Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway.

Enhanced apoptotic cancer cell killing after Foscan photodynamic therapy combined with fenretinide via de novo sphingolipid biosynthesis pathway.

J Photochem Photobiol B. 2016 Mar 16;159:191-195

Authors: Boppana NB, DeLor JS, Van Buren E, Bielawska A, Bielawski J, Pierce JS, Korbelik M, Separovic D

Abstract
We and others have shown that stresses, including photodynamic therapy (PDT), can disrupt the de novo sphingolipid biosynthesis pathway, leading to changes in the levels of sphingolipids, and subsequently, modulation of cell death. The de novo sphingolipid biosynthesis pathway includes a ceramide synthase-dependent reaction, giving rise to dihydroceramide, which is then converted in a desaturase-dependent reaction to ceramide. In this study we tested the hypothesis that combining Foscan-mediated PDT with desaturase inhibitor fenretinide (HPR) enhances cancer cell killing. We discovered that by subjecting SCC19 cells, a human head and neck squamous cell carcinoma cell line, to PDT+HPR resulted in enhanced accumulation of C16-dihydroceramide, not ceramide. Concomitantly, mitochondrial depolarization was enhanced by the combined treatment. Enhanced activation of caspase-3 after PDT+HPR was inhibited by FB. Enhanced clonogenic cell death after the combination was sensitive to FB, as well as Bcl2- and caspase inhibitors. Treatment of mouse SCCVII squamous cell carcinoma tumors with PDT+HPR resulted in improved long-term tumor cures. Overall, our data showed that combining PDT with HPR enhanced apoptotic cancer cell killing and antitumor efficacy of PDT. The data suggest the involvement of the de novo sphingolipid biosynthesis pathway in enhanced apoptotic cell killing after PDT+HPR, and identify the combination as a novel more effective anticancer treatment than either treatment alone.

PMID: 27085050 [PubMed - as supplied by publisher]

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Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.

Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.

Ann Oncol. 2016 Apr 15;

Authors: Clement PM, Gauler T, Machiels JH, Haddad RI, Fayette J, Licitra LF, Tahara M, Cohen EE, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G, de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Vermorken JB, LUX-H&N 1 investigators

Abstract
BACKGROUND: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in pre-specified subgroups of patients aged ≥65 and <65 years.
PATIENTS AND METHODS: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary endpoint; overall survival (OS) was the key secondary endpoint. Other endpoints: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed.
RESULTS: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older (median 2.8 versus 2.3 months, HR=0.68 [95% CI 0.45-1.03], P=0.061) and younger patients (2.6 versus 1.6 months, HR=0.79 [0.62-1.01], P=0.052). In older and younger patients, median OS with afatinib versus methotrexate was 7.3 versus 6.4 months (HR=0.84 [0.54-1.31]) and 6.7 versus 6.2 months (HR=0.98 [0.76-1.28]). ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend towards improved time to deterioration of global health status, pain and swallowing with afatinib was observed in both subgroups.
CONCLUSIONS: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT01345682.

PMID: 27084954 [PubMed - as supplied by publisher]

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Cervical Lymph Node Metastasis in Adenoid Cystic Carcinoma of the Larynx: A Collective International Review.

Cervical Lymph Node Metastasis in Adenoid Cystic Carcinoma of the Larynx: A Collective International Review.

Adv Ther. 2016 Mar 19;

Authors: Coca-Pelaz A, Barnes L, Rinaldo A, Cardesa A, Shah JP, Rodrigo JP, Suárez C, Eloy JA, Bishop JA, Devaney KO, Thompson LD, Wenig BM, Strojan P, Hamoir M, Bradley PJ, Gnepp DR, Silver CE, Slootweg PJ, Triantafyllou A, Vander Poorten V, Williams MD, Skálová A, Hellquist H, Teymoortash A, Medina JE, Robbins KT, Pitman KT, Kowalski LP, de Bree R, Mendenhall WM, Takes RP, Ferlito A

Abstract
Adenoid cystic carcinoma (AdCC) of the head and neck is a well-recognized pathologic entity that rarely occurs in the larynx. Although the 5-year locoregional control rates are high, distant metastasis has a tendency to appear more than 5 years post treatment. Because AdCC of the larynx is uncommon, it is difficult to standardize a treatment protocol. One of the controversial points is the decision whether or not to perform an elective neck dissection on these patients. Because there is contradictory information about this issue, we have critically reviewed the literature from 1912 to 2015 on all reported cases of AdCC of the larynx in order to clarify this issue. During the most recent period of our review (1991-2015) with a more exact diagnosis of the tumor histology, 142 cases were observed of AdCC of the larynx, of which 91 patients had data pertaining to lymph node status. Eleven of the 91 patients (12.1%) had nodal metastasis and, based on this low proportion of patients, routine elective neck dissection is therefore not recommended.

