The feeding paradox in advanced dementia: a local perspective.
Feeding problems are common in older people with advanced dementia. When eating difficulties arise tube feeding is often initiated, unless there is a valid advance directive that refuses enteral feeding. Tube feeding has many pitfalls and complications. To date, no benefits in terms of survival, nutrition, or prevention of aspiration pneumonia have been demonstrated. Careful hand feeding is an alternative to tube feeding with advanced dementia. In Hong Kong, the Hospital Authority has established clear ethical guidelines for careful hand feeding. Notwithstanding, there are many practical issues locally if tube feeding is not used in older patients with advanced dementia. Training of doctors, nurses, and other members of the health care team is vital to the promulgation of careful hand feeding. Support from the government and Hospital Authority policy, health care staff training, public education, and promotion of advance care planning and advance directive are essential to reduce the reliance on tube feeding in advanced dementia.


Postmenopausal hormones and coronary artery disease: potential benefits and risks.
Various secondary prevention trials, including the Women's Health Initiative (WHI0, assessing the effects of hormone therapy (HT) on coronary artery disease (CAD) showed no benefit, and a trend towards early harm. However, in the WHI trial, there was a significant trend for decreasing CAD with time. The observational arms of WHI for both estrogen and estrogen/progestin suggested results which were similar to the cardioprotective effects reported in earlier observational studies. Women in these observational trials initiated hormones at a younger age and were generally healthier than women in the randomized trials. Hypotheses have been generated to explain the phenomenon of early harm, based on the induction of plaque instability in the older woman with existent significant atherosclerosis. A report of over 7000 early postmenopausal women initiating prospective trials on hormonal use did not find any evidence suggesting early harm. In the estrogen-only arm of the WHI trial, an analysis of the 50-59-year-old age group showed a near statistical decrease in coronary events: 63 (0.36-1.08), and a statistically significant reduction in a global coronary score, 0.66 (0.45-0.96). In a pooled analysis of 23 randomized clinical trials of hormonal therapy, those women within 10 years of menopause had a significant reduction in coronary events, 0.68 (0.48-0.96). Recent publications from WHI have shown a significant trend for reduced CAD and total mortality in younger women, as well as a reduced coronary calcium score when estrogen alone was given. In that neither aspirin nor statins have been shown to afford a statistical primary benefit for reducing CAD, the benefit of estrogen remains an attractive yet unproven possibility for younger women. In conclusion, while it is clear that HT has no place in the treatment of older women with CAD, emerging evidence strongly suggests a possible coronary benefit in younger healthy women.


Genetic heterogeneity and the classification of alcoholism.
Recent progress toward a systematic pathophysiological model of alcoholism has led to identification of two distinct subtypes of alcoholism. These subtypes may be distinguished in terms of distinct alcohol-related symptoms, personality traits, ages of onset, and patterns of inheritance. Type 1 alcoholism is characterized by anxious (passive-dependent) personality traits and rapid development of tolerance and dependence on the anti-anxiety effects of alcohol. This leads to loss of control, difficulty terminating binges once they start, guilt feelings, and liver complications following socially encouraged exposure to alcohol intake. In contrast, type 2 alcoholism is characterized by antisocial personality traits and persistent seeking of alcohol for its euphoriant effects. This leads to early onset of inability to abstain entirely, as well as fighting and arrests when drinking. Empirical findings about sex differences, ages of onset, associated personality traits, and longitudinal course are described in a series of adoption and family studies in Sweden and the United States. Implications for future research and clinical practice are discussed.


The cell-mediated response to schistosomal antigens at the clonal level. In vivo functions of cloned murine egg antigen-specific CD4+ T helper type 1 lymphocytes.
It is now well established that the granulomatous inflammation surrounding the eggs of Schistosoma mansoni is mediated by Th lymphocytes. Our laboratory has recently cloned murine CD4+ Th cells specific for schistosomal egg Ag (SEA). In the current study, SEA-specific IL-2-producing Th1 clones were tested for their ability to mediate local delayed-type hypersensitivity (DTH) reactions, as well as granuloma formation in vivo. Marked delayed-onset erythema and induration developed in footpads of normal syngeneic hosts injected with SEA together with SEA-specific Th1 clones. Histologic examination of these lesions revealed typical, predominantly mononuclear, cell infiltrates characteristic of DTH reactions. Conversely, no reactions were observed in allogeneic hosts, in the absence of SEA, or with the use of a control Th1 clone. Moreover, adoptive transfer of cloned SEA-specific Th1 cells to normal syngeneic mice mediated, in 4 days, the formation of vigorous granulomas around schistosomal eggs embolized in the lungs. Such granulomas, which were quantitated by computer-assisted morphometric analysis, were comparable in size to those elicited by lung-embolized eggs in SEA/CFA-immunized mice. In contrast, significantly smaller granulomas were observed in normal recipients of eggs plus a control Th1 clone or of eggs alone. Our data indicate that Ag-specific, MHC-restricted, local DTH reactions, as well as egg granuloma formation in vivo, can be mediated by monoclonal SEA-specific Th1 cells. They suggest that T cell sensitization to only small numbers of SEA determinants may be sufficient to elicit the hepatointestinal granulomatous inflammation associated with schistosomiasis.


Cloning of European eel (Anguilla anguilla) FSH-beta subunit, and expression of FSH-beta and LH-beta in males and females after sex determination.
The European eel (Anguilla anguilla) is a catadromic teleost species with a complex life cycle, both in sea and freshwater environments. The sex determination phase of gonadal development occurs in a freshwater environment. Polymorphism occurs in increasing rates with respect to gender. While males stop growing at approximately 150 g, females continue to grow to being much larger. In this study, we cloned the cDNA FSH-beta subunit of the European eel (A. anguilla), and measured the mRNA levels of FSH-beta and LH-beta in males and females after sex determination. The FSH-beta subunit cDNA consisted of 1068 bp, encoding a 127 amino acid peptide. A comparison between European and Japanese eels of the FSH-beta amino acid sequence showed 98% similarity.


Lactoferrin Enhanced Apoptosis and Protected Against Thioacetamide-Induced Liver Fibrosis in Rats.
Liver fibrosis is the common pathologic consequence of all chronic liver diseases. Lactoferrin (Lf) was investigated for its possible hepatoprotective effect against thioacetamide (TAA)-induced liver fibrosis rat model. Rats received TAA (200 mg/kg/biweekly, ip) for four successive weeks. Lf (200 mg/kg/day, p.o.) or vehicle (VHC) was administered for one month before and another month during TAA injection. Body weight and mortality rate were assessed during the month of TAA-intoxication. Thereafter, serum and liver tissues were analyzed for liver function, oxidative, fibrotic and apoptotic markers. Lf conserved rats against TAA-induced body weight-loss and mortality. Preservation of serum albumin, alkaline phosphatase and total bilirubin levels was also observed. Lf also protected rats against TAA-induced decrease in reduced glutathione and increase in malondialdehyde liver contents. Normal liver contents of hydroxyproline, nuclear factor kappa B and alpha fetoprotein; as markers of fibrosis; were increased with TAA and conserved with Lf-TAA. Lf maintained the normal architecture of the liver and immunohistochemical findings revealed increase in apoptotic bodies compared to TAA that favored necrosis. In conclusion, Lf improved liver function, reduced oxidative stress and liver fibrosis, and enhanced apoptosis in rats with liver fibrosis, suggesting it to have useful therapeutic potential in patients with liver fibrosis.


Omental synovial sarcoma mimicking an ovarian malignancy: A case report.
Synovial sarcoma is clinically rare, and cases of synovial sarcoma arising in the omentum are particularly rare. Only 3 cases have been reported in the literature to dtae, and they were associated with a poor prognosis. We herein report a rare case of aggressive primary omental synovial sarcoma presenting as an ovarian malignancy. A 53-year-old multigravida woman was referred to our hospital due to progressive abdominal distension. Magnetic resonance imaging revealed a large heterogeneous mass with an irregular component occupying the lower abdominal cavity, with an intact uterus. Intraoperative examination revealed a solid mass arising from the lower omentum. The diagnosis of omental synovial sarcoma was established based on postoperative pathological and immunohistochemical examination of the tumor. The patient underwent multiple surgical resection procedures due to the development of metastases in the liver, lungs and abdominal cavity and received adjuvant chemotherapy including doxorubicin-ifosfamide, pazopanib and trabectedin. Such rare neoplasms may be difficult to diagnose preoperatively based on radiological examinations alone. Thus, gynecologists should be aware of the possibility of omental synovial sarcoma, and combined surgical and chemotherapeutic interventions are required to control such aggressive tumors.


Antisense oligonucleotides, a novel tool for the control of cytokine effects on human cartilage. Focus on interleukins 1 and 6 and proteoglycan synthesis.
To prevent the negative effects of interleukin-1 (IL-1) and IL-1-induced IL-6 on cartilage proteoglycan (PG) synthesis, we used an antisense oligonucleotide (ASO) specific for IL-6 messenger RNA (mRNA) to inhibit IL-6 production. Explants of human articular cartilage were cultured in the presence or absence of IL-6-ASO, IL-1, and exogenous IL-6. As metabolic parameters, cartilage production of IL-6 was determined in the B9 bioassay and PG as incorporation of 35SO4. The IL-6-ASO prevented IL-1-induced production of IL-6 in the cartilage explants, as well as IL-1-induced inhibition of PG synthesis. This inhibition was restored, despite the presence of IL-6-ASO, when exogenous IL-6 was added. A control ASO (not specific for IL-6 mRNA) was not effective. The IL-6-ASO used can penetrate the extracellular matrix of articular cartilage, enter the chondrocytes, and inhibit the IL-1-induced production of IL-6. Furthermore, IL-6-ASO can prevent the IL-1-induced inhibition of cartilage PG synthesis. The effect of exogenous IL-6 shows that IL-1 requires IL-6 for inhibition of PG synthesis.


