L mutation causes severe channel dysfunction, and paroxysmal migraine attacks can be accompanied by seizures, coma, and hemiplegia; patients expressing the R192Q mutation exhibit hemiplegia only. Familial hemiplegic migraine knock-in mice expressing the S218L or R192Q mutation are highly susceptible to cortical spreading depression, the electrophysiological surrogate for migraine aura, and develop severe and prolonged motor deficits after spreading depression. The S218L mutants also develop coma and seizures and sometimes die. To investigate underlying mechanisms for these symptoms, we used multielectrode electrophysiological recordings, diffusion-weighted magnetic resonance imaging, and c-fos immunohistochemistry to trace spreading depression propagation into subcortical structures. We showed that unlike the wild type, cortical spreading depression readily propagated into subcortical structures in both familial hemiplegic migraine type 1 mutants. Whereas the facilitated subcortical spread appeared limited to the striatum in R192Q, hippocampal and thalamic spread was detected in the S218L mutants with an allele-dosage effect. Both strains exhibited increased susceptibility to subcortical spreading depression and reverberating spreading depression waves. Altogether, these data show that spreading depression propagates between cortex, basal ganglia, diencephalon, and hippocampus in genetically susceptible brains, which could explain the prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura.


Seasonal, sexual, and individual variation in endurance and activity metabolism in lizards.
Amphibolurus nuchalis were collected in central Australia during mid- (January) and late summer (March). Endurance time at 1 km/h on a motorized treadmill is greater in larger lizards, scaling as M0.65. Maximal O2 consumption (VO2max) scales as M0.96; standard metabolic rate (SMR) scales as M0.83. Factorial aerobic scope thus increases ontogenetically (9.4 at 1 g vs. 15 at 50 g). All organ masses scale allometrically; larger lizards have relatively smaller livers, but larger hearts and thigh muscles. Hematocrit and hemoglobin increase during early ontogeny, but are mass independent in adults. Maximal in vitro catalytic rates were determined for citrate synthase (CS) and pyruvate kinase (PK) in liver, heart, and thigh muscle and for lactate dehydrogenase (LDH) (lactate oxidation) in heart. All enzyme activities (expressed per g tissue) scale positively, except CS in heart. Females exhibit lower SMR and heart CS activity. March animals exhibit elevated endurance, VO2max, heart LDH, and thigh CS and PK activities. Individual variation in endurance correlates with individual differences in heart LDH and thigh CS and/or PK activities. Individual differences in VO2max are partly related to variation in hematocrit.