Evidence that in xeroderma pigmentosum variant cells, which lack DNA polymerase eta, DNA polymerase iota causes the very high frequency and unique spectrum of UV-induced mutations.
Xeroderma pigmentosum variant (XPV) patients have normal DNA excision repair, yet are predisposed to develop sunlight-induced cancer. They exhibit a 25-fold higher than normal frequency of UV-induced mutations and very unusual kinds (spectrum), mainly transversions. The primary defect in XPV cells is the lack of functional DNA polymerase (Pol) eta, the translesion synthesis DNA polymerase that readily inserts adenine nucleotides opposite photoproducts involving thymine. The high frequency and striking difference in kinds of UV-induced mutations in XPV cells strongly suggest that, in the absence of Pol eta, an abnormally error-prone polymerase substitutes. In vitro replication studies of Pol iota show that it replicates past 5'T-T3' and 5'T-U3' cyclobutane pyrimidine dimers, incorporating G or T nucleotides opposite the 3' nucleotide. To test the hypothesis that Pol iota causes the high frequency and abnormal spectrum of UV-induced mutations in XPV cells, we identified an unlimited lifespan XPV cell line expressing two forms of Pol iota, whose frequency of UV-induced mutations is twice that of XPV cells expressing one form. We eliminated expression of one form and compared the parental cells and derivatives for the frequency and kinds of UV-induced mutations. All exhibited similar sensitivity to the cytotoxicity of UV((254 nm)), and the kinds of mutations induced were identical, but the frequency of mutations induced in the derivatives was reduced to </=50% that of the parent. These data strongly support the hypothesis that in cells lacking Pol eta, Pol iota is responsible for the high frequency and abnormal spectrum of UV-induced mutations, and ultimately their malignant transformation.


The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors?
Neuroendocrine (NE) tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma are metastatic in nature, and secrete biogenic amines and hormones. In this review, we will discuss the possibility that activation of the Ras/Raf signaling pathway may be a therapeutic target for patients with select NE tumors. In-vitro activation of Raf-1 in NE tumors either by expression of the ectopic catalytic domain of Raf-1 or by a pharmacologic drug, ZM336372, resulted in growth inhibition. In addition, activation of the Ras/Raf pathway led to a significant reduction in NE markers such as serotonin, chromogranin A and calcitonin. These data support development of Raf-1-activating compounds for treatment of patients with NE tumors of selective subtypes.


INSIST-ED: Italian Society of Andrology registry on penile prosthesis surgery. First data analysis.
The Italian Society of Andrology, i.e. "Società Italiana di Andrologia" (S.I.A.), launched on December 2014 a prospective, multicenter, monitored and internal review board approved Registry for penile implants, the "INSIST-ED" (Italian Nationwide Systematic Inventarisation of Surgical Treatment for ED) Registry. Purpose of this first report is to present a baseline data analysis of the characteristics of penile implant surgery in Italy. The INSIST-ED Registry is open to all surgeons implanting penile prostheses (all brands, all models) in Italy, providing anonymous patient, device, surgical procedure, outcome, follow-up data, for both first and revision surgeries. A Registry project Board overviews all the steps of the project, and a Registry Monitor interacts with the Registry implanting surgeons. As by April 8, 2016, 31 implanting surgeons actively joined the Registry, entering 367 surgical procedures in its database, that comprise: 310 first implants, 43 prosthesis substitutions, 14 device explants without substitution. Implanted devices account for: 288 three-component devices (81,3%), 20 two-component devices (5,4%), 45 non-hydraulic devices (12,3%). Leading primary ED etiologies in first implant surgeries resulted: former radical pelvic surgery in 111 cases (35,8%), Peyronie's disease in 66 cases (21,3%), diabetes in 39 cases (12,6%). Two intraoperative complications have been recorded. Main reasons for 57 revision surgeries were: device failure (52,6%), erosion (19,3%), infection (12,3%), patient dissatisfaction (10,5%). Surgical settings for patients undergoing a first penile implant were: public hospitals in 251 cases (81%), private environments in 59 cases (19%). The INSIST-ED Registry represents the first European experience of penile prosthesis Registry. This baseline data analysis shows that: three-pieces inflatable prosthesis is the most implanted device, leading etiology of erectile dysfunction (ED) in patient receiving a prosthesis is former radical pelvic surgery, primary reason for revision surgery is device failure, primary settings for first penile implant surgery are public hospitals. Evaluation of penile implant impact on recipients quality of life is presently ongoing.


Katanin, the microtubule-severing ATPase, is concentrated at centrosomes.
The assembly and function of the mitotic spindle involve specific changes in the dynamic properties of microtubules. One such change results in the poleward flux of tubulin in which spindle microtubules polymerize at their kinetochore-attached plus ends while they shorten at their centrosome-attached minus ends. Since free microtubule minus ends do not depolymerize in vivo, the poleward flux of tubulin suggests that spindle microtubules are actively disassembled at or near their centrosomal attachment points. The microtubule-severing ATPase, katanin, has the ability actively to sever and disassemble microtubules and is thus a candidate for the role of a protein mediating the poleward flux of tubulin. Here we determine the subcellular localization of katanin by immunofluorescence as a preliminary step in determining whether katanin mediates the poleward flux of tubulin. We find that katanin is highly concentrated at centrosomes throughout the cell cycle. Katanin's localization is different from that of gamma-tubulin in that microtubules are required to maintain the centrosomal localization of katanin. Direct comparison of the localization of katanin and gamma-tubulin reveals that katanin is localized in a region surrounding the gamma-tubulin-containing pericentriolar region in detergent-extracted mitotic spindles. The centrosomal localization of katanin is consistent with the hypothesis that katanin mediates the disassembly of microtubule minus ends during poleward flux.


The introduction of mesenchymal stromal cells induces different immunological responses in the lungs of healthy and M. tuberculosis infected mice.
Mesenchymal stromal cells (MSC) have strong immunomodulatory properties and therefore can be used to control inflammation and tissue damage. It was suggested recently that MSC injections can be used to treat multi-drug resistant tuberculosis (TB). However, MSC trafficking and immunomodulatory effects of MSC injections during Mycobacterium tuberculosis (Mtb) infection have not been studied. To address this issue we have analyzed MSC distribution in tissues and local immunological effects of MSC injections in Mtb infected and uninfected mice. After intravenous injection, MSC accumulated preferentially in the lungs where they were located as cell aggregates in the alveolar walls. Immunological analysis of MSC effects included detection of activated, IFN-γ and IL-4 producing CD4+ lymphocytes, the frequency analysis of dendritic cells (CD11c+F4/80) and macrophages (CD11c-F4/80+) located in the lungs, the expression of IA/IE and CD11b molecules by these cells, and evaluation of 23 cytokines/chemokines in lung lysates. In the lungs of uninfected mice, MSC transfer markedly increased the percentage of IFN-γ+ CD4+ lymphocytes and dendritic cells, elevated levels of IA/IE expression by dendritic cells and macrophages, augmented local production of type 2 cytokines (IL-4, IL-5, IL-10) and chemokines (CCL2, CCL3, CCL4, CCL5, CXCL1), and downregulated type 1 and hematopoietic cytokines (IL-12p70, IFN-γ, IL-3, IL-6, GM-CSF). Compared to uninfected mice, Mtb infected mice had statistically higher "background" frequency of activated CD69+ and IFN-γ+ CD4+ lymphocytes and dendritic cells, and higher levels of cytokines in the lungs. The injections of MSC to Mtb infected mice did not show statistically significant effects on CD4+ lymphocytes, dendritic cells and macrophages, only slightly shifted cytokine profile, and did not change pathogen load or slow down TB progression. Lung section analysis showed that in Mtb infected mice, MSC could not be found in the proximity of the inflammatory foci. Thus, in healthy recipients, MSC administration dramatically changed T-cell function and cytokine/chemokine milieu in the lungs, most likely, due to capillary blockade. But, during Mtb infection, i.e., in the highly-inflammatory conditions, MSC did not affect T-cell function and the level of inflammation. The findings emphasize the importance of the evaluation of MSC effects locally at the site of their predominant post-injection localization and question MSC usefulness as anti-TB treatment.


Monitoring compliance with high-level commitments in health: the case of the CARICOM Summit on Chronic Non-Communicable Diseases.
The CARICOM Summit on Chronic Non-Communicable Diseases - the first government summit ever devoted to noncommunicable diseases (NCDs) - was convened by the Caribbean Community (CARICOM) in Trinidad and Tobago in September 2007. Leaders in attendance issued the declaration of Port of Spain, a call for the prevention and control of four major NCDs and their risk factors. An accountability instrument for monitoring compliance with summit commitments was developed for CARICOM by the University of the West Indies in 2008 and revised in 2010. The instrument - a one-page colour-coded grid with 26 progress indicators - is updated annually by focal points in Caribbean health ministries, verified by each country's chief medical officer and presented to the annual Caucus of Caribbean Community Ministers of Health. In this study, the G8 Research Group's methods for assessing compliance were applied to the 2009 reporting grid to assess each country's performance. Given the success of the CARICOM Summit, a United Nations high-level meeting of the General Assembly on the prevention and control of NCDs was held in September 2011. In May 2013 the World Health Assembly adopted nine global targets and 25 indicators to measure progress in NCD control. This study shows that the CARICOM monitoring grid can be used to document progress on such indicators quickly and comprehensibly. An annual reporting mechanism is essential to encourage steady progress and highlight areas needing correction. This paper underscores the importance of accountability mechanisms for encouraging and monitoring compliance with the collective political commitments acquired at the highest level.