Host-Microbe Metagenomics: a Lens To Refocus Our Perspective on Infectious and Inflammatory Diseases.
A dynamic relationship involving pathogen, host immune response, and microbiome characterizes the biological framework of many infectious and inflammatory diseases. Combined host/microbe metagenomics (mNGS) enables simultaneous assessment of all three features, enabling the study and diagnosis of diverse infectious and inflammatory processes ranging from pneumonia to sepsis to inflammatory diseases such as rheumatoid arthritis. Host/microbe mNGS holds promise for new mechanistic insights, diagnostic approaches, and precision medicine interventions.


Myeloid neoplasms with concurrent BCR-ABL1 and CBFB rearrangements: A series of 10 cases of a clinically aggressive neoplasm.
Chronic myeloid leukemia (CML) is defined by the presence of t(9;22)(q34;q11.2)/BCR-ABL1. Additional chromosomal abnormalities confer an adverse prognosis and are particularly common in the blast phase of CML (CML-BP). CBFB rearrangement, particularly CBFB-MYH11 fusion resulting from inv(16)(p13.1q22) or t(16;16)(p13.1;q22), is an acute myeloid leukemia (AML)-defining alteration that is associated with a favorable outcome. The co-occurrence of BCR-ABL1 and CBFB rearrangement is extremely rare, and the significance of this finding remains unclear. We identified 10 patients with myeloid neoplasms harboring BCR-ABL1 and CBFB rearrangement. The study group included six men and four women with a median age of 51 years (range, 20-71 years). The sequence of molecular alterations could be determined in nine cases: BCR-ABL1 preceded CBFB rearrangement in seven, CBFB rearrangement preceded BCR-ABL1 in one, and both alterations were discovered simultaneously in one patient. BCR-ABL1 encoded for p210 kD in all cases in which BCR-ABL1 preceded CBFB rearrangement; a p190 kD was identified in the other three cases. Two patients were treated with the FLAG-IDA regimen (fludarabine, cytarabine, idarubicin, and G-CSF) and tyrosine kinase inhibitors (TKI); seven with other cytarabine-based regimens and TKIs, and one with ponatinib alone. At last follow up (median, 16 months; range 2-85), 7 of 10 patients had died. The co-existence of BCR-ABL1 and CBFB rearrangement is associated with poor outcome and a clinical course similar to that of CML-BP, and unlike de novo AML with CBFB rearrangement, suggesting that high-intensity chemotherapy with TKI should be considered in these patients.


Overcoming Downscaling Limitations in Organic Semiconductors: Strategies and Progress.
Organic semiconductors have great potential to revolutionize electronics by enabling flexible and eco-friendly manufacturing of electronic devices on plastic film substrates. Recent research and development led to the creation of printed displays, radio-frequency identification tags, smart labels, and sensors based on organic electronics. Over the last 3 decades, significant progress has been made in realizing electronic devices with unprecedented features, such as wearable sensors, disposable electronics, and foldable displays, through the exploitation of desirable characteristics in organic electronics. Neverthless, the down-scalability of organic electronic devices remains a crucial consideration. To address this, efforts are extensively explored. It is of utmost importance to further develop these alternative patterning methods to overcome the downscaling challenge. This review comprehensively discusses the efforts and strategies aimed at overcoming the limitations of downscaling in organic semiconductors, with a particular focus on four main areas: 1) lithography-compatible organic semiconductors, 2) fine patterning of printing methods, 3) organic material deposition on pre-fabricated devices, and 4) vertical-channeled organic electronics. By discussing these areas, the full potential of organic semiconductors can be unlocked, and the field of flexible and sustainable electronics can be advanced.


Efficacy and feasibility of laparoscopic subtotal cholecystectomy for acute cholecystitis.
For patients with acute cholecystitis, conversion from laparoscopic cholecystectomy to open surgery is not uncommon due to possibilities of serious hemorrhage at the liver bed and bile duct injury. Recent studies reported successful laparoscopic subtotal cholecystectomy for acute cholecystitis. The purpose of this study was to determine the efficacy and feasibility of such an operation based on the experience of surgeons at our facility. In this study, we enrolled 144 patients who had received either laparoscopic subtotal cholecystectomy (LSC), laparoscopic cholecystectomy (LC), or open cholecystectomy (OC) for acute cholecystitis from January 2004 to December 2009 at the Department of Surgery of our hospital. Their symptoms, signs, operative findings, pathologic results and postoperative results were compared and analyzed. There were 26 patients in the LSC group 80 in the LC group and 38 in the OC group. There were no differences in mean age, sex, and symptoms of acute cholecystitis. The LSC group showed higher CRP levels (p<0.001) and a higher grade according to the Tokyo criteria (p=0.001). The mean operative time was 115.6 minutes and mean blood loss was 158.9 ml without intra-operative or postoperative transfusion. There weren't any bile duct injuries during the operation. No group suffered bile leakage. Drains were removed 3.3 days after the operation in the LC group, the shortest time compared to the other groups (p<0.001). LC and LSC groups demonstrated shorter postoperative hospital days and time to diet resumption than the OC group (p<0.001). LSC appears to be a safe and effective treatment in cases of severe acute cholecystitis that require consideration of conversion to open surgery.


Novel antennal lobe substructures revealed in the small hive beetle Aethina tumida.
The small hive beetle, Aethina tumida, is an emerging pest of social bee colonies. A. tumida shows a specialized life style for which olfaction seems to play a crucial role. To better understand the olfactory system of the beetle, we used immunohistochemistry and 3-D reconstruction to analyze brain structures, especially the paired antennal lobes (AL), which represent the first integration centers for odor information in the insect brain. The basic neuroarchitecture of the A. tumida brain compares well to the typical beetle and insect brain. In comparison to other insects, the AL are relatively large in relationship to other brain areas, suggesting that olfaction is of major importance for the beetle. The AL of both sexes contain about 70 olfactory glomeruli with no obvious size differences of the glomeruli between sexes. Similar to all other insects including beetles, immunostaining with an antiserum against serotonin revealed a large cell that projects from one AL to the contralateral AL to densely innervate all glomeruli. Immunostaining with an antiserum against tachykinin-related peptides (TKRP) revealed hitherto unknown structures in the AL. Small TKRP-immunoreactive spherical substructures are in both sexes evenly distributed within all glomeruli. The source for these immunoreactive islets is very likely a group of about 80 local AL interneurons. We offer two hypotheses on the function of such structures.


Effect of experimental diabetic retinopathy on the non-image-forming visual system.
Diabetic retinopathy is a leading cause of blindness. Intrinsically photosensitive retinal ganglion cells (ipRGCs), which express the photopigment melanopsin, are involved in non-image-forming visual responses such as photoentrainment of circadian rhythms and pupillary light reflex. Since several reports indicate that retinal ganglion cells are affected by diabetes, we investigated the non-image-forming visual system in an advanced stage of experimental diabetes in rats induced by streptozotocin. After 15 wks of diabetes induction, clear alterations in the visual function were observed and all animals developed mature cataracts. At this time point, concomitantly with a significant decrease in the number of Brn3a(+) retinal ganglion cells, no differences in the number of melanopsin-containing cells, melanopsin levels, and retinal projections to the suprachiasmatic nuclei and the olivary pretectal nucleus were observed. At high light intensity, afferent pupil light reflex appears to be conserved in diabetic animals. After 15 wks of diabetes induction, a significant decrease in light-induced c-Fos expression in the suprachiasmatic nuclei was found. In diabetic animals, the locomotor activity pattern was conserved, although a delay in the time needed for re-entrainment after a phase delay was observed. In diabetic animals, lensectomy reversed the alterations in c-Fos expression and in the locomotor activity rhythm. These results suggest that the neuronal substrate of the non-image-forming visual system remained largely unaffected at advanced stages of diabetes, and that lensectomy, a relatively easy and safe surgery, could partially restore circadian alterations induced by diabetes.


Synergistic inhibitory effect of apomine and lovastatin on osteosarcoma cell growth.
Osteosarcoma is the most frequent malignant primary bone tumor that occurs mainly in the young, with an incidence peak observed at age 18 years. Both apomine and lovastatin have antitumor activity in a variety of cancer cell lines. Apomine, a 1,1-bisphosphonate-ester, increases the rate of degradation of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway, whereas lovastatin competitively inhibits HMG-CoA reductase enzyme activity, thereby preventing protein prenylation and cholesterol synthesis. The authors of this report investigated the effect of combined treatment with apomine and lovastatin in vitro on human and murine osteosarcoma cell lines and in vivo using a murine syngeneic model of osteosarcoma. Apomine and lovastatin synergistically decreased viability and induced apoptosis in both murine and human osteosarcoma cell lines. Combined apomine and lovastatin strongly decreased HMG-CoA reductase enzyme levels compared with lovastatin treatment alone. Consequently, the accumulation of unprenylated ras-related protein 1A induced by lovastatin was enhanced in the presence of apomine. All synergistic effects on cell viability, apoptosis, and protein prenylation were overcome by the addition of mevalonate or geranylgeraniol, 2 mevalonate pathway intermediates downstream from the target enzyme, HMG-CoA reductase. This confirmed that the mechanism of synergy in osteosarcoma cells is through augmented inhibition of HMG-CoA reductase. Finally, treatment of POS-1 osteosarcoma-bearing mice with a combination of apomine and lovastatin significantly reduced tumor progression in these mice compared with single treatments, which had no effect at the doses used. The results from this study revealed that combination therapy with apomine and lovastatin may be a novel treatment strategy for osteosarcoma.


[Pacemakers and defibrillators: what should we know about home monitoring?].
Cardiac stimulators and defibrillators dispose of diagnostic capabilities. Home monitoring permits to have information about the cardiac rhythm of the patient and about the function of the pacemaker or the defibrillator. Technical aspects, safety and legal issues of home monitoring are discussed in this article.


Flow-through photometric sensor for determination of sulfonamides.
A sensor based on integration of spectrophotometric detection and retention of the product of the Bratton-Marshall reaction for the determination of sulfanilamide, sulfamethazine, sulfaquinoxaline and sulfathiazole is reported. The methods developed using this sensor in a flow injection manifold feature linear ranges for these analytes between 10 and 1200 ng ml(-1) with relative standard deviations smaller than 2.6% in all instances and they were applied to the determination of sulfonamides in spiked milk and water samples with excellent results. The two main advantages of these sensor-based methods over other automated and non-automated counterparts are enhanced sensitivity as a result of in situ concentration and avoidance of using a de-bubbler to eliminate the nitrogen produced in the flowing system.