PMID: 27084720 [PubMed - as supplied by publisher]

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Fractionated Boron Neutron Capture Therapy in Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

Fractionated Boron Neutron Capture Therapy in Locally Recurrent Head and Neck Cancer: A Prospective Phase I/II Trial.

Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):396-403

Authors: Wang LW, Chen YW, Ho CY, Hsueh Liu YW, Chou FI, Liu YH, Liu HM, Peir JJ, Jiang SH, Chang CW, Liu CS, Lin KH, Wang SJ, Chu PY, Lo WL, Kao SY, Yen SH

Abstract
PURPOSE: To investigate the efficacy and safety of fractionated boron neutron capture therapy (BNCT) for recurrent head and neck (H&N) cancer after photon radiation therapy.
METHODS AND MATERIALS: In this prospective phase 1/2 trial, 2-fraction BNCT with intravenous L-boronophenylalanine (L-BPA, 400 mg/kg) was administered at a 28-day interval. Before each fraction, fluorine-18-labeled-BPA-positron emission tomography was conducted to determine the tumor/normal tissue ratio of an individual tumor. The prescription dose (D80) of 20 Gy-Eq per fraction was selected to cover 80% of the gross tumor volume by using a dose volume histogram, while minimizing the volume of oral mucosa receiving >10 Gy-Eq. Tumor responses and adverse effects were assessed using the Response Evaluation Criteria in Solid Tumors v1.1 and the Common Terminology Criteria for Adverse Events v3.0, respectively.
RESULTS: Seventeen patients with a previous cumulative radiation dose of 63-165 Gy were enrolled. All but 2 participants received 2 fractions of BNCT. The median tumor/normal tissue ratio was 3.4 for the first fraction and 2.5 for the second, whereas the median D80 for the first and second fraction was 19.8 and 14.6 Gy-Eq, respectively. After a median follow-up period of 19.7 months (range, 5.2-52 mo), 6 participants exhibited a complete response and 6 exhibited a partial response. Regarding acute toxicity, 5 participants showed grade 3 mucositis and 1 participant showed grade 4 laryngeal edema and carotid hemorrhage. Regarding late toxicity, 2 participants exhibited grade 3 cranial neuropathy. Four of six participants (67%) receiving total D80 > 40 Gy-Eq had a complete response. Two-year overall survival was 47%. Two-year locoregional control was 28%.
CONCLUSIONS: Our results suggested that 2-fraction BNCT with adaptive dose prescription was effective and safe in locally recurrent H&N cancer. Modifications to our protocol may yield more satisfactory results in the future.

PMID: 27084657 [PubMed - in process]

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Long-Term Outcomes After Proton Beam Therapy for Sinonasal Squamous Cell Carcinoma.

Long-Term Outcomes After Proton Beam Therapy for Sinonasal Squamous Cell Carcinoma.

Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):368-76

Authors: Russo AL, Adams JA, Weyman EA, Busse PM, Goldberg SI, Varvares M, Deschler DD, Lin DT, Delaney TF, Chan AW