Fulminant scleral abscess secondary to infected scleral buckle with Moraxella species.
We here report a case of scleral buckle infection with fulminant scleral abscess secondary to Moraxella species. A 54-year-old chronic alcoholic male with a history of retinal detachment repair, with scleral buckle 8 years prior, presented with complaints of severe pain, redness, and swelling in the right eye since 2 weeks. The patient was diagnosed with scleral buckle infection, the buckle was removed, and cultures revealed Moraxella species. The postoperative course included fulminant scleral abscess treated with dual antibiotic therapy that included ceftriaxone and moxifloxacin. All systemic antibiotics were discontinued after 3 weeks, retina remained attached, and no recurrence occurred over a 1-year follow-up. Moraxella, though commonly associated with bacterial keratitis, can also lead to buckle infection, especially in chronic alcoholic and immunocompromised patients. In buckle infection, infected buckle along with sutures should be immediately removed without damaging underlying compromised sclera. Lastly, culture and drug sensitivity play a very important role in buckle infections.


Antitumor activity of Nitronaphthal-NU, a novel mixed-function agent.
Nitronaphthal-NU (Compound 1) was synthesized as a mixed-function antitumor agent based on the structures of the clinical drug CCNU and experimental compound Mitonafide. In vitro screening in four human tumor cell lines namely SNB-78 CNS, HOP-62 Lung, T47D Breast and SiHa - cervix revealed significant cytotoxicity in the former two cell lines much greater than CCNU and comparable to Mitonafide used as standards. In vivo antitumoral potency assessed in the murine ascites tumors Sarcoma-180 (S-180) and Ehrlich ascites carcinoma (EAC) by measuring the increase in median survival times of drug treated (T) over untreated control (C) mice, revealed highly significant (p<0.001) tumor regression effects greater than standards. Life span of mice bearing advanced tumor for 10 days before the drug challenge was also considerably increased. Its toxicity was assessed in vivo in normal and S-180 bearing mice by measuring drug-induced changes in haematological parameters, femoral bone marrow and splenic cellularities as well as hepatotoxicity and nephrotoxicity sequentially on days 9, 15 and 21 following drug treatment at the optimum dose of 50 mg/kg from day 1 to 7. Results indicate that it did not adversely affect haematopoiesis. The other parameters were within normal limit. The compound comparable to standards inhibited the synthesis of DNA and RNA in S-1 80 tumor cells.


[IT network establishment for neuropatients].
On March 11, 2011, big earthquake and subsequent gigantic tsunami killed more than 20,000 peoples in Tohoku area of Japan. Neurological patients were one such victim because they are usually very vulnerable to such a huge tragedy due to their physical disability including artificial ventilator-support. On occasion of the last tsunami, most cases showed "all or nothing" to lose life or to survive, and there were only a little cases who needed emergency surgical treatment. In the very early period, some neurological patients required electric power to keep their lifesupportive ventilator at evacuation house or even at home. In a week to a couple of months, many neurological patients needed continuous supply of their daily drugs which are essential to keep themselves in steady physical conditions and even for keeping their life.Japanese Neurological Society (JNS) began to establish an emergent assistant network system from January 2012 in an attempt of supplying materials, drugs and energy power to neurological patients who require both under a very early period after any natural or political disaster and a later period. For example, JNS is going to apply IT system to connect distant but safer hospitals which accept emergent patients from the center of disastrous place. JNS may also send emergency medical team to the disastrous place to save neurological patients by passing necessary medicine and materials or moving patients to safer hospitals. JNS will make such a tentative program public on our website to collect many other constructive opinions from general member of the society and neurological patients. After getting those opinions, JNS made up the exact team for this purpose after general meeting of JNS on this May 2012.Based on this team, disaster-mimic trial will be performed in Tokyo, Shizuoka, and Kochi where the next big disaster is going to hit the cities.


High-sulfur in beef cattle diets: a review.
While many cattle feeding areas in the United States have long dealt with high sulfate water, increased feeding of ethanol coproducts such as distillers grains with solubles to beef cattle has led to a corresponding increase in dietary sulfur. As a result, sulfur metabolism in the ruminant has been the focus of many research studies over the past 10 yr, and advances in our knowledge have been made. Excessive sulfur in cattle diets may have implications on trace mineral absorption, dry matter intake, and overall cattle growth. This review will focus on what we have learned about the metabolism of sulfur in the ruminant, including ruminal sulfate reducing bacteria, the role of ruminally available sulfur, factors affecting the production of hydrogen sulfide in the rumen, and the potential mechanisms behind sulfur toxicity in cattle. Additionally, this review will discuss potential strategies to minimize risk of sulfur toxicity when cattle are fed high-sulfur diets, including dietary and management strategies. Further research related to high-sulfur diets including implications for carcass characteristics, meat quality, and animal health will also be discussed. As ethanol production processes continue to change, the nutrient profile of the resulting coproducts will as well. Often removal of one nutrient such as oil will result in the concentration of other nutrients such as sulfur. Therefore, it seems even more likely that a better understanding of sulfur metabolism in the ruminant will be important to beef cattle feeding in the future.


A new approach for neurological evaluation of infants in resource-poor settings.
Research assessing the neurological development of infants in developing countries is scanty as no suitable standardised tests are available for field-use in constrained circumstances. We describe the development and application of two simple assessments. Firstly, we aimed to develop a test suitable for assessing acute neurological disturbances caused by such diverse effects as infections, drugs or toxins. This test (Shoklo Neurological Test) is aimed at infants between 9 and 36 months. The second test (Shoklo Developmental Test) is aimed not only to follow the evolution of the signs tested initially in the acute phase but also to evaluate later neurodevelopmental sequelae which might be caused by the same events. The latter test is suitable for infants aged from 3 to 12 months. Both tests can be performed easily in non-optimal conditions. The examinations were tested in a cohort of infants from a Karen refugee camp and administered in a rural setting by health workers, after appropriate training. In order to validate the tests we also applied them to a cohort of London infants. The Griffiths Developmental Scales were applied in the same infants and both the Shoklo Neurological and the Shoklo Developmental Tests showed good correlation with this standardised neurodevelopmental assessment.


Description of Danio absconditus, new species, and redescription of Danio feegradei (Teleostei: Cyprinidae), from the Rakhine Yoma hotspot in south-western Myanmar.
Danio feegradei Hora is redescribed based on recently collected specimens from small coastal streams on the western slope of the Rakhine Yoma, ranging from the Thade River drainage southward to slightly north of Kyeintali. Danio absconditus, new species, is described from the Kyeintali Chaung and small coastal streams near Gwa, south of the range of D. feegradei. Both species are distinguished from other Danio by the presence of a dark, elongate or round spot at the base of the caudal fin and a cleithral marking composed of a small black spot margined by a much smaller orange spot. Danio feegradei is characterized by the colour pattern, with series of white spots along the otherwise dark side; D. absconditus by about 7--11 dark vertical bars on the abdominal side. Within Danio, the presence of a complete lateral line, cleithral spot, and 14 circumpeduncular scales is shared with D. dangila and similar species, but these character states may be plesiomorphic as suggested by the shared presence of cleithral spot and complete lateral line in Devario and Betadevario. In other Danio the cleithral spot is absent, the lateral line is short or absent, and the circumpeduncular scale count is lower (10-12). Twenty teleost species are reported from streams on the western slope of the Rakhine Yoma, all probably endemic. The parapatric distribution of D. absconditus and D. feegradei is unique within the genus, and may be partly explained by changes in eustatic sea levels.


Theory-based interventions in STIs/HIV Prevention: A systematic review of the literature in Iran.
Background: Various theory-based interventions (TBIs) have been done to prevent STI/HIV. The current study aimed at reviewing the TBIs for STI/HIV prevention in Iran. Methods: We systematically searched 6 English and Persian electronic databases to identify TBIs conducted for STI/HIV prevention in Iran. General searches were conducted using PubMed MeSH terms. Articles were included if they were interventional and conducted using models and theories, aimed at reducing the risk of STIs, were quasi-experimental or experimental, and if their full text was available. Results: Overall, 1042 studies were found. Finally, 13 original studies met our inclusion criteria. The findings indicated that HBM and TPB were the most frequently used theory/models. High school students and drug abusers were the most common target groups in the included studies. Conclusion: The results revealed that the majority of the conducted TBIs contained a methodological weakness. Conducting randomized controlled trials is needed to evaluate the effectiveness of the TBIs.


The effect of flurbiprofen on the development of anencephaly in early stage chicken embryos.
The study investigated the effect of flurbiprofen on the development of anencephaly in early stage chicken embryos. We looked at four groups with a total of 36 embryos. There was a control group, a normal saline group, a normal-dose group and a high-dose group with ten, ten, eight and eight eggs with embryo respectively. Two embryos in the control group, studied with light microscopy at 48 h, were consistent with 28-29 hours' incubation in the Hamburger-Hamilton System. They had open neural tubes. The other embryos in this group were considered normal. One embryo in the normal saline group was on the occlusion stage at 48 h. One embryo showed an open neural tube. They were compatible with 28-29 hours' incubation in the Hamburger-Hamilton system. The remaining eight embryos showed normal development. In the normal dose group, one embryo showed underdevelopment of the embryonic disc and the embryo was dead. In four embryos, the neural tubes were open. One cranial malformation was found that was complicated with anencephaly in one embryo. In two embryos the neural tubes were closed, as they showed normal development, and they reached their expected stages according to the Hamburger-Hamilton classification. There was no malformation or growth retardation. Four experimental embryos were anencephalic in the high dose group, and three embryos had open neural tubes. One embryo exhibited both anencephaly and a neural tube closure defect. None of the embryos in this group showed normal development. Even the usual therapeutic doses of flurbiprofen increased the risk of neural tube defect. Flurbiprofen was found to significantly increase the risk of anencephaly. The provision of improved technical materials and studies with larger sample sizes will reveal the stage of morphological disruption during the development of embryos.