Relapse of kala-azar after use of multiple drugs: a case report and brief review of literature.
We present a case of kala-azar infection that recurred in a patient after completion of the standard treatment course of miltefosine, amphotericin B-deoxycholate (short course), and amphotericin B lipid formulations. The patient was cured after continuous amphotericin B-deoxycholate administration for 4 weeks. This is a unique case of relapse following the use of three important drugs. Although amphotericin B-deoxycholate is a second line drug in Nepal, it has shown a satisfactory clinical response with continuous treatment for 4 weeks. Therefore, an extended course of amphotericin B-deoxycholate may be beneficial in patients with resistance to the standard short course and other anti-leishmania drugs.


[Influence of working time regulations on the organisation and quality of clinical workflow].
The present lecture is a personal report on changing working conditions for physicians in German hospitals over the last 20 years. Documentation, coding and other administrative requirements have constantly risen and will increase once again from 2004 onwards when the complete reimbursement system in German hospitals will be rearranged on the basis of diagnosis-related groups, though without providing an adequate workforce of professional coders. Moreover, the European Court ruled that any doctor's on-call hours spent in a hospital should be regarded as part of his full working time, which in Germany is presently restricted to an average 38.5 hours a week. Consequently, this will lead to a huge demand of personnel on the one hand and an increasing fragmentation of doctor-patient relationships on the other hand, as there will be a continuous change of doctors on duty. Here, it is outlined that this fragmentation will have a negative impact on treatment quality and education and training of future physicians.


Applications of a computer simulation model of the natural history of CD4 T-cell number in HIV-infected individuals.
Data from the Multicenter AIDS Cohort Study (MACS) of 1637 gay men, recruited in 1984 and 1985 in Los Angeles and followed at 6-monthly intervals, are used to develop a computer simulation model of the typical pattern of CD4 T-cell number changes in HIV-infected AIDS-free subjects. The empirical model incorporates the following features: (1) within-person and between-person variability in CD4 measurements; (2) variation in the rates of decline of CD4 values; (3) variation in the level of CD4 at which clinical AIDS is diagnosed, and (4) greater absolute variation in CD4 values in men with high CD4 levels compared with men with low CD4 values. Three applications of the model to assist in the design and interpretation of clinical trials are given. Further applications to clinical trials and to estimate the current and future spectrum of HIV-mediated immunological disease in the USA, as measured by the CD4 values, are discussed.


Growth hormone-releasing hormone (GHRH)-induced effects on sleep EEG and nocturnal secretion of growth hormone, cortisol and ACTH in patients with major depression.
Studies in normal human subjects and animals suggest that the neuropeptide growth hormone-releasing hormone (GHRH) is a common regulator of the sleep EEG and nocturnal hormone secretion. In healthy volunteers GHRH prompts an increase in the amount of slow wave sleep (SWS) and in growth hormone (GH) secretion and blunting of cortisol release. Inhibition of GHRH may contribute to sleep-endocrine aberrances during depression. We tested the effects of pulsatile application of 4 x 50 micrograms GHRH on the sleep EEG and simultaneously investigated nocturnal hormone secretion in 10 inpatients (four females, six males) with the acute episode of major depression. In contrast to the effects of placebo, GH secretion increased distinctly and rapid-eye-movement (REM) density decreased during the second half of night. No other significant changes in sleep-endocrine activity, including SWS, cortisol and ACTH secretion, could be observed. We assume that hypothalamic-pituitary-adrenocortical system activity and slow wave sleep are inert to the influence of GHRH during acute depression. Cortisol and ACTH remained unchanged even in a subsample of five younger (aged 19-28 years) patients. This observation is in contrast to our recent finding that cortisol secretion is blunted in young normal volunteers after GHRH. But on the other hand, GHRH is capable of stimulating GH and inducing a decrease in REM density in these subjects.


Emerging use of everolimus in the treatment of neuroendocrine tumors.
Neuroendocrine tumors (NETs) consist of a diverse family of malignancies, which are derived from neuroendocrine cells, most commonly originating from the gastroenteropancreatic (GEP) tract or the bronchopulmonary system. In general, NETs are more indolent than epithelial tumors, with median survival rates of longer than 30 months. The upregulation of mTOR pathway has been shown to play a pivotal role in NET pathogenesis. Inhibition of mTOR protein with everolimus represents a progress in the treatment of advanced NETs. Everolimus has shown a significant improvement in progression-free survival (PFS) among patients with pancreatic NETs (pNETs) and nonfunctional GEP and lung NETs in the Phase III RAD001 in Advanced Neuroendocrine Tumors (RADIANT)-3 and RADIANT-4 studies, respectively. In addition, the combination of everolimus with octreotide showed a clinically significant improvement versus octreotide alone in functional NETs in the RADIANT-2 trial. These studies led to the US Food and Drug Administration (FDA) and European Medical Agency (EMA) approval of everolimus. Safety profile of everolimus is generally acceptable. The most common adverse events are stomatitis, diarrhea, rash and fatigue. There is a growing range of novel treatment options in the setting of NETs, but there are no data comparing the activity of different treatment strategies. Thus, treatment decisions are based on different aspects, such as clinical course, patient symptomatology, primary tumor site, tumor functionality, rate of progression and burden of disease. Further research is required to clarify the treatment sequencing to achieve the maximum prolongation in survival and maintenance of quality of life. Future research should concentrate on identification of predictive biomarkers for benefit from different therapies, and studies should also include quality of life as an important measurement in this disease.


Mutational spectrum of thalassemias and other hemoglobinopathies in West Bengal, Eastern India.
Thalassemia, an autosomal recessive blood disease, shows a variety of clinical expression in terms of asymptomatic to severe blood transfusion dependence. More than 500 alleles have been characterized in or around the β-globin region. Most of the geographical regions have their own characteristic alleles that predominantly circulate within the communities present in that particular region. In this article, we try to throw some light to explore the spectrum of β-thalassemia (β-thal) alleles present in West Bengal, the eastern part of India. This study comprises thalassemia carriers and diseased persons from different districts of West Bengal. We not only explored the complete mutational spectrum of this state but we also tried to fix the critical range of the values of different hematological parameters [Hb A2, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH)] for the heterozygotes or carriers of β-thal with the same mutational background. At the same time, we also tried to evaluate the maximum weighted frequency of these parameters for the heterozygotes or carriers of β-thal with the same mutational background, so that by observing these cut-off values of standard hematological parameters, we were able to predict the carrier or diseased status for mass scale screening and also try to correlate the values of these parameters with different combinations of β-thal mutation-specific alleles that can be more informative in mass scale (carrier) screening.


Paraplegia after thoracotomy: a single center experience with pediatric patients and a review of the literature.
Paraplegia is an infrequent although fearsome complication of anesthesia and surgical procedures, such as epidural anesthesia and thoracotomy. It may occur in both adults and children and a medullary lesion may be confirmed by magnetic resonance imaging, rather than computed tomography. The aim of this study is to describe the experience of two pediatric tertiary centers, contextualizing it with the other cases reported in literature. We reported three pediatric cases of post-operative paraplegia in oncological patients, focusing on the potential causes and underling the possible strategies to prevent this complication. From our study, two principal features emerged: 1) Epidural anesthesia may expose children to a greater risk of spinal cord permanent damage due to the execution of the procedure under general anesthesia, which deprives the anesthesiologist of an important feedback about the position of the device; 2) In thoracotomy, the risk of paraplegia tends to increase along with the proximity to the costo-vertebral angle, especially if electrocautery or hemostatic materials are used. A prompt post-surgical neurological status routine assessment in pediatric patients undergoing epidural anesthesia or thoracotomy should be mandatory and, associated with the correct imaging study, may lead to the most appropriate therapeutic pathway and to a better prognosis. Anesthesia, Children, Epidural, Thoracotomy, Paraplegia.


Nasal immunization with a malaria transmission-blocking vaccine candidate, Pfs25, induces complete protective immunity in mice against field isolates of Plasmodium falciparum.
Malaria transmission-blocking vaccines based on antigens expressed in sexual stages of the parasites are considered one promising strategy for malaria control. To investigate the feasibility of developing noninvasive mucosal transmission-blocking vaccines against Plasmodium falciparum, intranasal immunization experiments with Pichia pastoris-expressed recombinant Pfs25 proteins were conducted. Mice intranasally immunized with the Pfs25 proteins in the presence of a potent mucosal adjuvant cholera toxin induced robust systemic as well as mucosal antibodies. All mouse immunoglobulin G (IgG) subclasses except IgG3 were found in serum at comparable levels, suggesting that the immunization induced mixed Th1 and Th2 responses. Consistent with the expression patterns of the Pfs25 proteins in the parasites, the induced immune sera specifically recognized ookinetes but not gametocytes. In addition, the immune sera recognized Pfs25 proteins with the native conformation but not the denatured forms, indicating that mucosal immunization induced biologically active antibodies capable of recognizing conformational epitopes of native Pfs25 proteins. Feeding Anopheles dirus mosquitoes with a mixture of the mouse immune sera and gametocytemic blood derived from patients infected with P. falciparum resulted in complete interference with oocyst development in mosquito midguts. The observed transmission-blocking activities were strongly correlated with specific serum antibody titers. Our results demonstrated for the first time that a P. falciparum transmission-blocking vaccine candidate is effective against field-isolated parasites and may justify the investigation of noninvasive mucosal vaccination regimens for control of malaria, a prototypical mucosa-unrelated mosquito-borne parasitic disease.


Chemical composition and flavor of ecuadorian cocoa liquor.
The contribution of the chemical composition to the flavor of cocoa liquor from an Ecuadorian selfed population of clone EET 95 was investigated. Polyphenols, purine alkaloids, organic acids, and sugars were quantified, and the key sensory characteristics of cocoa were scored by a trained panel. Despite the short bean fermentation (2 days) commonly used for Arriba cocoa, acetic acid content was closely correlated to liquor pH, demonstrating its essential role in cocoa liquor acidification. Polyphenols were positively correlated to astringency, bitterness, and the green note and negatively correlated to the fruity character. Alkaloid and polyphenol levels fluctuated significantly within the selfed progeny and tended to be lower than those of the heterozygous clone EET 95 (inbreeding effect). These results support the idea that polyphenols might be essential to the overall perception of cocoa liquor characteristics and indicate that the composition and the sensory quality of cocoa liquor are the result of both a genotypic contribution and the conditions of fermentation and roasting.