Abstract
PURPOSE: Squamous cell carcinoma (SCC) is the most common sinonasal cancer and is associated with one of the poor outcomes. Proton therapy allows excellent target coverage with maximal sparing of adjacent normal tissues. We evaluated the long-term outcomes in patients with sinonasal SCC treated with proton therapy.
METHODS AND MATERIALS: Between 1991 and 2008, 54 patients with Stage III and IV SCC of the nasal cavity and paranasal sinus received proton beam therapy at our institution to a median dose of 72.8 Gy(RBE). Sixty-nine percent underwent prior surgical resection, and 74% received elective nodal radiation. Locoregional control and survival probabilities were estimated with the Kaplan-Meier method. Multivariate analyses were performed using the Cox proportional-hazards model. Treatment toxicity was scored using the Common Terminology Criteria for Adverse Events version 4.0.
RESULTS: With a median follow-up time of 82 months in surviving patients, there were 10 local, 7 regional, and 11 distant failures. The 2-year and 5-year actuarial local control rate was 80%. The 2-year and 5-year rates of overall survival were 67% and 47%, respectively. Only smoking status was predictive for worse locoregional control, with current smokers having a 5-year rate of 23% compared with 83% for noncurrent smokers (P=.004). Karnofsky performance status ≤80 was the most significant factor predictive for worse overall survival in multivariate analysis (adjusted hazard ratio 4.5, 95% confidence interval 1.6-12.5, P=.004). There were nine grade 3 and six grade 4 toxicities, and no grade 5 toxicity. Wound adverse events constituted the most common grade 3-4 toxicity.
CONCLUSIONS: Our long-term results show that proton radiation therapy is well tolerated and yields good locoregional control for SCC of the nasal cavity and paranasal sinus. Current smokers and patients with poor performance status had inferior outcomes. Prospective study is necessary to compare IMRT with proton therapy in the treatment of sinonasal malignancy.

PMID: 27084654 [PubMed - in process]

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Evaluation of Robustness to Setup and Range Uncertainties for Head and Neck Patients Treated With Pencil Beam Scanning Proton Therapy.

Evaluation of Robustness to Setup and Range Uncertainties for Head and Neck Patients Treated With Pencil Beam Scanning Proton Therapy.

Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):154-62

Authors: Malyapa R, Lowe M, Bolsi A, Lomax AJ, Weber DC, Albertini F

Abstract
PURPOSE: To evaluate the robustness of head and neck plans for treatment with intensity modulated proton therapy to range and setup errors, and to establish robustness parameters for the planning of future head and neck treatments.
METHODS AND MATERIALS: Ten patients previously treated were evaluated in terms of robustness to range and setup errors. Error bar dose distributions were generated for each plan, from which several metrics were extracted and used to define a robustness database of acceptable parameters over all analyzed plans. The patients were treated in sequentially delivered series, and plans were evaluated for both the first series and for the combined error over the whole treatment. To demonstrate the application of such a database in the head and neck, for 1 patient, an alternative treatment plan was generated using a simultaneous integrated boost (SIB) approach and plans of differing numbers of fields.
RESULTS: The robustness database for the treatment of head and neck patients is presented. In an example case, comparison of single and multiple field plans against the database show clear improvements in robustness by using multiple fields. A comparison of sequentially delivered series and an SIB approach for this patient show both to be of comparable robustness, although the SIB approach shows a slightly greater sensitivity to uncertainties.
CONCLUSIONS: A robustness database was created for the treatment of head and neck patients with intensity modulated proton therapy based on previous clinical experience. This will allow the identification of future plans that may benefit from alternative planning approaches to improve robustness.

PMID: 27084638 [PubMed - in process]

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Quality of Life and Value Considerations in Head and Neck Proton Beam Therapy: The Holy Grail at Last, or the Quest Continues?

Quality of Life and Value Considerations in Head and Neck Proton Beam Therapy: The Holy Grail at Last, or the Quest Continues?

Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):40-2

Authors: Sher DJ, Ringash J

PMID: 27084622 [PubMed - in process]

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Intensity Modulated Proton Therapy for Head and Neck Tumors: Gilding the Lily or Holy Grail?

Intensity Modulated Proton Therapy for Head and Neck Tumors: Gilding the Lily or Holy Grail?

Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):37-9

Authors: Frank SJ

PMID: 27084621 [PubMed - in process]

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The Utility of Recurrent Laryngeal Nerve Monitoring During Open Pharyngeal Diverticula Procedures.

The Utility of Recurrent Laryngeal Nerve Monitoring During Open Pharyngeal Diverticula Procedures.

Ann Otol Rhinol Laryngol. 2016 Apr 15;

Authors: Coughlan CA, Verma SP

Abstract
OBJECTIVES: The recurrent laryngeal nerve is at risk of injury during open pharyngeal diverticula operations. The utility of recurrent laryngeal nerve (RLN) monitoring during these procedures was investigated.
METHODS: A retrospective chart review was performed of 8 open pharyngeal diverticulectomies completed between 2009 and 2014. Intraoperative RLN monitoring took place during all operations.
RESULTS: Open pharyngectomy and myotomy was successfully performed in all cases. In two cases the RLN was encountered outside of its normal course. The identity of the nerve was confirmed with electrical stimulation and normal EMG response. Vocal fold motion was preserved in all cases.
CONCLUSIONS: Use of intraoperative nerve monitoring in pharyngeal diverticula procedures may be beneficial, especially during open operations for Killian-Jamieson diverticulum (KJD) and large Zenker diverticulum (ZD), where the RLN is typically encountered outside of its normal course.