Analysis of DNA strand-specific differential expression with high density tiling microarrays.
DNA microarray technology allows the analysis of genome structure and dynamics at genome-wide scale. Expression microarrays (EMA) contain probes for annotated open reading frames (ORF) and are widely used for the analysis of differential gene expression. By contrast, tiling microarrays (TMA) have a much higher probe density and provide unbiased genome-wide coverage. The purpose of this study was to develop a protocol to exploit the high resolution of TMAs for quantitative measurement of DNA strand-specific differential expression of annotated and non-annotated transcripts. We extensively filtered probes present in Affymetrix Genechip Yeast Genome 2.0 expression and GeneChip S. pombe 1.0FR tiling microarrays to generate custom Chip Description Files (CDF) in order to compare their efficiency. We experimentally tested the potential of our approach by measuring the differential expression of 4904 genes in the yeast Schizosaccharomyces pombe growing under conditions of oxidative stress. The results showed a Pearson correlation coefficient of 0.943 between both platforms, indicating that TMAs are as reliable as EMAs for quantitative expression analysis. A significant advantage of TMAs over EMAs is the possibility of detecting non-annotated transcripts generated only under specific physiological conditions. To take full advantage of this property, we have used a target-labelling protocol that preserves the original polarity of the transcripts and, therefore, allows the strand-specific differential expression of non-annotated transcripts to be determined. By using a segmentation algorithm prior to generating the corresponding custom CDFs, we identified and quantitatively measured the expression of 510 transcripts longer than 180 nucleotides and not overlapping previously annotated ORFs that were differentially expressed at least 2-fold under oxidative stress. We show that the information derived from TMA hybridization can be processed simultaneously for high-resolution qualitative and quantitative analysis of the differential expression of well-characterized genes and of previously non-annotated and antisense transcripts. The consistency of the performance of TMA, their genome-wide coverage and adaptability to updated genome annotations, and the possibility of measuring strand-specific differential expression makes them a tool of choice for the analysis of gene expression in any organism for which TMA platforms are available.


Preservation of the nerves to the frontalis muscle during pterional craniotomy.
There continues to be confusion over how best to preserve the branches of the facial nerve to the frontalis muscle when elevating a frontotemporal (pterional) scalp flap. The object of this study was to examine the full course of the branches of the facial nerve that must be preserved to maintain innervation of the frontalis muscle during elevation of a frontotemporal scalp flap. Dissection was performed to follow the temporal branches of facial nerves along their course in 5 adult, cadaveric heads (n = 10 extracranial facial nerves). Preserving the nerves to the frontalis muscle requires an understanding of the course of the nerves in 3 areas. The first area is on the outer surface of the temporalis muscle lateral to the superior temporal line (STL) where the interfascial or subfascial approaches are applied, the second is in the area medial to the STL where subpericranial dissection is needed, and the third is along the STL. Preserving the nerves crossing the STL requires an understanding of the complex fascial relationships at this line. It is important to preserve the nerves crossing the lateral and medial parts of the exposure, and the continuity of the nerves as they pass across the STL. Prior descriptions have focused largely on the area superficial to the temporalis muscle lateral to the STL. Using the interfascial-subpericranial flap and the subfascial-subpericranial flap avoids opening the layer of loose areolar tissue between the temporal fascia and galea in the area lateral to the STL and between the galea and frontal pericranium in the area medial to the STL. It also preserves the continuity of the nerve crossing the STL. This technique allows for the preservation of the nerves to the frontalis muscle along their entire trajectory, from the uppermost part of the parotid gland to the frontalis muscle.


Phylogeography of a successful aerial disperser: the golden orb spider Nephila on Indian Ocean islands.
The origin and diversification patterns of lineages across the Indian Ocean islands are varied due to the interplay of the complex geographic and geologic island histories, the varying dispersal abilities of biotas, and the proximity to major continental landmasses. Our aim was to reconstruct phylogeographic history of the giant orbweaving spider (Nephila) on western Indian Ocean islands (Madagascar, Mayotte, Réunion, Mauritius, Rodrigues), to test its origin and route of dispersal, and to examine the consequences of good dispersal abilities for colonization and diversification, in comparison with related spiders (Nephilengys) inhabiting the same islands, and with other organisms known for over water dispersal. We used mitochondrial (COI) and nuclear (ITS2) markers to examine phylogenetic and population genetic patterns in Nephila populations and species. We employed Bayesian and parsimony methods to reconstruct phylogenies and haplotype networks, respectively, and calculated genetic distances, fixation indices, and estimated clade ages under a relaxed clock model. Our results suggest an African origin of Madagascar Nephila inaurata populations via Cenozoic dispersal, and the colonization of the Mascarene islands from Madagascar. We find evidence of gene flow across Madagascar and Comoros. The Mascarene islands share a common 'ancestral' COI haplotype closely related to those found on Madagascar, but itself absent, or as yet unsampled, from Madagascar. Each island has one or more unique haplotypes related to the ancestral Mascarene haplotype. The Indian Ocean N. inaurata are genetically distinct from the African populations. Nephila spiders colonized Madagascar from Africa about 2.5 (0.6-5.3) Ma. Our results are consistent with subsequent, recent and rapid, colonization of all three Mascarene islands. On each island, however, we detected unique haplotypes, consistent with a limited gene flow among the islands subsequent to colonization, a scenario that might be referred to as speciation in progress. However, due to relatively small sample sizes, we cannot rule out that we simply failed to collect Mascarene haplotypes on Madagascar, a scenario that might imply human mediated dispersal. Nonetheless, the former interpretation better fits the available data and results in a pattern similar to the related Nephilengys. Nephilengys, however, shows higher genetic divergences with diversification on more remote islands. That the better disperser of the two lineages, Nephila, has colonized more islands but failed to diversify, demonstrates how dispersal ability can shape both the patterns of colonization and formation of species across archipelagos.


Nausea and Vomiting Not Related to Cancer Therapy: Intractable Problem or Clinical Challenge?
Unlike therapy-related nausea and vomiting (chemotherapy or radiotherapy induced), nausea and vomiting (N/V) in patients with advanced cancer is often multicausal and thus presents unique challenges. Few professional guidelines address the palliative management of N/V, and those that do are insufficiently detailed to bolster clinical decision-making. Nonetheless, oncology advanced practitioners (APs) are frequently challenged to manage these high-impact symptoms. This requires collaborating with other oncology care providers and cultivating a knowledge base to educate and mentor professional colleagues to optimize N/V unrelated to treatment. Literature reviewed included current and classic articles that address the physiologic bases of N/V related to disease and with malignant bowel obstruction, agents used to alleviate nausea or N/V, and nonpharmacologic adjunctive measures. This information was framed within palliative care and symptom management clinical experience. This review article summarizes what is known about the neuropharmacology of N/V in advanced disease. Focused assessment, pharmacologic agents (antiemetics, central neuromodulators, and peripheral prokinetic agents), and nondrug adjunctive measures that may be useful for N/V are included. Managing N/V in advanced cancer is a quality-of-life imperative that requires persistence and interprofessional collaboration among oncology APs and other clinicians to personalize management. This work can change the perception that N/V related to progressive disease is frequently intractable to one that considers it as a manageable clinical challenge.


Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2.
Patients with biallelic mutations in BRCA2 are in Fanconi anaemia group D1. We analysed the severity of the mutations in 27 cases, classified according to their association with breast cancer in heterozygotes, and their predicted functional effect. Twenty mutations were frameshifts or truncations, three involved splice sites, five were missense variants of unknown severity and two were benign polymorphisms. Five patients had VACTERL-H association. Leukaemia was reported in 13 patients, and solid tumours in 15; 6 patients had two or more malignancies. The cumulative probability of any malignancy was 97% by age 5.2 years. IVS7+1G-->A and IVS7+2T-->G were associated with AML, and 886delGT and 6174delT with brain tumours. However, patients with other alleles remained at very high risk of these events. Missense mutations formed a distinct cluster in a highly conserved region of the BRCA2 protein. The small group of patients with biallelic mutations in BRCA2 is distinctive in the severity of the phenotype, and early onset and high rates of leukaemia and specific solid tumours, and may comprise an extreme variant of Fanconi anaemia. Several of the alleles were not associated with cancer in presumed carriers, and thus counselling presents more uncertainties than usual.


Desmoplastic Infantile Ganglioglioma/Astrocytoma (DIG/DIA) Are Distinct Entities with Frequent BRAFV600 Mutations.
Desmoplastic infantile ganglioglioma (DIG) and desmoplastic infantile astrocytoma (DIA) are extremely rare tumors that typically arise in infancy; however, these entities have not been well characterized in terms of genetic alterations or clinical outcomes. Here, through a multi-institutional collaboration, the largest cohort of DIG/DIA to date is examined using advanced laboratory and data processing techniques. Targeted DNA exome sequencing and DNA methylation profiling were performed on tumor specimens obtained from different patients (n = 8) diagnosed histologically as DIG/DIGA. Two of these cases clustered with other tumor entities, and were excluded from analysis. The remaining 16 cases were confirmed to be DIG/DIA by histology and by DNA methylation profiling. Somatic BRAF gene mutations were discovered in 7 instances (43.8%); 4 were BRAFV600E mutations, and 3 were BRAFV600D mutations. Three instances of malignant transformation were found, and sequencing of the recurrence demonstrated a new TP53 mutation in one case, new ATRX deletion in one case, and in the third case, the original tumor harbored an EML4-ALK fusion, also present at recurrence. DIG/DIA are distinct pathologic entities that frequently harbor BRAFV600 mutations. Complete surgical resection is the ideal treatment, and overall prognosis is excellent. While, the small sample size and incomplete surgical records limit a definitive conclusion about the risk of tumor recurrence, the risk appears quite low. In rare cases with wild-type BRAF, malignant progression can be observed, frequently with the acquisition of other genetic alterations.Implications: DIG/DIA are a distinct molecular entity, with a subset frequently harboring either BRAF V600E or BRAF V600D mutations. Mol Cancer Res; 16(10); 1491-8. ©2018 AACR.