The transient responses of hybridoma cells to nutrient additions in continuous culture: II. Glutamine pulse and step changes.
The transient and steady-state responses of hybridoma growth and metabolism to glutamine pulse and step changes have been examined. Metabolic quotients are reported for oxygen, glucose, lactate, ammonia, glutamine, alanine, and other amino acids. The specific glutamine consumption rate increased rapidly after all glutamine additions, but the responses of the glucose and oxygen consumption rates and the cell concentration were found to depend on the intial feed glutamine concentration. The glucose consumption rate was 1.4-10.9 times that of glutamine, and serine and branched-chain amino acids were consumed in larger amounts at the higher glucose: glutamine uptake ratios. It was estimated that maintenance accounted for ca. 60% of the cellular ATP requirements at specific growth rates ranging from 0.57 to 0.68 day(-1).


Bimodular continuous attractor neural networks with static and moving stimuli.
We investigated the dynamical behaviors of bimodular continuous attractor neural networks, each processing a modality of sensory input and interacting with each other. We found that when bumps coexist in both modules, the position of each bump is shifted towards the other input when the intermodular couplings are excitatory and is shifted away when inhibitory. When one intermodular coupling is excitatory while another is moderately inhibitory, temporally modulated population spikes can be generated. On further increase of the inhibitory coupling, momentary spikes will emerge. In the regime of bump coexistence, bump heights are primarily strengthened by excitatory intermodular couplings, but there is a lesser weakening effect due to a bump being displaced from the direct input. When bimodular networks serve as decoders of multisensory integration, we extend the Bayesian framework to show that excitatory and inhibitory couplings encode attractive and repulsive priors, respectively. At low disparity, the bump positions decode the posterior means in the Bayesian framework, whereas at high disparity, multiple steady states exist. In the regime of multiple steady states, the less stable state can be accessed if the input causing the more stable state arrives after a sufficiently long delay. When one input is moving, the bump in the corresponding module is pinned when the moving stimulus is weak, unpinned at intermediate stimulus strength, and tracks the input at strong stimulus strength, and the stimulus strengths for these transitions increase with the velocity of the moving stimulus. These results are important to understanding multisensory integration of static and dynamic stimuli.


MicroRNA-124-3p affects proliferation, migration and apoptosis of bladder cancer cells through targeting AURKA.
The aim of this study was to establish the relationship between miR-124-3p and Aurora A kinase (AURKA) in bladder cancer (BC). The expressions of miR-124-3p and AURKA in BC tissues and cell lines were detected using RT-PCR and western blot. BC cells were transfected with miR-124-3p mimics and AURKA siRNA. After this cell proliferation, migration, cell cycle and apoptosis were measured using CCK-8, colony formation assay, wound healing assay and cytometry tests. The relationship between miR-124-3p and AURKA was confirmed with luciferase reporter assay. Mice xenograft models were constructed to examine the effects of AURKA on BC in vivo. MiR-124-3p expression was significantly down-regulated in BC tissues and cell lines, while AURKA was significantly up-regulated compared to normal samples. MiR-124-3p targeted AURKA and decreased its expression. Transfection of miR-124-3p mimics and AURKA siRNA was shown to down-regulate BC cell proliferation and migration as well as induce cell apoptosis. As suggested by xenograft models, the inhibition of AURKA can effectively suppress tumor growth. MiR-124-3p has significant impact on proliferation, migration and apoptosis of BC cells by targeting AURKA.


Visuomanual coordination in childhood: adaptation to visual distortion.
The aim of the experiment was to study the adaptive capacities of children to perform drawing movements while being visually perturbed. Children aged 5-11 years and a group of adults drew diamonds via information provided through a computer screen. The screen display was either upright or rotated 180 degrees. Results showed that the absence of direct vision of the hand yielded more perturbation in the youngest group of children compared to all other groups. In spite of some initial difficulty, all children reached accurate control after five trials. When faced with spatial rotations of the visual field, youngsters were again more perturbed than others. All children showed the same rate of adaptation to visual rotations, but they differed on adaptive strategies. Five- and 7-year-olds shifted to a feedforward mode of control consisting of the production of a rapid gesture, followed by error evaluation in order to correct their next movement. Older children were characterised by a progressive integration of reafferent visual and proprioceptive information. It resulted in an increase in duration of strokes and reduced speed, meaning enhanced on-line retrieval of information. However, 9-year-old children experienced more difficulty recuperating sensory information during movement than 11-year-olds, and kept using error feedback. Finally, visuomanual coordination in children aged 11 years, while slightly differing from that of adults, was not yet totally mature.


Medical Metaphors: Increasing Clarity but at What Cost?
Clinicians often use metaphors to explain complex ideas. Metaphors also have the potential to reinforce unhelpful thinking regarding symptoms. We surveyed musculoskeletal specialists regarding use of metaphors in their daily practice and then assessed the contexts in which they are used, the themes of metaphors, and potential for reinforcement of common misconceptions (unhelpful thinking). Two primary research questions were posed: 1- What are the common characteristics of the medical metaphors used in patient-clinician communication by musculoskeletal specialists? And, 2- What percentage of medical metaphors used in patient-clinician communication have potential to induce unhelpful thinking and what are the characteristics of those metaphors? Eighty-one orthopedic and trauma specialists provided examples of metaphors they use in daily practice. Qualitative analysis of responses was performed through open coding of the data with the use of a constant-comparative technique involving several rounds of reading and rereading the data. The 157 metaphors were categorized into 15 different themes. The most common themes were mechanical, objects, and sports and leisure. We also classified metaphors as addressing the natural history of the disease, treatment, mechanism, anatomy, or other. Thirty-five metaphors (22%) were identified as having the potential to reinforce unhelpful thinking. The most common purpose of these metaphors was for explaining the mechanism or natural history of the disease. Metaphors can either reinforce or reorient potentially unhealthy misconceptions. They can also reinforce despair and worry, or they can improve hope and sense of control. Orthopedic surgeons can be strategic and thoughtful in their use of metaphors, planning and practicing specific metaphors for optimal mental, social, and physical health.


Me or my: two different patterns of pronoun case errors.
This paper investigates why some young children prefer to replace I with me (me-children), whereas others prefer to replace I with my (my-children). The data come from 12 children, observed monthly, from 1;0 to 3;0. It was found that the percentage of errors in which me replaced I (the me-error rate) was positively correlated with the correct production of me as an objective pronoun (the me-total). The me for I and my for I errors were antagonistic, with one of the patterns almost always dominating over the other, resulting in a clear individual difference between me-children and my-children. It was also found that the me-total during the period in which my for I replacements first emerged prefigured whether a child would become a me-child or a my-child.


Ocular vestibular-evoked myogenic potentials in healthy pilots and student pilots.
Excellent vestibular function (including utricular function) is important for pilots to maintain correct spatial orientation during flight. Vestibular-evoked myogenic potential (VEMP) recorded from extraocular muscles, the so-called ocular VEMP (oVEMP), can be used to evaluate utricular function. However, oVEMP has not been applied to pilots because of lack of reliable normative data. Hence, this study is designed to establish preliminary normative data for oVEMP induced by air-conducted sound in pilots and student pilots. There were 62 healthy student pilots (30 male and 32 age-matched female) and 31 healthy male fighter pilots who were recruited as study participants. During binaural air-conducted sound stimulation oVEMP was recorded bilaterally. The latencies of nI and pI, nI-pI interval, peak-to-peak nI-pI amplitude, and asymmetry ratio (AR) of oVEMP in all participants were collected. Meanwhile, the effects of gender and age on oVEMP were also investigated. The latencies of nI and pI, nI-pI interval, nI-pI interpeak amplitude, and AR of oVEMP in all participants were 10.35 +/- 0.66 ms, 15.18 +/- 1.07 ms, 4.75 +/- 0.99 ms, 6.75 +/- 4.13 microV, and 13.22 +/- 9.13%, respectively. No significant difference existed between male student pilots and male pilots in terms of oVEMP parameters. The only significant difference was the nI-pI amplitude between age-matched male and female student pilots: 6.96 +/- 3.85 microV for male student pilots and 5.47 +/- 3.10 microV for female student pilots. oVEMP should be interpreted with the AR rather than raw amplitude itself. Each institution should determine its own normal values.


Delay and Speed of Visual Feedback of a Keystroke Cause Illusory Heaviness and Stiffness.
Imposing a delay between an action (e.g., a limb movement) and its related visual feedback (e.g., a cursor movement on the display) induces a peculiar sensation of heaviness or stiffness. Earlier studies have examined this delay-induced heaviness or stiffness sensation in relation to the non-arbitrary causal relationship between an action and its effect. Here, "non-arbitrary causal relationship" means that an action produces a specific and deterministic pattern of visual feedback; for example, a leftward limb movement consistently and deterministically causes a leftward visual motion. In modern graphical user interfaces, on the other hand, users often control visual information by pressing keys, wherein the relationship between the keystroke and the change in visual information is arbitrary. The present study examined whether the sensation of heaviness, stiffness and bumpiness could be caused when participants' keystroke produced a delayed arbitrary visual feedback. Participants were asked to press and hold down an assigned key to cause temporal luminance changes in a square centered on the display, an arbitrary visual feedback of their keystroke. Not only the onset delay of the temporal luminance change from the participant's keystroke but also the speed of the temporal luminance change were examined as a visual cue to heaviness, stiffness, or bumpiness. In Experiment 1, the participants' task was to give a rating for the strength of the heaviness, stiffness, or bumpiness perceived when they pressed the key. Our results showed that the heaviness and stiffness ratings increased as the delay increased and decreased as the speed increased. To check whether the manipulation of the delay and speed of the visual feedback caused changes in the subjective evaluation of sensorimotor incongruence, in Experiment 2, we asked the participants to give a rating for the sense of agency. The rating scores decreased as the delay increased and increased as the speed increased. The delay and speed influenced the rating scores for the sense of agency in the opposite direction to those for heaviness/stiffness. We discuss that the brain determines the heaviness and stiffness during a keystroke based on internalized statistics relating to the delay and speed of the action feedback.