PMID: 27084587 [PubMed - as supplied by publisher]

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Patients exposed to diagnostic head and neck radiation for the management of shunted hydrocephalus have a significant risk of developing thyroid nodules.

Patients exposed to diagnostic head and neck radiation for the management of shunted hydrocephalus have a significant risk of developing thyroid nodules.

Pediatr Surg Int. 2016 Apr 15;

Authors: Aldrink JH, Adler B, Haines J, Watkins D, Matthews M, Lubeley L, Wang W, King DR

Abstract
PURPOSE: External radiation to the head and neck can lead to an increased incidence of thyroid nodules. We investigated whether patients requiring repeated head and neck imaging for the management of shunted hydrocephalus had a higher incidence of ultrasound-detected thyroid nodules compared to reports of comparable age.
METHODS: Patients treated at our institution for shunted hydrocephalus from 1990 to 2003 were contacted. Enroled patients underwent a thyroid ultrasound. Demographic data and radiation exposure history were obtained retrospectively.
RESULTS: Thyroid nodules were identified sonographically in 15/112 patients (13.6 %). Patients with thyroid nodules were older (mean 24.3 ± 7.6 years) than those without (mean 18.4 ± 8.0 years) (p = 0.005). Those with a detectable thyroid nodule had a longer follow up time compared to those who did not (mean 21.9 ± 5.5 vs. 15.1 ± 7 years, respectively) (p = 0.018).
CONCLUSION: Patients with shunted hydrocephalus are exposed to substantial head and neck radiation from diagnostic imaging and have a higher incidence of thyroid nodules detected by ultrasonography. These patients should be provided ongoing surveillance for detection of thyroid nodules and the possibility of malignancy.

PMID: 27083898 [PubMed - as supplied by publisher]

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What is Menière's disease? A contemporary re-evaluation of endolymphatic hydrops.

What is Menière's disease? A contemporary re-evaluation of endolymphatic hydrops.

J Neurol. 2016 Apr;263(Suppl 1):71-81

Authors: Gürkov R, Pyykö I, Zou J, Kentala E

Abstract
Menière's disease is a chronic condition with a prevalence of 200-500 per 100,000 and characterized by episodic attacks of vertigo, fluctuating hearing loss, tinnitus, aural pressure and a progressive loss of audiovestibular functions. Over 150 years ago, Prosper Menière was the first to recognize the inner ear as the site of lesion for this clinical syndrome. Over 75 years ago, endolymphatic hydrops was discovered as the pathologic correlate of Menière's disease. However, this pathologic finding could be ascertained only in post-mortem histologic studies. Due to this diagnostic dilemma and the variable manifestation of the various audiovestibular symptoms, diagnostic classification systems based on clinical findings have been repeatedly modified and have not been uniformly used in scientific publications on Menière's disease. Furthermore, the higher level measures of impact on quality of life such as vitality and social participation have been neglected hitherto. Recent developments of high-resolution MR imaging of the inner ear have now enabled us to visualize in vivo endolymphatic hydrops in patients with suspected Menière's disease. In this review, we summarize the existing knowledge from temporal bone histologic studies and from the emerging evidence on imaging-based evaluation of patients with suspected Menière's disease. These indicate that endolymphatic hydrops is responsible not only for the full-blown clinical triad of simultaneous attacks of auditory and vestibular dysfunction, but also for other clinical presentations such as "vestibular" and "cochlear Menière's disease". As a consequence, we propose a new terminology which is based on symptomatic and imaging characteristics of these clinical entities to clarify and simplify their diagnostic classification.

PMID: 27083887 [PubMed - as supplied by publisher]

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Current concepts and future approaches to vestibular rehabilitation.

Current concepts and future approaches to vestibular rehabilitation.