Cysteine-induced modifications of zero-valent silver nanomaterials: implications for particle surface chemistry, aggregation, dissolution, and silver speciation.
The persistence of silver nanoparticles in aquatic environments and their subsequent impact on organisms depends on key transformation processes, which include aggregation, dissolution, and surface modifications by metal-complexing ligands. Here, we studied how cysteine, an amino acid representative of thiol ligands that bind monovalent silver, can alter the surface chemistry, aggregation, and dissolution of zero-valent silver nanoparticles. We compared nanoparticles synthesized with two coatings, citrate and polyvinylpirrolidone (PVP), and prepared nanoparticle suspensions (approximately 8 μM total Ag) containing an excess of cysteine (400 μM). Within 48 h, up to 47% of the silver had dissolved, as indicated by filtration of the samples with a 0.025-μm filter. Initial dissolution rates were calculated from the increase of dissolved silver concentration when particles were exposed to cysteine and normalized to the available surface area of nanoparticles in solution. In general, the rates of dissolution were almost 3 times faster for citrate-coated nanoparticles relative to PVP-coated nanoparticles. Rates tended to be slower in solutions with higher ionic strength in which the nanoparticles were aggregating. X-ray absorption spectroscopy analysis of the particles suggested that cysteine adsorbed to silver nanoparticles surfaces through the formation of Ag(+I)--sulfhydryl bonds. Overall, the results of this study highlight the importance of modifications by sulfhydryl-containing ligands that can drastically influence the long-term reactivity of silver nanoparticles in the aquatic environment and their bioavailability to exposed organisms. Our findings demonstrate the need to consider multiple interlinked transformation processes when assessing the bioavailability, environmental risks, and safety of nanoparticles, particularly in the presence of metal-binding ligands.


Fluid Structure Interaction on Paravalvular Leakage of Transcatheter Aortic Valve Implantation Related to Aortic Stenosis: A Patient-Specific Case.
This study investigated the impact of paravalvular leakage (PVL) in relation to the different valve openings of the transcatheter aortic valve implantation (TAVI) valve using the fluid structure interaction (FSI) approach. Limited studies were found on the subject of FSI with regards to TAVI-PVL condition, which involves both fluid and structural responses in coupling interaction. Hence, further FSI simulation with the two-way coupling method is implemented to investigate the effects of hemodynamics blood flow along the patient-specific aorta model subjected to the interrelationship between PVL and the different valve openings using the established FSI software ANSYS 16.1. A 3D patient-specific aorta model is constructed using MIMICS software. The TAVI valve identical to Edward SAPIEN XT 26 (Edwards Lifesciences, Irvine, California), at different Geometrical Orifice Areas (GOAs), is implanted into the patient's aortic annulus. The leaflet opening of the TAVI valve is drawn according to severity of GOA opening represented in terms of 100%, 80%, 60%, and 40% opening, respectively. The result proved that the smallest percentage of GOA opening produced the highest possibility of PVL, increased the recirculatory flow proximally to the inner wall of the ascending aorta, and produced lower backflow velocity streamlines through the side area of PVL region. Overall, 40% GOA produced 89.17% increment of maximum velocity magnitude, 19.97% of pressure drop, 65.70% of maximum WSS magnitude, and a decrement of 33.62% total displacement magnitude with respect to the 100% GOA.


Disparities in care and outcomes for primary liver cancer in England during 2008-2018: a cohort study of 8.52 million primary care population using the QResearch database.
Liver cancer has one of the fastest rising incidence and mortality rates among all cancers in the UK, but it receives little attention. This study aims to understand the disparities in epidemiology and clinical pathways of primary liver cancer and identify the gaps for early detection and diagnosis of liver cancer in England. This study used a dynamic English primary care cohort of 8.52 million individuals aged ≥25 years in the QResearch database during 2008-2018, followed up to June 2021. The crude and age-standardised incidence rates, and the observed survival duration were calculated by sex and three liver cancer subtypes, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and other specified/unspecified primary liver cancer. Regression models were used to investigate factors associated with an incident diagnosis of liver cancer, emergency presentation, late stage at diagnosis, receiving treatments, and survival duration after diagnosis by subtype. 7331 patients were diagnosed with primary liver cancer during follow-up. The age-standardised incidence rates increased over the study period, particularly for HCC in men (increased by 60%). Age, sex, socioeconomic deprivation, ethnicity, and geographical regions were all significantly associated with liver cancer incidence in the English primary care population. People aged ≥80 years were more likely to be diagnosed through emergency presentation and in late stages, less likely to receive treatments and had poorer survival than those aged <60 years. Men had a higher risk of being diagnosed with liver cancer than women, with a hazard ratio (HR) of 3.9 (95% confidence interval 3.6-4.2) for HCC, 1.2 (1.1-1.3) for CCA, and 1.7 (1.5-2.0) for other specified/unspecified liver cancer. Compared with white British, Asians and Black Africans were more likely to be diagnosed with HCC. Patients with higher socioeconomic deprivation were more likely to be diagnosed through the emergency route. Survival rates were poor overall. Patients diagnosed with HCC had better survival rates (14.5% at 10-year survival, 13.1%-16.0%) compared to CCA (4.4%, 3.4%-5.6%) and other specified/unspecified liver cancer (12.5%, 10.1%-15.2%). For 62.7% of patients with missing/unknown stage in liver cancer, their survival outcomes were between those diagnosed in Stages III and IV. This study provides an overview of the current epidemiology and the disparities in clinical pathways of primary liver cancer in England between 2008 and 2018. A complex public health approach is needed to tackle the rapid increase in incidence and the poor survival of liver cancer. Further studies are urgently needed to address the gaps in early detection and diagnosis of liver cancer in England. The Early Detection of Hepatocellular Liver Cancer (DeLIVER) project is funded by Cancer Research UK (Early Detection Programme Award, grant reference: C30358/A29725).


A Unique Case of Intranasal Metastasis from Occult Poorly Differentiated Thyroid Carcinoma.
Poorly differentiated thyroid carcinomas (PDTCs) lie, both morphologically and behaviorally, between well-differentiated and undifferentiated carcinomas. Metastasis of poorly differentiated thyroid carcinoma to the intranasal cavity has not been reported previously in the literature. A 48-year-old male patient presented with massive epistaxis and nasal obstruction. On nasal examination, a bleeding, vascular mass was seen filling the left nasal cavity. The histopathological report of the nasal mass was well-differentiated thyroid carcinoma metastasis. Whole body scintigraphy, ultrasonography and positron emission tomography were done to rule out other possible metastases in the body and determine the origin of the tumor, which was identified as the left lobe of the thyroid gland, and there were multiple metastases involving the lung, sacroiliac area, and left humerus. Histopathological examination of a thyroidectomy specimen revealed PDTC consisting of insular, follicular, and papillary components. Postoperatively, the patient received radioactive iodine ablation therapy (iodine-131) and a course of external beam radiation therapy to the sacroiliac area and other metastatic regions. No recurrences were observed in a follow-up period of 5 years after surgery. The metastasis of differentiated thyroid carcinoma as a component of PDTC to the intranasal cavity has not been reported before. It is interesting that the well-differentiated component of the tumor was metastasized in our patient. Due to the aggressiveness of PDTC and the poor survival rates in patients who undergo surgery alone, a multidisciplinary treatment approach is required.


A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer.
Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers.


A survey of university students' perceptions of learning management systems in a low-resource setting using a technology acceptance model.
Learning management systems have been widely advocated for the support of distance learning. In low-resource settings, the uptake of these systems by students has been mixed. This study aimed to identify, through the use of the Technology Acceptance Model, the individual, organizational, and technological factors that could be influencing the use of learning management systems. A simple quantitative descriptive survey was conducted of nursing and health science students at a university in South Africa as part of their first exposure to a learning management system. A total of 274 respondents (56.7%) completed the survey questionnaire, made up of 213 nursing respondents (87.7%) and 61 health sciences respondents (25%). Overall, the respondents found the learning management system easy to use and useful for learning. There were significant differences between the two groups of respondents, with the respondents from health sciences being both younger and more computer literate. The nursing respondents, who received more support and orientations, reported finding the learning management system more useful. Recommendations are made for training and support to ensure uptake.


Allergy to semisynthetic penicillins in cystic fibrosis.
Allergic reactions to anti-Pseudomonal penicillin derivatives are an increasing problem in therapy of cystic fibrosis lung disease. We evaluated 15 patients, ages 12 to 37 years, with documented allergic reactions to carbenicillin, ticarcillin, or piperacillin. Intradermal skin test reactions were positive for benzylpenicillin in seven patients, penicilloyl-polylysine in one, and ticarcillin or piperacillin in eight, for a total of 11 of 11 tested. Results of radioallergosorbent testing to penicilloyl conjugates were positive in eight of 14 patients and equivocal in four others. Overall, skin tests or RAST results were positive in 13 of 15 patients. All patients were desensitized with a semisynthetic penicillin by continuous serial intravenous infusion of 10-fold dose increments, beginning with 10(-6) of the therapeutic dose. Desensitization was successful in 25 of 26 instances. After intravenously administered therapy, maintenance of desensitization with dicloxacillin orally was unsuccessful in four of six patients. We conclude that (1) allergy to semisynthetic penicillins in cystic fibrosis usually is IgE mediated; (2) such allergy can be evaluated by skin testing; (3) it can be safely and in most cases successfully treated by intravenous desensitization; and (4) allergic patients should be desensitized on each subsequent admission for intravenously administered therapy.


The Safety Profile of Intentional or Iatrogenic Sacrifice of the Artery of Adamkiewciz and Its Vicinity's Spinal Segmental Arteries: A Systematic Review.
Systematic review. There is paucity of consensus on whether (1) the artery of Adamkiewicz (AoA) and (2) the number of contiguous segmental spinal arteries (SSAs) that can be safely ligated without causing spinal cord ischemia. The objective of this review is to determine the risk of motor neurological deficits from iatrogenic sacrifice of the (1) AoA and (2) its vicinity's SSAs. Systematic review of the spine and vascular surgery was carried out in accordance to PRISMA guidelines. Outcomes in terms of risk of postoperative motor neurological deficit with occlusion of the AoA, bilateral contiguous SSAs, or unilateral contiguous SSAs were analyzed. Ten articles, all retrospective case series, were included. Three studies (total N = 50) demonstrated a postoperative neurological deficit risk of 4.0% when the AoA is occluded. When 1 to 6 pairs of SSAs (without knowledge of AoA location) were ligated, the postoperative neurological deficit risk was 0.6%, as compared with 5.4% when more than 6 bilateral pairs of SSAs were ligated (relative risk [RR] = 0.105, 95% CI 0.013-0.841, P = .0337). For unilateral ligation of SSAs of two to nine levels, the risk of postoperative neurological deficit does not exceed 1.3%. The current best evidence indicates that (1) occlusion of the AoA and (2) occlusion of up to 6 pairs of SSAs is associated with a low risk of postoperative neurological deficit. This limited number of low quality studies restrict the ability to draw definitive conclusions. Ligation of AoA and SSAs should only be undertaken when absolutely required to mitigate the small but devastating risk of paralysis.


MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling.
MicroRNAs (miRNAs) are genomically encoded small RNAs that hybridize with messenger RNAs, resulting in degradation or translational inhibition of targeted transcripts. The potential for miRNAs to regulate cell-lineage determination or differentiation from pluripotent progenitor or stem cells is unknown. Here, we show that microRNA1 (miR-1) is an ancient muscle-specific gene conserved in sequence and expression in Drosophila. Drosophila miR-1 (dmiR-1) is regulated through a serum response factor-like binding site in cardiac progenitor cells. Loss- and gain-of-function studies demonstrated a role for dmiR-1 in modulating cardiogenesis and in maintenance of muscle-gene expression. We provide in vivo evidence that dmiR-1 targets transcripts encoding the Notch ligand Delta, providing a potential mechanism for the expansion of cardiac and muscle progenitor cells and failure of progenitor cell differentiation in some dmiR-1 mutants. These findings demonstrate that dmiR-1 may "fine-tune" critical steps involved in differentiation of cardiac and somatic muscle progenitors and targets a pathway required for progenitor cell specification and asymmetric cell division.


Characterization of an active control system for holographic setup stabilization.
We report on the realization and characterization of an active control system of the optical holographic setup used for fabrication of holographic gratings in liquid-crystalline composite materials. The system exploits a reference diffraction grating and a piezomirror in closed-loop feedback. The piezoelectric mirror exhibits a hysteresis that depends not only on the applied voltage, but also on the history of the mirror motion. In an open-loop configuration, the hysteresis can be reduced by adjusting the delay time between the application of two different control voltage values; in a closed-loop operation, it is possible to eliminate the residual hysteresis. By testing the system in different conditions, it has been shown that residual fluctuations are comparable to the resolution of the piezomirror operation.


POR*28 SNP is associated with lipid response to atorvastatin in children and adolescents with familial hypercholesterolemia.
In children and adolescents with familial hypercholesterolemia (FH) pharmacotherapy with statins is the cornerstone in the current regimen to reduce low-density lipoprotein cholesterol (LDLc) and premature coronary heart disease risk. There is, however, a great interindividual variation in response to therapy, partially attributed to genetic factors. The polymorphic enzyme POR transfers electrons from NADPH to CYP450 enzymes including CYP3A, which metabolize atorvastatin. POR*28 polymorphism is associated with increased CYP3A enzyme activity. We analyzed the association of POR*28 allele with response to atorvastatin. One hundred and five FH children and adolescents treated with atorvastatin at doses 10-40 mg were included in the study. Total cholesterol (TChol) and LDLc were measured at baseline and after 6 months of treatment. POR*28 allele was analyzed with TaqMan assay. CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G genotypes were also determined with TaqMan or PCR-RFLP methods. POR*28 carriers had significantly lower percent mean reduction of TChol (33.1% in *1/*1, 29.8% in *1/*28 and 25.9% in *28/*28 individuals, p = 0.045) and of LDLc (43.9% in *1/*1, 40.9% in *1/*28 and 30.8% in *28/*28 individuals, p = 0.013). In multivariable linear regression adjusted for confounding factors, POR*28 genotypes, additionally to baseline cholesterol level, accounted for an estimated 8.3% and 7.3% of overall variability in % TChol and LDLc reduction (β: 4.05; 95% CI: 1.73-6.37; p = 0.001 and β: 5.08; 95% CI: 1.62-8.54; p = 0.004, respectively). CYP3A4*22, CYP3A5*3 and SLCO1B1 521T>C and 388A>G polymorphisms were not associated with lipid reductions and did not modify the effect of POR*28 on atorvastatin response. In children with FH, carriage of POR*28 allele is associated with reduced effect of atorvastatin on TChol and LDLc and therefore identifies FH children that may require higher atorvastatin doses to achieve full therapeutic benefits. Additional studies in different populations are needed to replicate this association.


Purification of a vesicle-vacuole (V) fraction from Aspergillus.
Recent studies conducted in our laboratory demonstrate that Aspergillus parasiticus synthesizes and stores aflatoxin in transport vesicles and endosomes. Proteomics data suggest that enzymes involved in the synthesis of other secondary metabolites as well as enzymes involved in response to heat, osmotic, and oxidative stress also localize to these subcellular organelles. In order to better understand how cells integrate the regulation and function of secondary metabolite biosynthesis and stress response, it is important to understand the composition and function of the membrane-bound organelles that house this biosynthetic machinery. Isolation of vesicles, endosomes, and vacuoles (V fraction) is, therefore, an essential method to study secondary metabolism in A. parasiticus at the cellular level. Here, we describe a "one-step density gradient" method for purification of a highly heterogeneous cell fraction consisting of transport vesicles, endosomes, and vacuoles from protoplasts prepared from A. parasiticus cells harvested during aflatoxin synthesis.


Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE.
Anti-IgE-dependent activation of rat and human mast cells resulted in the preferential generation of the cyclooxygenase products prostaglandin D2 (PGD2) and prostaglandin I2 (PGI2) in the rat and PGD2 in the human. The average net generation of PGD2, determined by gas chromatography-mass spectrometry, was 13.1 ng/10(6) purified rat mast cells and 39.5 ng/10(6) dispersed, enriched human mast cells. After IgE-dependent activation, there was a linear relationship between the net quantities of PGD2 generated and of histamine secreted from dispersed human pulmonary cells when the number of mast cells was varied but the total number of cells was held constant, indicating that it is the number of mast cells participating in IgE-dependent activation, rather than total mast cell number, that determines PGD2 generation. A linear relationship was also shown between PGD2 generation, determined by radioimmunoassay, and the release of the granule marker beta-hexosaminidase from purified rat mast cells on the dose-response portion of the plot of their response to anti-IgE challenge. With higher concentrations of anti-IgE, PGD2 generation from rat mast cells plateaued, whereas net percent beta-hexosaminidase release increased further. In kinetic studies of rat mast cells activated with anti-IgE, the onset (1 to 2 min) and time of maximum generation (5 to 10 min) for PGD2 were delayed relative to the onset (15 to 30 sec) and completion (1 to 2 min) of beta-hexosaminidase release. Thus, the extracellular appearance of PGD2 during IgE-dependent mast cell activation represents a response additional to the secretion of granule-associated mediators.


Beneficial effects of angiotensin converting enzyme inhibition on renal function in patients with diabetic nephropathy.
The effects of angiotensin converting enzyme inhibition with captopril were investigated in patients with diabetic nephropathy and hypertension. After nine days' treatment with captopril glomerular filtration rate was unchanged in 13 patients, whereas renal plasma flow had increased from 265 to 302 ml/min/1.73 m2 body surface area (p less than 0.05) and the filtration fraction had decreased from 14.3 to 12.8% (p less than 0.025). During two years' treatment with captopril in 14 patients the mean arterial blood pressure had fallen by 5 mm Hg (p less than 0.005) and the deterioration in glomerular filtration rate had decreased from 10.3 to 2.4 ml/min/year (p less than 0.005). There was no correlation between the fall in blood pressure and the reduction in the deterioration of glomerular filtration rate. These findings suggest that the effects of angiotensin converting enzyme inhibition on renal haemodynamics protect renal function. Inhibitors of angiotensin converting enzyme should be considered for lowering blood pressure in patients with diabetic nephropathy.


PTM MarkerFinder, a software tool to detect and validate spectra from peptides carrying post-translational modifications.
Mass spectrometry (MS) analysis of peptides carrying post-translational modifications is challenging due to the instability of some modifications during MS analysis. However, glycopeptides as well as acetylated, methylated and other modified peptides release specific fragment ions during CID (collision-induced dissociation) and HCD (higher energy collisional dissociation) fragmentation. These fragment ions can be used to validate the presence of the PTM on the peptide. Here, we present PTM MarkerFinder, a software tool that takes advantage of such marker ions. PTM MarkerFinder screens the MS/MS spectra in the output of a database search (i.e., Mascot) for marker ions specific for selected PTMs. Moreover, it reports and annotates the HCD and the corresponding electron transfer dissociation (ETD) spectrum (when present), and summarizes information on the type, number, and ratios of marker ions found in the data set. In the present work, a sample containing enriched N-acetylhexosamine (HexNAc) glycopeptides from yeast has been analyzed by liquid chromatography-mass spectrometry on an LTQ Orbitrap Velos using both HCD and ETD fragmentation techniques. The identification result (Mascot .dat file) was submitted as input to PTM MarkerFinder and screened for HexNAc oxonium ions. The software output has been used for high-throughput validation of the identification results.


Some probability models for diagnosing neurogenic disorders.
Healthy human skeletal muscles are composed of two distinguishable types of fibre, apparently randomly arranged within fascicles (bundles of fibres surrounded by connective tissue). Large groups of fibres of the same type indicate a neurogenic muscle disorder. An objective method for detecting nonrandom arrangements of fibres could improve the diagnosis of such disorders, particularly at an early stage. The number of enclosed fibres (NEF)--fibres surrounded by others of the same type--is considered here as a measure of nonrandomness. The distribution of NEF is shown to be approximately negative binomial for a non-free-sampling model, which is then compared with a free-sampling model studied previously. A modification for a known boundary effect is also investigated. The models are applied to data from m. vastus lateralis obtained post mortem from 24 previously healthy men. Finally, the relationship between size of biopsy and the accuracy of predictions is discussed.