Will they fit? Determinants of the adaptability of stock TMJ prostheses where custom TMJ prostheses were utilized.
Currently only two alloplastic temporomandibular joint (TMJ) total joint replacement (TJR) systems are available in the United States. The aim of this study was to define variables that determine whether a Biomet stock prosthesis could have been used to reconstruct a TMJ previously reconstructed with a TMJ Concepts patient-fitted prosthesis. All of the TMJ Concepts prostheses placed between 2010 and 2018 at the University of Texas - Health at San Antonio were analyzed retrospectively. There were 128 cases (241 joints) with intact stereolithographic models analyzed for successful adaptation of the Biomet stock TMJ prosthesis. Anatomical, demographic, etiological, and perioperative data were gathered for each joint to investigate possible causes of failure of stock adaptation. The majority of joints, 74% (178/241), could have had a stock prosthesis adapt. All joints with ≥40mm gap arthroplasty failed stock prosthesis adaptation. Only 50% (32/64) of the joints with at least one previous open TMJ surgery and 60% (58/96) of the joints with concomitant orthognathic surgery could have had a stock TMJ prosthesis. The stock prosthesis could not be adapted for any of the patients requiring TMJ replacement for congenital disorders or those requiring TMJ salvage. Overall, the majority of cases treated with a patient-specific TMJ TJR could have been treated with a stock prosthesis.


Handheld optical coherence tomography-reflectance confocal microscopy probe for detection of basal cell carcinoma and delineation of margins.
We present a hand-held implementation and preliminary evaluation of a combined optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) probe for detecting and delineating the margins of basal cell carcinomas (BCCs) in human skin <italic<in vivo</italic<. A standard OCT approach (spectrometer-based) with a central wavelength of 1310 nm and 0.11 numerical aperture (NA) was combined with a standard RCM approach (830-nm wavelength and 0.9 NA) into a common path hand-held probe. Cross-sectional OCT images and enface RCM images are simultaneously displayed, allowing for three-dimensional microscopic assessment of tumor morphology in real time. Depending on the subtype and depth of the BCC tumor and surrounding skin conditions, OCT and RCM imaging are able to complement each other, the strengths of each helping overcome the limitations of the other. Four representative cases are summarized, out of the 15 investigated in a preliminary pilot study, demonstrating how OCT and RCM imaging may be synergistically combined to more accurately detect BCCs and more completely delineate margins. Our preliminary results highlight the potential benefits of combining the two technologies within a single probe to potentially guide diagnosis as well as treatment of BCCs.


Changes in attitudes toward homosexuals.
Cross-sectional data on the attitudes of Canadian university students, and their parents, indicate attitudes toward homosexuals have become increasingly tolerant and accepting over the past 14 years. Various experimental findings and self-attributions indicate the major cause of this change is increased contact with persons known to be homosexuals. Other factors, such as the evidence for biological origins of sexual orientation, and boomerang effects from hostility toward homosexuals also appear to have played a role.


Combining registry, primary, and secondary data sources to identify the impact of cancer on labor market outcomes.
Some cancers are rapidly becoming chronic conditions that are more and more often diagnosed in working-age individuals. The authors developed a research agenda to study the labor market outcomes attributable to detection and treatment for cancer, and research design and data collection strategies to improve upon other research on these questions. In this article, they describe their approach to combining secondary data sources, primary data collection, and cancer registry data to evaluate the impact cancer has on labor market outcomes such as employment, hours worked, wages, and health insurance. They then critically assess how well their study design and data collection strategy accomplished its objectives. The intention is to offer guidance on how researchers, who are interested in the economic consequences of cancer, as well as of other chronic conditions, might develop and execute studies that examine labor market outcomes. As more attention is placed on the economic aspects of disease, the methods used to estimate productivity loss and other economic outcomes attributable to these conditions require careful scrutiny so that reliable findings can be used to shape health care decisions and policy.


Australian orchids and the doctors they commemorate.
Botanical taxonomy is a repository of medical biographical information. Such botanical memorials include the names of some indigenous orchids of Australia. By searching reference texts and journals relating to Australian botany and Australian orchidology, as well as Australian and international medical and botanical biographical texts, I identified 30 orchids indigenous to Australia whose names commemorate doctors and other medical professionals. Of these, 24 have names that commemorate a total of 16 doctors who worked in Australia. The doctors and orchids I identified include: doctor-soldiers Richard Sanders Rogers (1862-1942), after whom the Rogers' Greenhood (Pterostylis rogersii) is named, and Robert Brown (1773-1858), after whom the Purple Enamel Orchid (Elythranthera brunonis) is named; navy surgeon Archibald Menzies (1754-1842), after whom the Hare Orchid (Leptoceras menziesii) is named; radiologist Hugo Flecker (1884-1957) after whom the Slender Sphinx Orchid (Cestichis fleckeri) is named; and general medical practitioner Hereward Leighton Kesteven (1881-1964), after whom the Kesteven's Orchid (Dendrobium kestevenii) is named. Biographic references in scientific names of plants comprise a select but important library of Australian medical history. Such botanical taxonomy commemorates, in an enduring manner, clinicians who have contributed to biology outside clinical practice.


Synthesis and characterization of Cu3(BTC)2 membranes by thermal spray seeding and secondary growth.
Crack-free Cu3(BTC)2 membranes were successfully prepared by thermal spray seeding and secondary growth method. Thermal spray seeding method, combining thermal seeding and pressurized spraying, uniformly distributed seed solution on the support, anchoring seed crystals tightly on the support. After secondary growth of the seeded support in the autoclave, continuous crack-free membrane was obtained by controlling cooling and drying steps. The gas permeation test was conducted at various temperatures using H2, CO2, CH4 and N2 gases.


Racial and ethnic disparities in kidney transplantation.
Success of renal transplantation, as a viable alternative to dialysis, has been tempered by long-standing racial disparities. Ethnic minorities have less access to transplantation, are less likely to be listed for transplantation, and experience a higher rate of graft failure. Reasons for the existing racial disparities at various stages of the transplantation process are complex and multi-factorial. They include a combination of behavioral, social, environmental, and occupational factors, as well as potential intended or unintended discrimination within the healthcare system. Immunologic factors such as human leukocyte antigen matching, composition of the organ donor pool, and patient immune response, all of which affect post-transplantation graft rejection rates and patient survival, also contribute to health disparities between ethnic groups.


Clinical implications of COX-1 and/or COX-2 inhibition for the distal gastrointestinal tract.
Side effects of the distal gastrointestinal tract after NSAID use are common and more frequent than previously recognized. Increased mucosal permeability and mucosal inflammation are often silent but appear after NSAID treatment with most dual COX inhibitors. Other clinical manifestations include: anemia, occult blood loss, malabsorption, protein-loss, ileal dysfunction, diarrhea, mucosal ulceration and strictures due to diaphragm disease. More common complications are lower gastrointestinal bleeding and perforation, which represent at least one third of all gastrointestinal complications observed with NSAID use. Studies with selective COX-2 inhibitors have shown that, in the short term, these agents do not increase mucosal permeability or induce anemia due to occult bleeding and that, when compared to dual COX inhibitors, lower gastrointestinal complications may be reduced by 50%. In order to minimize the impact of these side effects, it is important to increase the current standards of suspicion by physicians who treat these patients, since drug discontinuation may further reduce damage, and clinical experience with agents that may prevent or treat distal tract damage is very limited. From this perspective, selective COX-2 inhibitors may be the drugs of choice in the high-risk patient that needs NSAIDs. Another important area of uncertainty is the impact of NSAID use in patients with inflammatory bowel diseases. Data from different animal models of inflammatory bowel disease suggest that inhibition of both COX-1 and COX-2 derived prostaglandins affects the severity of the mucosal inflammation. However, current epidemiological and clinical data are contradictory. Since many patients.


CD4+CD25+ T lymphocytes in human tonsils suppress the proliferation of CD4+CD25- tonsil cells.
Animal studies define CD4+CD25+ T cells as a subset that protect against autoimmune inflammation. We wanted to investigate whether CD4+CD25+ T cells from patients with recurrent tonsillitis could suppress the proliferation of other tonsil cells, in vitro, as this immunological tissue also may serve as a model for chronic inflammation. Tonsil CD4+CD25+ cells markedly suppressed the proliferation of CD4+CD25- T cells in Concanavalin A-stimulated cocultures compared with cultures containing CD4+CD25- T cells only. The suppression exerted by the CD4+CD25+ cells was abrogated if these cells were irradiated before coculture or if interleukin (IL)-2 was added to the culture medium. CD4+CD25+ T cells proliferated poorly in response to mitogen, when cultured alone. Substitution with CD4+CD25+ T cells isolated from peripheral blood, enriched by similar methods, did not downregulate the proliferation of CD4+CD25- responder cells from tonsils. The augmented suppressive ability of tonsil CD4+CD25+ T cells compared with cells of this phenotype from blood, on CD4+CD25- responder cells from tonsils, suggests that there may be a functional difference between CD25+ cells from the two locations. In conclusion, CD4+CD25+ T cells from inflamed tonsils distinctly suppressed T-cell responses to mitogen in vitro, pointing to a regulatory role for CD4+CD25+ cells retrieved from inflammatory reactions in humans.


Hormonal therapy in menopausal transition: implications for improvement of health-related quality of life.
The study aim was to assess scores of the Menopause Rating Scale (MRS) among women who use and desire to use hormonal therapy (HT), as well as to evaluate factors contributing to HT use and desire to use HT among women in menopausal transition. A total of 513 mid-aged women participated in the study. Data were collected using socio-demographic questionnaire, MRS and Beck Depression Inventory. The prevalence of current HT use was 9.7%, while 4.5% of women who did not use HT expressed a desire to start using HT. The MRS cutoff score for HT use was 10.5 and 11.5 among those who desire to use HT. Living in the central city districts, having lower body mass index, younger age at menopause, more gynecological illnesses, and worse MRS were associated with HT use. Living in the central city districts, having fewer births, more gynecological and chronic illnesses and having more depressive symptoms were associated with the desire to use HT. Mid-aged women who perceive their quality of life as poor due to climacteric symptoms should be advised to consider HT to improve their health status and everyday functioning.