J Neurol. 2016 Apr;263(Suppl 1):65-70

Authors: Tjernström F, Zur O, Jahn K

Abstract
Over the last decades methods of vestibular rehabilitation to enhance adaptation to vestibular loss, habituation to changing sensory conditions, and sensory reweighting in the compensation process have been developed. However, the use of these techniques still depends to a large part on the educational background of the therapist. Individualized assessment of deficits and specific therapeutic programs for different disorders are sparse. Currently, vestibular rehabilitation is often used in an unspecific way in dizzy patients irrespective of the clinical findings. When predicting the future of vestibular rehabilitation, it is tempting to foretell advances in technology for assessment and treatment only, but the current intense exchange between clinicians and basic scientists also predicts advances in truly understanding the complex interactions between the peripheral senses and central adaptation mechanisms. More research is needed to develop reliable techniques to measure sensory dependence and to learn how this knowledge can be best used-by playing off the patient's sensory strength or working on the weakness. To be able using the emerging concepts, the neuro-otological community must strive to educate physicians, physiotherapists and nurses to perform the correct examinations for assessment of individual deficits and to look for factors that might impede rehabilitation.

PMID: 27083886 [PubMed - as supplied by publisher]

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Vestibular assistance systems: promises and challenges.

Vestibular assistance systems: promises and challenges.

J Neurol. 2016 Apr;263(Suppl 1):30-35

Authors: Guyot JP, Perez Fornos A, Guinand N, van de Berg R, Stokroos R, Kingma H

Abstract
The handicap resulting from a bilateral vestibular deficit is often underestimated. In most cases the deficit settles gradually. Patients do not understand what is happening to them and have many difficulties to describe their symptoms. They have to consult several doctors with different medical specialties before diagnosis. Once the diagnosis is made there is no biological way to "repair" the deficient vestibular apparatus and vestibular exercises are mildly effective. Attempts have been made to help patients using substitution devices replacing the defective vestibular information by tactile or acoustic cues. Currently, efforts are being made towards the development of a vestibular implant, conceptually similar to the cochlear implant for the rehabilitation of deaf patients. In recent years, several experiments on animal models have demonstrated the feasibility of this project. This paper reports the steps accomplished in human experiments and the main results obtained in our laboratory.

PMID: 27083882 [PubMed - as supplied by publisher]

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(S007) Results of a Phase II Trial Using Cetuximab Plus Docetaxel With Low-Dose Fractionated Radiation for Recurrent Unresectable Locally Advanced Head and Neck Carcinoma.

(S007) Results of a Phase II Trial Using Cetuximab Plus Docetaxel With Low-Dose Fractionated Radiation for Recurrent Unresectable Locally Advanced Head and Neck Carcinoma.

Oncology (Williston Park). 2016 Apr 15;30(4 Suppl 1)

Authors:

PMID: 27083676 [PubMed - as supplied by publisher]

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Monoaminergic Neuropathology in Alzheimer's disease.

Monoaminergic Neuropathology in Alzheimer's disease.

Prog Neurobiol. 2016 Apr 12;

Authors: Šimić G, Leko MB, Wray S, Harrington C, Delalle I, Jovanov-Milošević N, Bažadona D, Buée L, Silva R, Giovanni GD, Wischik C, Hof PR

Abstract
None of the proposed mechanisms of Alzheimer's disease (AD) fully explains the distribution patterns of the neuropathological changes at the cellular and regional levels, and their clinical correlates. One aspect of this problem lies in the complex genetic, epigenetic, and environmental landscape of AD: early-onset AD is often familial with autosomal dominant inheritance, while the vast majority of AD cases are late-onset, with the ε4 variant of the gene encoding apolipoprotein E (APOE) known to confer a 5-20 fold increased risk with partial penetrance. Mechanisms by which genetic variants and environmental factors influence the development of AD pathological changes, especially neurofibrillary degeneration, are not yet known. Here we review current knowledge of the involvement of the monoaminergic systems in AD. The changes in the serotonergic, noradrenergic, dopaminergic, histaminergic, and melatonergic systems in AD are briefly described. We also summarize the possibilities for monoamine-based treatment in AD. Besides neuropathologic AD criteria that include the noradrenergic locus coeruleus (LC), special emphasis is given to the serotonergic dorsal raphe nucleus (DRN). Both of these brainstem nuclei are among the first to be affected by tau protein abnormalities in the course of sporadic AD, causing behavioral and cognitive symptoms of variable severity. The possibility that most of the tangle-bearing neurons of the LC and DRN may release amyloid β as well as soluble monomeric or oligomeric tau protein trans-synaptically by their diffuse projections to the cerebral cortex emphasizes their selective vulnerability and warrants further investigations of the monoaminergic systems in AD.