Melatonin receptor agonists-ramelteon and melatonin-for bipolar disorder: a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials.
Objective: This study was a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials, investigating the efficacy and tolerability/safety of melatonin receptor agonists, such as ramelteon and melatonin, for patients with bipolar disorder. Methods: We carried out a literature search through PubMed and the Cochrane Library from the date of inception to January 6, 2019. The risk ratio (RR), number needed to treat (NNT), and standardized mean difference (SMD) ±95% CI were calculated. The primary outcome was all-cause discontinuation. Results: We identified three ramelteon (n=746) and two melatonin (n=53) studies. One of these two melatonin studies reported only data on all-cause discontinuation, whereas the other study did not report data relevant for a meta-analysis. We found no significant differences between the treatment and placebo groups regarding all-cause discontinuation, neither individually (p: ramelteon=0.86, melatonin=1.00) nor pooled together (p=0.85). Although we found no significant differences between ramelteon and placebo regarding the relapse due to mania/hypomania or mixed episode; Pittsburgh Sleep Quality Index scores; depression scales scores; Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form scores; and the incidence of individual adverse events, such as headaches, insomnia, somnolence, anxiety, and dizziness, ramelteon was associated with a lower incidence of relapse due to depression than placebo (RR=0.67, 95% CI=0.48-0.94, p=0.02, NNT=14). Conclusion: Ramelteon might prevent relapse due to depression in patients with bipolar disorder. However, because of the small number of studies included in the present systematic review and meta-analysis, further studies comparing ramelteon and placebo with larger samples of patients with bipolar disorder are warranted. We also did not evaluate the efficacy and safety of melatonin for patients with bipolar disorder in detail.


Water and tissue equivalence of a new PRESAGE(®) formulation for 3D proton beam dosimetry: a Monte Carlo study.
To evaluate the water and tissue equivalence of a new PRESAGE(®) 3D dosimeter for proton therapy. The GEANT4 software toolkit was used to calculate and compare total dose delivered by a proton beam with mean energy 62 MeV in a PRESAGE(®) dosimeter, water, and soft tissue. The dose delivered by primary protons and secondary particles was calculated. Depth-dose profiles and isodose contours of deposited energy were compared for the materials of interest. The proton beam range was found to be ≈27 mm for PRESAGE(®), 29.9 mm for soft tissue, and 30.5 mm for water. This can be attributed to the lower collisional stopping power of water compared to soft tissue and PRESAGE(®). The difference between total dose delivered in PRESAGE(®) and total dose delivered in water or tissue is less than 2% across the entire water∕tissue equivalent range of the proton beam. The largest difference between total dose in PRESAGE(®) and total dose in water is 1.4%, while for soft tissue it is 1.8%. In both cases, this occurs at the distal end of the beam. Nevertheless, the authors find that PRESAGE(®) dosimeter is overall more tissue-equivalent than water-equivalent before the Bragg peak. After the Bragg peak, the differences in the depth doses are found to be due to differences in primary proton energy deposition; PRESAGE(®) and soft tissue stop protons more rapidly than water. The dose delivered by secondary electrons in the PRESAGE(®) differs by less than 1% from that in soft tissue and water. The contribution of secondary particles to the total dose is less than 4% for electrons and ≈1% for protons in all the materials of interest. These results demonstrate that the new PRESAGE(®) formula may be considered both a tissue- and water-equivalent 3D dosimeter for a 62 MeV proton beam. The results further suggest that tissue-equivalent thickness may provide better dosimetric and geometric accuracy than water-equivalent thickness for 3D dosimetry of this proton beam.


Ligamentum Teres Reconstruction May Lead to Improvement in Outcomes Following a Secondary Hip Arthroscopy for Symptomatic Microinstability: A Systematic Review.
To present the indications, surgical technique, outcomes, and complications for patients undergoing arthroscopic reconstruction of the ligamentum teres (LT). Articles were included if they had postoperative patient-reported outcomes (PROs) for arthroscopic LT reconstruction. Studies were analyzed for patient demographics, clinical assessment and indications, radiographic and magnetic resonance imaging data, concomitant procedures performed, PROs, surgical techniques, intra-articular classifications, complications, and need for follow-up surgeries. For PROs, the standard mean difference was calculated. The proportion of patients achieving patient acceptable symptomatic state for postoperative modified Harris Hip Score (≥74) was recorded. The number of patients achieving minimal clinically important difference for modified Harris Hip Score (Δ ≥8) was calculated. The majority of the cases were revision arthroscopies. Of the 3 studies reporting on patients undergoing LT reconstruction due to microinstability, 4, 9, and 11 patients demonstrated a mean improvement of 25.7, 35.2, and 27.7 in modified Harris Hip, respectively. In addition, one of the studies reported a mean improvement of 31.1 and 4.2 in Nonarthritic Hip Score and visual analog scale, respectively. Of the 3 studies, the percentile of patients surpassing minimal clinically important difference and patient acceptable symptomatic state ranged between 50% and 100% and 33.3% and 88.8%, respectively. Overall, 5 patients underwent revision hip arthroscopy due to adhesions, iliopsoas impingement, and persistent microinstability, and 3 patients underwent a secondary hip arthroplasty due to refractory pain and radiographic evidence of hip osteoarthritis. Reconstruction of the LT may be considered in surgical management for patients with symptomatic hip instability due to soft-tissue causes. Current evidence supports for LT reconstruction predominantly for patients experiencing refractory instability following previous hip preservation procedures. Patients' expectations as well as the relatively high reoperation rate (i.e., 33%) should be discussed before the procedure. Level IV, systematic review of Level IV studies.


Ligand exchange of major histocompatibility complex class II proteins is triggered by H-bond donor groups of small molecules.
Hydrogen bonds (H-bonds) are crucial for the stability of the peptide-major histocompatibility complex (MHC) complex. In particular, the H-bonds formed between the peptide ligand and the MHC class II binding site appear to have a great influence on the half-life of the complex. Here we show that functional groups with the capacity to disrupt hydrogen bonds (e.g. -OH) can efficiently catalyze ligand exchange reactions on HLA-DR molecules. In conjunction with simple carrier molecules (such as propyl or benzyl residues), they trigger the release of low affinity ligands, which permits the rapid binding of peptides with higher affinity. Similar to HLA-DM, these compounds are able to influence the MHC class II ligand repertoire. In contrast to HLA-DM, however, these simple small molecules are still active at neutral pH. Under physiological conditions, they increase the number of "peptide-receptive" MHC class II molecules and facilitate exogenous peptide loading of dendritic cells. The drastic acceleration of the ligand exchange on these antigen presenting cells suggests that, in general, availability of H-bond donors in the extracellular milieu controls the rate of MHC class II ligand exchange reactions on the cell surface. These molecules may therefore be extremely useful for the loading of antigens onto dendritic cells for therapeutic purposes.


Early Pregnancy Biochemical Predictors of Gestational Diabetes Mellitus.
Universal oral glucose tolerance-based screening is employed to identify pregnant women with gestational diabetes mellitus (GDM), as treatment of this condition decreases the risk of associated complications. A simple and accurate blood test which identifies women at low or high risk for GDM in the first trimester would have the potential to decrease costs and improve outcomes through prevention or treatment. This review summarizes published data on early pregnancy biomarkers which have been tested as predictors of GDM. A large number of first-trimester biochemical predictors of GDM have been reported, mostly in small case-control studies. These include glycemic markers (fasting glucose, post-load glucose, hemoglobin A1C), inflammatory markers (C-reactive protein, tumor necrosis factor-alpha), insulin resistance markers (fasting insulin, sex hormone-binding globulin), adipocyte-derived markers (adiponectin, leptin), placenta-derived markers (follistatin-like-3, placental growth factor, placental exosomes), and others (e.g., glycosylated fibronectin, soluble (pro)renin receptor, alanine aminotransferase, ferritin). A few large studies suggest that first-trimester fasting glucose or hemoglobin A1C may be useful for identifying women who would benefit from early GDM treatment. To translate the findings from observational studies of first-trimester biomarkers for GDM to clinical practice, trials or cost-effectiveness analyses of screening and treatment strategies based on these novel biomarkers are needed.


Strong upregulation of inflammatory genes accompanies photoreceptor demise in canine models of retinal degeneration.
We have analyzed the complex pattern of the inflammatory response in early-onset canine models of human retinitis pigmentosa, rcd1, xlpra2 and erd, as well as late-onset xlpra1, in comparative manner. The time course of immune response genes and proteins expression was examined along the timeline of photoreceptors degeneration. Gene expression analysis of the early-onset models prior to and after the peak of photoreceptors death identified the involvement of multiple immune response genes including those encoding constituents of the NLRP3 inflammasome, its substrates, pro-IL1B, pro-IL18, and common components of IL1B, IL18 and TLR4 pathways. Out of two activated caspase-1 cleavage products, IL1B and IL18, only IL1B was detected in rcd1 and xlpra2 while precursor IL18 remained unprocessed in the same protein extract highlighting prominence of IL1B pathway. An overall immune response was most prominent in rcd1 followed by xlpra2 and least prominent in erd. Noticeably, in rcd1 and xlpra2, but not in erd, early induction of the immune response was accompanied by sustained intraretinal migration and activation of retinal microglia. Lastly, delayed activation of the anti-inflammatory factors in all early-onset models was insufficient to counterbalance rapidly progressing inflammation. In contrast to early-onset models, in late-onset xlpra1 retinas a subset of the pro-inflammatory genes was highly upregulated long before any disease-related structural changes occurred, but was counterbalanced by an adequate anti-inflammatory response. Results point out to upregulated immune response accompanying disease progression in animal models of retinal degeneration, and to potential benefits of early anti-inflammatory therapy.