Glucose-depletion suppresses synaptic transmissions in rat dorsolateral septal nucleus.
Removal of extracellular glucose hyperpolarized the post-synaptic membrane of dorsolateral septal nucleus (DLSN) neurons. Glucose-depletion suppressed the excitatory postsynaptic potential (EPSP) and the late hyperpolarizing potential (LHP) without affecting the responses induced by glutamate or baclofen. Glibenclamide did not antagonize the effects produced by glucose-depletion. These results suggest that glucose is necessary to maintain the membrane excitability and transmitter-release in rat DLSN.


Open-Source Machine Learning in Computational Chemistry.
The field of computational chemistry has seen a significant increase in the integration of machine learning concepts and algorithms. In this Perspective, we surveyed 179 open-source software projects, with corresponding peer-reviewed papers published within the last 5 years, to better understand the topics within the field being investigated by machine learning approaches. For each project, we provide a short description, the link to the code, the accompanying license type, and whether the training data and resulting models are made publicly available. Based on those deposited in GitHub repositories, the most popular employed Python libraries are identified. We hope that this survey will serve as a resource to learn about machine learning or specific architectures thereof by identifying accessible codes with accompanying papers on a topic basis. To this end, we also include computational chemistry open-source software for generating training data and fundamental Python libraries for machine learning. Based on our observations and considering the three pillars of collaborative machine learning work, open data, open source (code), and open models, we provide some suggestions to the community.


Pragmatic randomised controlled trial to evaluate the effectiveness and cost effectiveness of a multi-component intervention to reduce substance use and risk-taking behaviour in adolescents involved in the criminal justice system: A trial protocol (RISKIT-CJS).
Adolescence is a critical developmental stage when young people make lifestyle choices that have the potential to impact on their current and future health and social wellbeing. The relationship between substance use and criminal activity is complex but there is clear evidence that the prevalence of problematic substance use is far higher among adolescent offenders than the general adolescent population. Adolescent offenders are a marginalized and vulnerable population who are significantly more likely to experience health and social inequalities in later life than their non-offending peers. There is a paucity of evidence on effective interventions to address substance use and risk-taking behaviours in adolescent offender populations but it is clear that preventative or abstinence orientated interventions are not effective. RISKIT-CJS is an intervention developed in collaboration with young people taking account of the current best evidence. Feasibility and pilot studies have found the intervention addresses the needs of adolescents, is acceptable and has demonstrated potential in reducing substance use and risk-taking behavior. The study is a mixed method, two-armed, prospective, pragmatic randomized controlled trial with individual randomisation to either treatment as usual alone or the RISKIT-CJS intervention in addition to treatment as usual. Adolescents, aged 13 to 17 years inclusive, engaged with the criminal justice system who are identified as having problematic substance use are eligible to participate. The study will be conducted across three geographical areas; South and South East England, London and North East England between March 2017 and February 2019. The study represents an ambitious programme of work to address an area of need for a marginalized and vulnerable population. ISRCTN77037777 registered 15/09/2016.


Giving weight to incretin-based pharmacotherapy for obesity-related sleep apnea: a revolution or a pipe dream?
Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.


Comparison of monoclonal and polyclonal antibodies directed against immunoglobulin light and heavy chains in non-Hodgkin's lymphoma.
A study comparing the usage of monoclonal and polyclonal antibodies specific for immunoglobulin light and heavy chains was performed on frozen-tissue sections of 30 B-cell non-Hodgkin's lymphomas. In 16 cases, monotypic staining for an immunoglobulin light chain was demonstrated with monoclonal antibodies using a three-step avidin-biotin peroxidase complex (ABC) method; 13 cases were positive for kappa. In 14 cases, no immunoglobulin light-chain production was demonstrated. Repeat staining of 11 of these 14 cases with polyclonal anti-sera by a direct immunoperoxidase method demonstrated monotypic staining for light chain in 10 cases, 9 of which were positive for lambda. In 22 of 30 non-Hodgkin's lymphomas, an immunoglobulin heavy chain was identified using monoclonal anti-sera. In eight cases, however, no heavy chain was found. Repeated staining with polyclonal sera of additional sections in three of eight cases demonstrated heavy-chain production in each case. Decreased sensitivity, especially for the detection of the lambda light chain, rendered this particular lot of monoclonal antibodies unsuitable for immunophenotyping non-Hodgkin's lymphomas. Variability of antigenic sites on the immunoglobulin molecule seems a likely explanation for these observations.


Patterns of drug use from adolescence to young adulthood: III. Predictors of progression.
Possible linkages of influence among classes of drugs in the observed sequential progression from adolescence to young adulthood are investigated through event history analyses. Three stages are examined: initiation to marijuana, to the use of other illicit drugs, and to prescribed psychoactive drugs. The data are based on a follow-up cohort of former adolescents representative of high school students in grade 10 and 11 in New York State who were reinterviewed nine years later at ages 24-25. The sequential order between alcohol and/or cigarettes and marijuana reflects not only the effect of the use of legal drugs on marijuana initiation, but also age effects on onset of these drugs, controlling for individual characteristics measured in adolescence; marijuana use by one's friends in adolescence is an additional important predictor of marijuana initiation. Prior use of marijuana is necessary for progression to other illicit drugs. Multiple factors are involved in the progression to prescribed drugs, with adolescent depressive symptomatology and use of other illicit drugs important for both sexes, and maternal use of psychoactive drugs, dropping out of school, and prior use of marijuana of additional importance for women. Although licit drugs influence initiation into marijuana independently of age effects, it is especially for the progression from marijuana to other illicit drugs that the earlier drug is associated with the progression to a higher stage drug.


Hypercaloric cafeteria-like diet induced UCP3 gene expression in skeletal muscle is impaired by hypothyroidism.
The uncoupling protein UCP3 belongs to a family of mitochondrial carriers located in the inner mitochondrial membrane of certain cell types. It is expressed almost exclusively at high levels in skeletal muscle and its physiological role has not been fully determined in this tissue. In the present study we have addressed the possible interaction between a hypercaloric diet and thyroid hormone (T3), which are strong stimulators of UCP3 gene expression in skeletal muscle. Male Wistar rats weighing 180 +/- 20 g were rendered hypothyroid by thyroidectomy and the addition of methimazole (0.05%; w/v) to drinking water after surgery. The rats were fed a hypercaloric cafeteria diet (68% carbohydrates, 13% protein and 18% lipids) for 10 days and sacrificed by decapitation. Subsequently, the gastrocnemius muscle was dissected, total RNA was isolated with Trizol and UCP3 gene expression was determined by Northern blotting using a specific probe. Statistical analysis was performed by one-way analysis of variance (ANOVA) followed by the Student-Newman-Keuls post-test. Skeletal muscle UCP3 gene expression was decreased by 60% in hypothyroid rats and UCP3 mRNA expression was increased 70% in euthyroid cafeteria-fed rats compared to euthyroid chow-fed animals, confirming previous studies. Interestingly, the cafeteria diet was unable to stimulate UCP3 gene expression in hypothyroid animals (40% lower as compared to euthyroid cafeteria-fed animals). The results show that a hypercaloric diet is a strong stimulator of UCP3 gene expression in skeletal muscle and requires T3 for an adequate action.


Liver Enzymes and Their Association with Some Cardiometabolic Diseases: Evidence from a Large Kurdish Cohort.
According to reports, liver enzymes might play a role in the incidence and development of cardiometabolic diseases such as metabolic syndrome (MetS), hypertension (HTN), and cardiovascular diseases (CVD). We conducted a study to investigate this hypothesis among the Iranian Kurdish population. We analyzed data from the baseline phase of the Ravansar noncommunicable disease (RaNCD) cohort. The association between liver enzymes (ALT, AST, ALT/AST ratio, GGT, and ALP) with cardiometabolic disease risk factors was investigated by multiple linear regression. The odds ratio of cardiometabolic diseases in each quartile category of liver enzyme concentration was estimated using multivariable logistic regression. The mean age of participants was 47.3 ± 4.1 years (48.1 years in males and 51.8 years in females). In the adjusted model, all enzymes were positively associated with MetS, HTN, and CVD risk factors except for the ALT/AST ratio with SBP and DBP. In the adjusted model, subjects in the fourth quartile for GGT, ALT/AST ratio, ALT, ALP, and AST had 3.29-, 2.94-, 2.45-, 2.00-, and 1.19-fold increased risk for MetS compared with subjects in the first quartile. Increased levels of GGT and ALP were positively associated with the risk of HTN (ORs = 1.33, 95%CI = 1.03-1.71 for GGT; ORs = 1.32, 95%CI = -1.68 for ALP). An increased GGT level was significantly associated with CVD (ORs = 1.54, 95%CI = 1.03-1.68). Within the normal range quartile, ALT had a significant correlation with the incidence of MetS. According to the present study, the levels of liver enzymes could be considered for early diagnosis of MetS, HTN, and CVD.


pH- and temperature-responsive supramolecular assemblies with highly adjustable viscoelasticity: a multi-stimuli binary system.
Stimuli-responsive materials are increasingly needed for the development of smart electronic, mechanical, and biological devices and systems relying on switchable, tunable, and adaptable properties. Herein, we report a novel pH- and temperature-responsive binary supramolecular assembly involving a long-chain hydroxyamino amide (HAA) and an inorganic hydrotrope, boric acid, with highly tunable viscous and viscoelastic properties. The system under investigation demonstrates a high degree of control over its viscosity, with the capacity to achieve over four orders of magnitude of control through the concomitant manipulation of pH and temperature. In addition, the transformation from non-Maxwellian to Maxwellian fluid behavior could also be induced by changing the pH and temperature. Switchable rheological properties were ascribed to the morphological transformation between spherical vesicles, aggregated/fused spherical vesicles, and bicontinuous gyroid structures revealed by cryo-TEM studies. The observed transitions are attributed to the modulation of the head group spacing between HAA molecules under different pH conditions. Specifically, acidic conditions induce electrostatic repulsion between the protonated amino head groups, leading to an increased spacing. Conversely, under basic conditions, the HAA head group spacing is reduced due to the intercalation of tetrahydroxyborate, facilitated by hydrogen bonding.


Hemp (Cannabis sativa L.).
Hemp (Cannabis sativa L.) suspension culture cells were transformed with Agrobacterium tumefaciens strain EHA101 carrying the binary plasmid pNOV3635. The plasmid contains a phosphomannose isomerase (PMI) selectable marker gene. Cells transformed with PMI are capable of metabolizing the selective agent mannose, whereas cells not expressing the gene are incapable of using the carbon source and will stop growing. Callus masses proliferating on selection medium were screened for PMI expression using a chlorophenol red assay. Genomic DNA was extracted from putatively transformed callus lines, and the presence of the PMI gene was confirmed using PCR and Southern hybridization. Using this method, an average transformation frequency of 31.23% ± 0.14 was obtained for all transformation experiments, with a range of 15.1-55.3%.


Management of Neonatal Diabetes due to a KCNJ11 Mutation with Automated Insulin Delivery System and Remote Patient Monitoring.
Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes. Management of hyperglycemia in neonates with subcutaneous insulin is challenging because of frequent feeding, variable quantity of milk intake with each feed, low insulin dose requirements, and high risk for hypoglycemia and associated complications in this population. We present a case of NDM in a proband initially presenting with focal seizures and diabetic ketoacidosis due to a pathologic mutation in the beta cell potassium ATP channel gene KCNJ11 c.679G > A (p.E227K). We describe the use of continuous glucose monitoring (CGM), insulin pump, automated insulin delivery system, and remote patient monitoring technologies to facilitate rapid and safe outpatient cross-titration from insulin to oral sulfonylurea. Our case highlights the safety and efficacy of these technologies for infants with diabetes, including improvements in glycemia, quality of life, and cost-effectiveness by shortening hospital stay.


What's old is new again: yeast mutant screens in the era of pooled segregant analysis by genome sequencing.
While once de-rigueur for identification of genes involved in biological processes, screening of chemically induced mutant populations is an approach that has largely been superseded for model organisms such as Saccharomyces cerevisiae. Availability of single gene deletion/overexpression libraries and combinatorial synthetic genetic arrays provide yeast researchers more structured ways to probe genetic networks. Furthermore, in the age of inexpensive DNA sequencing, methodologies such as mapping of quantitative trait loci (QTL) by pooled segregant analysis and genome-wide association enable the identification of multiple naturally occurring allelic variants that contribute to polygenic phenotypes of interest. This is, however, contingent on the capacity to screen large numbers of individuals and existence of sufficient natural phenotypic variation within the available population. The latter cannot be guaranteed and non-selectable, industrially relevant phenotypes, such as production of volatile aroma compounds, pose severe limitations on the use of modern genetic techniques due to expensive and time-consuming downstream analyses. An interesting approach to overcome these issues can be found in Den Abt et al. 1 (this issue of Microbial Cell), where a combination of repeated rounds of chemical mutagenesis and pooled segregant analysis by whole genome sequencing was applied to identify genes involved in ethyl acetate formation, demonstrating a new path for industrial yeast strain development and bringing classical mutant screens into the 21st century.


Comparative proteomic profiling of the serum differentiates pancreatic cancer from chronic pancreatitis.
Finland ranks sixth among the countries having highest incidence rate of pancreatic cancer with mortality roughly equaling incidence. The average age of diagnosis for pancreatic cancer is 69 years in Nordic males, whereas the average age of diagnosis of chronic pancreatitis is 40-50 years, however, many cases overlap in age. By radiology, the evaluation of a pancreatic mass, that is, the differential diagnosis between chronic pancreatitis and pancreatic cancer is often difficult. Preoperative needle biopsies are difficult to obtain and are demanding to interpret. New blood based biomarkers are needed. The accuracy of the only established biomarker for pancreatic cancer, CA 19-9 is rather poor in differentiating between benign and malignant mass of the pancreas. In this study, we have performed mass spectrometry analysis (High Definition MSE ) of serum samples from patients with chronic pancreatitis (13) and pancreatic cancer (22). We have quantified 291 proteins and performed detailed statistical analysis such as principal component analysis, orthogonal partial least square discriminant analysis and receiver operating curve analysis. The proteomic signature of chronic pancreatitis versus pancreatic cancer samples was able to separate the two groups by multiple statistical techniques. Some of the enriched pathways in the proteomic dataset were LXR/RXR activation, complement and coagulation systems and inflammatory response. We propose that multiple high-confidence biomarker candidates in our pilot study including Inter-alpha-trypsin inhibitor heavy chain H2 (Area under the curve, AUC: 0.947), protein AMBP (AUC: 0.951) and prothrombin (AUC: 0.917), which should be further evaluated in larger patient series as potential new biomarkers for differential diagnosis.


Insulin signaling and the regulation of insect diapause.
A rich chapter in the history of insect endocrinology has focused on hormonal control of diapause, especially the major roles played by juvenile hormones (JHs), ecdysteroids, and the neuropeptides that govern JH and ecdysteroid synthesis. More recently, experiments with adult diapause in Drosophila melanogaster and the mosquito Culex pipiens, and pupal diapause in the flesh fly Sarcophaga crassipalpis provide strong evidence that insulin signaling is also an important component of the regulatory pathway leading to the diapause phenotype. Insects produce many different insulin-like peptides (ILPs), and not all are involved in the diapause response; ILP-1 appears to be the one most closely linked to diapause in C. pipiens. Many steps in the pathway leading from perception of daylength (the primary environmental cue used to program diapause) to generation of the diapause phenotype remain unknown, but the role for insulin signaling in mosquito diapause appears to be upstream of JH, as evidenced by the fact that application of exogenous JH can rescue the effects of knocking down expression of ILP-1 or the Insulin Receptor. Fat accumulation, enhancement of stress tolerance, and other features of the diapause phenotype are likely linked to the insulin pathway through the action of a key transcription factor, FOXO. This review highlights many parallels for the role of insulin signaling as a regulator in insect diapause and dauer formation in the nematode Caenorhabditis elegans.


Synthesis and secretion of somatostatin-28 and -14 by fetal rat intestinal cells in culture.
A fetal rat intestinal cell (FRIC) culture model was established to investigate the factors controlling synthesis and secretion of somatostatin-28 (S-28) by the intestine. Immunohistochemical analysis demonstrated the presence of cells containing somatostatin-like immunoreactivity (SLI), many of which emitted long processes toward neighboring cells. Gel chromatography of SLI stored and secreted by nonstimulated FRIC cultures demonstrated a predominance of S-28 (59%), lesser amounts of S-14 (31%), and a minor peak of large molecular weight SLI (10%). Secretion of SLI was stimulated by treatment of cells for 2 h with 5 mM dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP; P less than 0.01) or 2 microM phorbol ester (P less than 0.05), but was unaffected by the calcium ionophore A23187 (2 micrograms/ml). Concomitant treatment with all three agents increased SLI secretion in an additive fashion to 254 +/- 25% of controls (P less than 0.0001). DBcAMP treatment did not alter the distribution of stored or secreted S-28 (59%) and S-14 (33%). After 24 h of exposure to DBcAMP, but not after treatment with phorbol ester, a threefold increment in prosomatostatin mRNA transcript levels was observed. FRIC cultures therefore synthesize and secrete a predominance of S-28 in a regulated manner, making them a promising model for future studies on the biosynthesis and secretion of intestinal somatostatin.


Abundance of Secreted Proteins of Trichoderma reesei Is Regulated by Light of Different Intensities.
In Trichoderma reesei light is an important factor in the regulation of glycoside hydrolase gene expression. We therefore investigated the influence of different light intensities on cellulase activity and protein secretion. Differentially secreted proteins in light and darkness as identified by mass spectrometry included members of different glycoside hydrolase families, such as CBH1, Cel3A, Cel61B, XYN2, and XYN4. Several of the associated genes showed light-dependent regulation on the transcript level. Deletion of the photoreceptor genes blr1 and blr2 resulted in a diminished difference of protein abundance between light and darkness. The amount of secreted proteins including that of the major exo-acting beta-1,4-glucanases CBH1 and CBH2 was generally lower in light-grown cultures than in darkness. In contrast, cbh1 transcript levels increased with increasing light intensity from 700 to 2,000 lux but dopped at high light intensity (5,000 lux). In the photoreceptor mutants Δblr1 and Δblr2 cellulase activity in light was reduced compared to activity in darkness, showing a discrepancy between transcript levels and secreted cellulase activity. Furthermore, evaluation of different light sensitivities revealed an increased light tolerance with respect to cellulase expression of QM9414 compared to its parental strain QM6a. Investigation of one of the differentially expressed proteins between light and darkness, CLF1, revealed its function as a factor involved in regulation of secreted protease activity. T. reesei secretes a different set of proteins in light compared to darkness, this difference being mainly due to the function of the major known photoreceptors. Moreover, cellulase regulation is adjusted to light intensity and improved light tolerance was correlated with increased cellulase production. Our findings further support the hypothesis of a light intensity dependent post-transcriptional regulation of cellulase gene expression in T. reesei.


Enhanced Serum Levels of sFlt1: Impact on Materno-Fetal CMV Transmission.
Antenatal Cytomegalovirus infection (CMV) can be associated with severe fetal symptoms and newborn outcome. The current prenatal diagnosis is based on amniocentesis (AC). No reliable biomarker for fetal infection is available. We measured Placenta-derived growth factor (PlGF), and soluble fms-like tyrosine kinase 1 (sFlt1), concentrations in maternal serum and amniotic fluid (AF) in context of maternal CMV primary infection. Blood sampling was carried out at the time of AC for detection of fetal CMV infection. The study cohort was divided into four subcohorts according to the presence or absence of fetal infection and preemptive hyperimmunoglobulin (HIG) treatment during the time interval between diagnosis of the CMV primary infection and AC. The study cohort involved 114 pregnancies. In the non-transmitting subcohorts (NT) with and without prior HIG treatment, the median sFlt1 concentrations were 1.5 ng/mL (NT, HIG+) and 1.4 ng/mL (NT, HIG-), respectively. In the two transmitting groups (T) the concentrations were 1.3 ng/mL (T, HIG+) and 2.3 ng/mL (T, HIG-), respectively (NT, HIG- vs. T, HIG-, p < 0.001). The corresponding PlGF levels and the sFlt1/PlGF ratios showed no significant differences between the cohorts. The empirical cut-off values <1504 pg/mL sFlt1 and <307 pg/mL PlGF, were associated with the exclusion of CMV transmission (p < 0.001). sFlt1 concentration in the maternal blood could be a predictive biomarker for maternofetal CMV transmission.