Preimplantation genetic testing for aneuploidy by microarray analysis of polar bodies in advanced maternal age: a randomized clinical trial.
Does preimplantation genetic testing for aneuploidy (PGT-A) by comprehensive chromosome screening (CCS) of the first and second polar body to select embryos for transfer increase the likelihood of a live birth within 1 year in advanced maternal age women aged 36-40 years planning an ICSI cycle, compared to ICSI without chromosome analysis? PGT-A by CCS in the first and second polar body to select euploid embryos for transfer does not substantially increase the live birth rate in women aged 36-40 years. PGT-A has been used widely to select embryos for transfer in ICSI treatment, with the aim of improving treatment effectiveness. Whether PGT-A improves ICSI outcomes and is beneficial to the patients has remained controversial. This is a multinational, multicentre, pragmatic, randomized clinical trial with intention-to-treat analysis. Of 396 women enroled between June 2012 and December 2016, 205 were allocated to CCS of the first and second polar body (study group) as part of their ICSI treatment cycle and 191 were allocated to ICSI treatment without chromosome screening (control group). Block randomization was performed stratified for centre and age group. Participants and clinicians were blinded at the time of enrolment until the day after intervention. Infertile couples in which the female partner was 36-40 years old and who were scheduled to undergo ICSI treatment were eligible. In those assigned to PGT-A, array comparative genomic hybridization (aCGH) analysis of the first and second polar bodies of the fertilized oocytes was performed using the 24sure array of Illumina. If in the first treatment cycle all oocytes were aneuploid, a second treatment with PB array CGH was offered. Participants in the control arm were planned for ICSI without PGT-A. Main exclusion criteria were three or more previous unsuccessful IVF or ICSI cycles, three or more clinical miscarriages, poor response or low ovarian reserve. The primary outcome was the cumulative live birth rate after fresh or frozen embryo transfer recorded over 1 year after the start of the intervention. Of the 205 participants in the chromosome screening group, 50 (24%) had a live birth with intervention within 1 year, compared to 45 of the 191 in the group without intervention (24%), a difference of 0.83% (95% CI: -7.60 to 9.18%). There were significantly fewer participants in the chromosome screening group with a transfer (relative risk (RR) = 0.81; 95% CI: 0.74-0.89) and fewer with a miscarriage (RR = 0.48; 95% CI: 0.26-0.90). The targeted sample size was not reached because of suboptimal recruitment; however, the included sample allowed a 90% power to detect the targeted increase. Cumulative outcome data were limited to 1 year. Only 11 patients out of 32 with exclusively aneuploid results underwent a second treatment cycle in the chromosome screening group. The observation that the similarity in birth rates was achieved with fewer transfers, less cryopreservation and fewer miscarriages points to a clinical benefit of PGT-A, and this form of embryo selection may, therefore, be considered to minimize the number of interventions while producing comparable outcomes. Whether these benefits outweigh drawbacks such as the cost for the patient, the higher workload for the IVF lab and the potential effect on the children born after prolonged culture and/or cryopreservation remains to be shown. This study was funded by the European Society of Human Reproduction and Embryology. Illumina provided microarrays and other consumables necessary for aCGH testing of polar bodies. M.B.'s institution (UZBrussel) has received educational grants from IBSA, Ferring, Organon, Schering-Plough, Merck and Merck Belgium. M.B. has received consultancy and speakers' fees from Organon, Serono Symposia and Merck. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott and Gedeon-Richter as well as personal fees from VitroLife, NMC Healthcare, ReprodWissen, BioSilu and ZIVA. W.V., C.S., P.M.B., V.G., G.A., M.D., T.E.G., L.G., G.Ka., G.Ko., J.L., M.C.M., M.P., A.S., M.T., K.V., J.G. and K.S. declare no conflict of interest. NCT01532284. 7 February 2012. 25 June 2012.


Quantitation of 4,4'-methylene diphenyl diisocyanate human serum albumin adducts.
4,4'-Methylene diphenyl diisocyanate (herein 4,4'-MDI) is used in the production of polyurethane foams, elastomers, coatings, adhesives and the like for a wide range of commercial products. Occupational exposure to MDI levels above current airborne exposure limits can elicit immune mediated hypersensitivity reactions such as occupational asthma in sensitive individuals. To accurately determine exposure, there has been increasing interest in developing analytical methods to measure internal biomarkers of exposure to MDI. Previous investigators have reported methodologies for measuring MDI diamine metabolites and MDI-Lysine (4,4'-MDI-Lys) adducts. The purpose of this study was to develop and validate an ultra performance liquid chromatography isotope dilution tandem mass spectrometry (UPLC-ID/MS/MS) quantitation method via a signature peptide approach to enable biomonitoring of 4,4'-MDI adducted to human serum albumin (HSA) in plasma. A murine, anti-4,4'-MDI monoclonal IgM antibody was bound to magnetic beads and utilized for enrichment of the MDI adducted HSA. Following enrichment, trypsin digestion was performed to generate the expected 414 site (primary site of adduction) 4,4'-MDI-adducted HSA signature peptide that was quantified by UPLC-ID/MS/MS. An Agilent 6530 UPLC/quadrupole time of flight MS (QTOF) system was utilized for intact adducted protein analysis and an Agilent 6490 UPLC/MS/MS system operated in multiple reaction monitoring (MRM) mode was utilized for quantification of the adducted signature peptide biomarker both for in chemico and worker serum samples. Worker serum samples were initially screened utilizing the previously developed 4,4'-MDI-Lys amino acid method and results showed that 12 samples were identified as quantifiable for 4,4'-MDI-Lys adducts. The signature peptide adduct approach was applied to the 12 worker samples identified as quantifiable for 4,4'-MDI-Lys adducts. Results indicated no positive results were obtained above the quantification limit by the signature peptide approach. If the 414 site of lysine adduction accounted for 100% of the 4,4'-MDI adductions in the signature peptide adduct approach, the three highest quantifiable samples by the 4,4'-MDI-Lys method should have at least been detectable by the signature peptide method. Results show that although the 4,4'-MDI signature peptide approach is more selective, it is 18 times less sensitive than the 4,4'-MDI-Lys method, thus limiting the ability to detect adduct levels relative to the 4,4'-MDI-Lys amino acid method.


Two dissociable phases in the contractile response of the guinea pig isolated vas deferens to adenosine triphosphate.
The effects of the ATP affinity label periodate-oxidized ATP (ATP-2',3'-dialdehyde; P-ATP) on contractile responses of the guinea pig vas deferens to ATP was characterized and compared to the effects of the specific P2x-purinoceptor photoaffinity label antagonist, arylazido aminopropionyl ATP (ANAPP3). After incubation of vas deferens with 10(-2) M P-ATP for 5 min, the second phase of biphasic contractions to ATP was inhibited selectively. The inhibitory effect of P-ATP was specific for ATP, and resulted from affinity labeling in that it was long-lasting, was not reversed by washing, was related in magnitude to exposure period and was attenuated by ATP present during the incubation. In contrast to P-ATP, ANAPP3 inhibited selectively the first phase of ATP-induced responses. P-ATP and ANAPP3 together inhibited both phases of response. P-ATP inhibited selectively the second phase of responses to 5'-substituted ATP analogs which develop a prolonged second phase [e.g., adenosine 5'-O-(3-thiotriphosphate) and adenosine tetraphosphate] or an abbreviated second phase (e.g., beta,gamma-methylene ATP, beta,gamma-imido ATP and alpha,beta-methylene ATP). The greater the duration of the second phase, the more pronounced was the inhibitory effect. Two distinct and dissociable mechanisms mediate the biphasic response to ATP: the initial phase involves ANAPP3-sensitive P2x-purinoceptors, whereas the second is blocked by P-ATP and appears to involve cleavage of the phosphate chain. An additional effect observed as a result of P-ATP-treatment was potentiation of the first phase of contraction to ATP. This novel and irreversible effect may arise from the inhibition of degradative ecto-phosphohydrolase activity.


Intracellular trafficking of LET-756, a fibroblast growth factor of C. elegans, is controlled by a balance of export and nuclear signals.
The superfamily of fibroblast growth factors (FGF), which counts 22 members in humans, exerts many functions during animal development and adult life. LET-756 is one of the two FGFs of the nematode C. elegans. Re-introduction of LET-756 in a null mutant strain restores viability, allowing the study of structural requirements for LET-756 trafficking and function. LET-756 protein has several regions and motifs, including a non-classical internal motif required for secretion. We show here that a main difference in the wild-type LET-756 molecule and a truncated molecule that mimics a partial loss-of-function mutant lies on subnuclear expression. Using Cos-1 cells and rescue activity we show that: (i) nuclear localization is due to various redundant NLS, one of them acting as a nucleolar localization signal; (ii) nuclear LET-756 is addressed to the speckles by a stretch of glutamine residues; (iii) nuclear LET-756 is trafficking between speckles and nucleoli; (iv) in the nucleolus, LET-756 is associated with proteins of the rRNA splicing compartment; (v) changing LET-756 secretion signal prevents its nuclear localization. We propose that LET-756 exerts its functions through a balance between secreted and nuclear forms due to two opposite addressing signals, (i) synergy of several NLS and (ii) attenuated secretion signal.


Management of bone metastases in breast cancer.
Patients with advanced breast cancer who develop bone metastases suffer an ongoing risk of skeletal complications that can have a significant impact on their quality of life (QoL). These complications include bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy (HCM), a potentially life-threatening condition. Treatment options include radiotherapy to palliate bone pain and/or prevent impending fracture, orthopedic surgery to prevent or repair fractures, analgesics, and bisphosphonates, which can significantly reduce the risk of skeletal complications and delay their onset. Of the known bisphosphonates, zoledronic acid is the most potent. Since its regulatory approval in the United States and Europe in 2001, zoledronic acid (4 mg by 15-minute infusion) has become widely used and has replaced pamidronate (90 mg by 2-hour infusion) as the standard of care for treating bone metastases from breast cancer and bone lesions from multiple myeloma. Zoledronic acid has also demonstrated significant long-term benefits in randomized trials in prostate cancer and other solid tumors, whereas other bisphosphonates have failed. In long-term, phase III clinical testing, zoledronic acid provided significant treatment benefits beyond those of pamidronate in patients with breast cancer and demonstrated a safety profile comparable with pamidronate. Therefore, zoledronic acid is now recommended from the first diagnosis of bone metastasis. Other intravenous bisphosphonates include clodronate and ibandronate. Both are approved in Europe, but their efficacy relative to pamidronate and zoledronic acid is not known.