Stoichiometry of cellular and viral components in the polyomavirus middle-T antigen-tyrosine kinase complex.
Our results indicate that only one type of tyrosine kinase is present within each middle-T antigen-tyrosine kinase complex, suggesting that middle-T antigen forms separate complexes with different tyrosine kinases. Furthermore, we determined that there is only one molecule of middle-T antigen within any one of these complexes. We interpret this to mean that in any given cell, polyomavirus transformation involves, at least in part, the simultaneous deregulation of a number of separate pathways controlling cellular proliferation. Finally, we also demonstrate that the separate middle-T:pp60c-src and middle-T:pp59c-fyn complexes are each able to interact with the same cellular p81/85-kDa phosphoprotein, a possible component of the phosphatidylinositol kinase.


Prevalence of RFC1-mediated spinocerebellar ataxia in a North American ataxia cohort.
We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America. A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in RFC1 (AAGGG) and DAB1 (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for RFC1, resulting in a combined 911 subjects tested. In the initial cohort, 41 samples were identified with 1 expanded allele in the RFC1 gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in RFC1 (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the DAB1 gene (spinocerebellar ataxia type 37). In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in RFC1 was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.


Nineteen-year-old female with idiopathic thrombosis of the internal jugular vein.
Internal jugular vein thrombosis is a rarely seen condition which may be due to infection or neoplastic, thrombophilic, traumatic or iatrogenic causes. If the thrombosis in the jugular vein leads to pulmonary embolism, septic emboli or atrial or dural sinus thrombosis, it may be life-threatening. We report a successfully treated case of a 19-year-old female patient presenting with swelling and neck pain who was diagnosed with a stepwise approach of this rare condition.


Small RNA Sequencing Uncovers New miRNAs and moRNAs Differentially Expressed in Normal and Primary Myelofibrosis CD34+ Cells.
Myeloproliferative neoplasms (MPN) are chronic myeloid cancers thought to arise at the level of CD34+ hematopoietic stem/progenitor cells. They include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). All can progress to acute leukemia, but PMF carries the worst prognosis. Increasing evidences indicate that deregulation of microRNAs (miRNAs) might plays an important role in hematologic malignancies, including MPN. To attain deeper knowledge of short RNAs (sRNAs) expression pattern in CD34+ cells and of their possible role in mediating post-transcriptional regulation in PMF, we sequenced with Illumina HiSeq2000 technology CD34+ cells from healthy subjects and PMF patients. We detected the expression of 784 known miRNAs, with a prevalence of miRNA up-regulation in PMF samples, and discovered 34 new miRNAs and 99 new miRNA-offset RNAs (moRNAs), in CD34+ cells. Thirty-seven small RNAs were differentially expressed in PMF patients compared with healthy subjects, according to microRNA sequencing data. Five miRNAs (miR-10b-5p, miR-19b-3p, miR-29a-3p, miR-379-5p, and miR-543) were deregulated also in PMF granulocytes. Moreover, 3'-moR-128-2 resulted consistently downregulated in PMF according to RNA-seq and qRT-PCR data both in CD34+ cells and granulocytes. Target predictions of these validated small RNAs de-regulated in PMF and functional enrichment analyses highlighted many interesting pathways involved in tumor development and progression, such as signaling by FGFR and DAP12 and Oncogene Induced Senescence. As a whole, data obtained in this study deepened the knowledge of miRNAs and moRNAs altered expression in PMF CD34+ cells and allowed to identify and validate a specific small RNA profile that distinguishes PMF granulocytes from those of normal subjects. We thus provided new information regarding the possible role of miRNAs and, specifically, of new moRNAs in this disease.


High efficacy of imatinib for recurrent gastrointestinal stromal tumor in the jejunum: a case report.
Gastrointestinal stromal tumor is a mesenchymal tumor of the digestive tract. Although there used to be no effective therapy for the tumor, there have been many recent reports on the efficacy of imatinib. We report on a 53-year-old female patient with a primary tumor of the jejunum who underwent 3 operations. As the tumor could not be removed at the 3rd operation, she was given imatinib orally. Results showed significant reduction ratios of the tumor area (83.0%) and volume (92.2%) at 18 months after starting imatinib administration. Also, the mean reduction ratios of the tumor area and volume per month (%/M) after starting imatinib treatment showed remarkable results, especially during the initial 3 weeks: 53.9%/M and 49.5%/M, respectively. Whether imatinib is the first choice of treatment for GIST or not, and what is the appropriate dose and period should be resolved.


Synthesis, electrochemistry, and gas-phase photoelectron spectroscopic and theoretical studies of 3,6-bis(perfluoroalkyl)-1,2-dithiins.
3,6-bis(trifluoromethyl)- and 3,6-bis(pentafluoroethyl)-1,2-dithiin (1a,b), the first known perfluoroalkyl-substituted 1,2-dithiins, were synthesized from (Z,Z)-1,4-bis(tert-butylthio)-1,3-butadiene (2) to evaluate the effects of electron-withdrawing groups on the ionization and oxidation potentials of 1,2-dithiins. Analysis of the photoelectron spectra of 1a and 1b provided a basis for assigning orbital compositions. Ab initio calculations on these compounds showed that they adopt a twist geometry as does 1,2-dithiin (1c) itself. Cyclic voltammetric studies on 1a and 1b revealed a reversible oxidation followed by an irreversible oxidation at much more positive potentials than for 1,2-dithiin and 3,6-dimethyl-1,2-dithiin (1d). The oxidation potentials determined electrochemically do not correlate with the ionization potentials determined by photoelectron spectroscopy. This result supports the previously advanced hypothesis that there is a geometry change on electrochemical oxidation leading to a planar radical cation.


Impact of ovarian insufficiency on bone health in childhood cancer survivors: Two cases.
To investigate the skeletal phenotype of adolescent girls with premature ovarian insufficiency (POI). Data are presented from two adolescent girls who participated in a clinical research protocol to evaluate axial bone mineral density (BMD) (via dual-energy x-ray absorptiometry, DXA) and appendicular bone density, microarchitecture, and strength (via high-resolution peripheral quantitative computed tomography, HRpQCT). Anthropometric data were also obtained, and pubertal staging was performed by a clinician. Both cases presented with an undetectable estradiol concentration and an elevated follicle stimulating hormone (FSH), meeting the criteria for POI. Each also received alkylating agents as part of their chemotherapy and radiotherapy, but in different locations as one presented with stage IV neuroblastoma and the other, metastatic medulloblastoma. Both had a low BMD of the axial and appendicular skeleton, as well as microarchitectural changes of the latter. The low BMD Z-score (<-2.0) seen when interpreting their DXA measurements for chronological age improved when adjusted for short stature, but it was not normalized. Lastly, most variables obtained by HRpQCT were abnormal for each participant, indicating that appendicular bone structure and strength were compromised. Chemotherapy and radiation affect growth, puberty, and bone accrual deleteriously. However, as these cases show, POI in an adolescent is not always classic primary ovarian insufficiency. Adolescents with brain cancer can present with signs of estrogen deficiency but may not be able to secrete FSH to the extent of elevation typically seen in long-term cancer survivors. Estrogen deficiency is almost universally present in either clinical setting and prompt recognition facilitates early provision of hormone replacement therapy that may then allow for a resumption of bone accrual as an adolescent approaches her peak bone mass.


Impact of the Long-Range Interaction on the Efficiency of the Li + ClH → LiCl + H Reaction.
Quantum and quasiclassical calculations have been performed to compute the low energy efficiency of the Li + ClH → LiCl + H reaction on some potential energy surfaces fitted to ab initio electronic energies using different functional forms. The outcomes of the calculations show marked differences at threshold and in the shape of the excitation function in seeming contrast with the height of the saddle to reaction and the width of the cone of acceptance. The differences in the computed reactive probability and cross section are rationalized in terms of the attractive/repulsive nature of the long-range interaction and the inability of trajectory techniques to deal with threshold effects. The vestiges of these features in the value of the thermal rate coefficients are also commented on.


Incidence and Clinical Features of Autoimmune Hepatitis in the Province of Santa Fe (Argentina).
The aim of the study is to investigate the incidence and clinical features of autoimmune hepatitis (AIH) in children from the province of Santa Fe, Argentina, for 10 years. From the records of all of the pediatric hepatologists in the province of Santa Fe, Argentina, we reviewed the clinical charts of patients <18 years who were diagnosed with AIH (simplified score >6 points) and followed between January 2003 and December 2013. Population data were extracted from the 2010 national census. Values were expressed as percentages and median ± interquartile range. Mann-Whitney U test was used for comparison between the groups. Sixty-seven patients fulfilled inclusion criteria, from which 11 (16%) were later reclassified as having "autoimmune sclerosing cholangitis" according to biochemical, histological, and radiological findings. A final sample of 56 patients (39 F) with AIH was analyzed, giving an annual incidence of 0.56/100,000. Median age at presentation was 8 (5.7-11) years, and the median follow-up was 4 (2-7) years. Type 1 AIH was diagnosed in 89%. An acute presentation was observed in 53%, while 13 (23%) showed cirrhosis on initial biopsy. Prednisone (87%) and azathioprine (60%) were the most common drugs prescribed. At the end of follow-up, 53/56 (95%) were alive, including 4 patients (7%) who underwent liver transplantation. AIH has an estimated incidence of 0.56/100,000 per year in children from the province of Santa Fe (Argentina). Overall survival rate was 95%. A subgroup of patients diagnosed as AIH develops predominant biliary disease and should be better classified as autoimmune sclerosing cholangitis.