Structure of the functional fragment of auxilin required for catalytic uncoating of clathrin-coated vesicles.
The three-dimensional structure of the C-terminal 20 kDa portion of auxilin, which consists of the clathrin binding region and the C-terminal J-domain, has been determined by NMR. Auxilin is an Hsp40 family protein that catalytically supports the uncoating of clathrin-coated vesicles through recruitment of Hsc70 in an ATP hydrolysis-driven process. This 20 kDa auxilin construct contains the minimal sequential region required to uncoat clathrin-coated vesicles catalytically. The tertiary structure consists of six helices, where the first three are unique to auxilin and believed to be important in the catalytic uncoating of clathrin. The last three helices correspond to the canonical J-domain of Hsp40 proteins. The first helix, helix 1, which contains a conserved FEDLL motif believed to be necessary for clathrin binding, is transient and not packed against the rest of the structure. Helix 1 is joined to helix 2 by a flexible linker. Helix 2 packs loosely against the J-domain surface, whereas helix 3 packs tightly and makes critical contributions to the J-domain core. A long insert loop, also unique to the auxilin J-domain, is seen between helix 4 and helix 5. Comparison with a previously reported structure of auxilin containing only helices 3-6 shows a significant difference in the invariant HPD segment of the J-domain. The region where helix 1 is located corresponds to the expected region of the unstructured G/F-rich domain seen in DnaJ, i.e., the canonical N-terminal J-domain protein. In contrast, the location of helix 1 differs from the substrate binding regions of two other Hsp40 proteins, Escherichia coli Hsc20 and viral large T antigen. The variety of biological functions performed by Hsp40 proteins such as auxilin, as well as the observed differences in the structure and function of their substrate binding regions, supports the notion that Hsp40 proteins act as target-specific adaptors that recruit their more general Hsp70 partners to specific biological roles.


Compromised Vitamin D Status Negatively Affects Muscular Strength and Power of Collegiate Athletes.
Increasing evidence indicates that compromised vitamin D status, as indicated by serum 25-hydroxyvitamin D (25-OH D), is associated with decreased muscle function. The purpose of this study was to determine the vitamin D status of collegiate athletes residing in the southern U.S. and its effects on muscular strength and anaerobic power. Collegiate athletes (n = 103) from three separate NCAA athletic programs were recruited for the study. Anthropometrics, vitamin D and calcium intake, and sun exposure data were collected along with serum 25-OH D and physical performance measures (Vertical Jump Test, Shuttle Run Test, Triple Hop for Distance Test and the 1 Repetition Maximum Squat Test) to determine the influence of vitamin D status on muscular strength and anaerobic power. Approximately 68% of the study participants were vitamin D adequate (>75 nmol/L), whereas 23% were insufficient (75-50 nmol/L) and 9%, predominantly non-Caucasian athletes, were deficient (<50 nmol/L). Athletes who had lower vitamin D status had reduced performance scores (p < .01) with odds ratios of 0.85 on the Vertical Jump Test, 0.82 on the Shuttle Run Test, 0.28 on the Triple Hop for Distance Test, and 0.23 on the 1 RM Squat Test. These findings demonstrate that even NCAA athletes living in the southern US are at risk for vitamin D insufficiency and deficiency and that maintaining adequate vitamin D status may be important for these athletes to optimize their muscular strength and power.


Minimally invasive thoracoscopic approach to thoracolumbar junction fractures.
A retrospective analysis of patients with thoracolumbar junction fractures who underwent video-assisted thoracoscopic surgery via a minimally invasive approach (minithoracotomy) for reconstruction of the anterior spinal column. Between 2002 and 2014, a total of 176 patients were treated by this technique. The patients received either posterior stabilization and, at the second stage, the minimally invasive technique via an anterior approach, or the minimally invasive anterior procedure alone. In the anterior procedure, the average operative time was 90 min. (50 to 130 min). Bony fusion without complications was achieved in all patients within a year of surgery. The loss of correction after the anterior procedure with an allograft or titanium cage was up to 2 degrees at two years follow-up. The minimally invasive approach (minithoracotomy up to 6-7 cm) combined with thoracoscopy is an alternative to an exclusively endoscopic technique enabling us to provide safe surgical treatment of the anterior spinal column.


Perimenopausal obesity.
Obesity is recognized as one of the most important underlying risk factors for a wide variety of diseases, including heart disease and diabetes. Women are particularly prone to obesity, and approaches that address life transitions across the life span suggest that a number of factors may converge at passage points, such as menopause, that contribute to weight accumulation in the aging woman. The menopausal phase of a woman's life brings a number of changes that may trigger and maintain weight gain. Although the prevalence of overweight and obesity is attributable to each of these factors, it is most likely the interaction among multiple factors that determines an individual's propensity for excess energy intake, sedentary behavior, patterns of fat distribution, and risk of developing obesity. The problem of weight change and obesity in perimenopausal women is best understood from an ecological perspective that can integrate the analysis of factors across levels, from the culture and built environment of the community to family-related factors to individual factors, such as subjective norms, values, attitudes, and beliefs, and biological/genetic predispositions. This review describes the literature relevant to weight change during perimenopause using a multilevel perspective and recommends future directions for the development of translational weight management research to meet the unique needs of women.


Nuclear distribution of the Ki-67 antigen during the cell cycle: comparison with growth fraction in human breast cancer cells.
It has been claimed that the commercially available Ki-67 monoclonal antibody recognizes a nuclear antigen which is solely expressed in cycling cells. Therefore, at present, Ki-67 is increasingly used as a tool in evaluating growth fractions (GFs) of human tumors. Here we describe specific patterns in the expression and topological distribution of this antigen during the cell cycle in MCF-7 human breast cancer cells. Our results support earlier findings that the antigen belongs to a class of antigens associated with the structural organization of meta- and anaphase chromosomes, and proteins located near the cortical regions of prenucleolar bodies and nucleoli. Using 5'-bromodeoxyuridine-labeling technology, we show that the expression may be undetectably low at the onset of DNA replication. Comparison of Ki-67 fractions (KFs) and GFs as estimated from continuous 5'-bromodeoxyuridine-labeling curves revealed that KF was invariably higher than GF: in exponentially growing cov362.c14 human ovary cancer cells, KF was only 3.5% higher than GF; in MCF-7 cells, 11.3 +/- 4.6%. In MCF-7 cultures either growing under suboptimal conditions or treated with 10(-6) M tamoxifen, the difference was more pronounced. Furthermore, we evaluated the decrease of Ki-67-positive cells in nutritionally deprived and cell cycle-specific, drug-treated cultures. Since the results indicate that nonproliferating cells may retain the antigen for a considerable period of time, KF may not always be a reliable indicator of GF.


Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain.
Glucagon-like peptide-1 (GLP-1) is released from endocrine L-cells lining the gut in response to food ingestion. However, GLP-1 is also produced in the nucleus of the solitary tract, where it acts as an anorectic neurotransmitter and key regulator of many autonomic and neuroendocrine functions. The expression and projections of GLP-1-producing neurons is highly conserved between rodent and primate brain, although a few key differences have been identified. The GLP-1 receptor (GLP-1R) has been mapped in the rodent brain, but no studies have described the distribution of GLP-1Rs in the nonhuman primate central nervous system. Here, we characterized the distribution of GLP-1R mRNA and protein in the adult macaque brain using in situ hybridization, radioligand receptor autoradiography, and immunohistochemistry with a primate specific GLP-1R antibody. Immunohistochemistry demonstrated that the GLP-1R is localized to cell bodies and fiber terminals in a very selective distribution throughout the brain. Consistent with the functional role of the GLP-1R system, we find the highest concentration of GLP-1R-immunoreactivity present in select hypothalamic and brainstem regions that regulate feeding, including the paraventricular and arcuate hypothalamic nuclei, as well as the area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus. Together, our data demonstrate that GLP-1R distribution is highly conserved between rodent and primate, although a few key species differences were identified, including the amygdala, where GLP-1R expression is much higher in primate than in rodent.


Association between exposure to traumatic events and anxiety disorders in a post-conflict setting: a cross-sectional community study in South Sudan.
The negative effect of exposure to traumatic events on mental health is well known. Most studies of the effects of trauma on mental health in war-affected populations have focused on post-traumatic stress disorder (PTSD) and depression. Although some studies confirm the existence of anxiety symptoms in war-affected populations, the extent to which exposure to traumatic events is independently associated with anxiety diagnoses (other than PTSD) has received less attention. The study aimed to determine whether having an anxiety diagnosis, other than PTSD, was associated with experiencing traumatic events in a post-conflict setting, across genders and after controlling for demographic and socio-economic variables. In this cross-sectional community study (n = 1200), we applied the Harvard Trauma Questionnaire (HTQ) to investigate the extent of trauma exposure and PTSD. The Mini-International Neuropsychiatric Interview (MINI) was used to investigate the prevalence of anxiety disorders: generalized anxiety disorder (GAD), panic disorder (PD), social phobia, obsessive-compulsive disorder (OCD), and agoraphobia. Multinomial logistic regression analyses were conducted to examine the association between these disorders, previous trauma exposure, and socio-economic factors. The participants were 56.4% male and 43.6% female. The age ranged between 18 and 73 years old (Mean 34.63, SD = 12.03). The estimated rates of GAD-only and PD-only (without comorbidity with PTSD) were 5.5% and 3.1%, respectively. Exposure to traumatic events and socio-economic disadvantage were significantly associated with having one or more anxiety diagnoses. After controlling for age, sex, rural/urban setting, and socio-economic disadvantage, exposure to trauma was independently associated with anxiety diagnosis. There were gender differences in the pattern of risk factors for having PTSD, GAD or PD. In individuals with a history of war-related trauma exposure, attention should be given to symptoms of GAD and PD, in addition to PTSD symptoms.