PMID: 27084356 [PubMed - as supplied by publisher]

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Subjective sleep problems in Huntington's disease: A pilot investigation of the relationship to brain structure, neurocognitive, and neuropsychiatric function.

Subjective sleep problems in Huntington's disease: A pilot investigation of the relationship to brain structure, neurocognitive, and neuropsychiatric function.

J Neurol Sci. 2016 May 15;364:148-53

Authors: Baker CR, Domínguez D JF, Stout JC, Gabery S, Churchyard A, Chua P, Egan GF, Petersén Å, Georgiou-Karistianis N, Poudel GR

Abstract
Subjective reports of sleep disturbance are a common feature of Huntington's disease (HD); however, there is limited research investigating the relationship between sleep problems with changes in brain and behaviour. This study aimed to investigate whether subjective reports of sleep problems in HD are associated with brain volume, neurocognitive decline, and neuropsychiatric symptoms. This retrospective pilot study used brain volume, neurocognitive and neuropsychiatric data from premanifest (pre-HD) and symptomatic HD (symp-HD). Subjective sleep problem was measured using the sleep item of the Beck's Depression Inventory-II (BDI-II). Pre-HD individuals reporting sleep problems had significantly poorer neuropsychiatric outcomes compared to those not reporting sleep problems. In the symp-HD group, those with sleep problems had significantly accelerated thalamic degeneration and poorer neuropsychiatric outcomes compared to those without sleep problems. There was no relationship between subjective sleep problems and neurocognitive measures. These findings suggest an association between subjective sleep disturbance, neuropathology, and development of neuropsychiatric symptoms in HD. Further studies using quantitative EEG-based monitoring of sleep in HD and changes in the brain and behaviour will be necessary to establish the causal nature of this relationship.

PMID: 27084236 [PubMed - in process]

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The diagnostic challenge of Divry van Bogaert and Sneddon Syndrome: Report of three cases and literature review.

The diagnostic challenge of Divry van Bogaert and Sneddon Syndrome: Report of three cases and literature review.

J Neurol Sci. 2016 May 15;364:77-83

Authors: Bersano A, Morbin M, Ciceri E, Bedini G, Berlit P, Herold M, Saccucci S, Fugnanesi V, Nordmeyer H, Faragò G, Savoiardo M, Taroni F, Carriero M, Boncoraglio Giorgio B, Perucca L, Caputi L, Parati Eugenio A, Kraemer M

Abstract
Divry van Bogaert Syndrome (DBS) is a familial juvenile-onset disorder characterized by livedo racemosa, white matter disease, dementia, epilepsy and angiographic finding of "cerebral angiomatosis". A similar syndrome including livedo racemosa and cerebrovascular disease, often associated with anticardiolipin antibodies, has been described as Sneddon Syndrome (SS) highlighting the question whether these two conditions have to be considered different entities or indeed different features of a unique syndrome. Herein, we report the clinical, neuroradiological, histopathological findings and follow up of three cases diagnosed as Divry-van Bogaert Syndrome, including an updated review of literature of both DBS and SS cases. Our findings support the assumption that DBS and SS are different disease entities. DBS is characterized by the typical angiographic feature of angiomatosis, a hereditary trait and a juvenile onset of cognitive impairment and leukoaraiosis, whereas SS has less severe manifestations of cerebrovascular disease associated with livedo racemosa but without the characteristic cerebral angiography. The report of our cases and the literature review underline the necessity of a detailed work-up and the collection of larger series to better clarify the DBS and SS phenotype and course.

PMID: 27084221 [PubMed - in process]

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Frequency of High Risk Characteristics Requiring Total Thyroidectomy for 1-4 cm Well Differentiated Thyroid Cancer.

Frequency of High Risk Characteristics Requiring Total Thyroidectomy for 1-4 cm Well Differentiated Thyroid Cancer.

Thyroid. 2016 Apr 15;

Authors: Kluijfhout WP, Pasternak JD, Lim J, Kwon JS, Vriens MR, Clark OH, Shen WT, Gosnell J, Suh I, Duh QY

Abstract
Background Extent of thyroidectomy for low risk well differentiated thyroid cancer (WDTC) remains controversial. Historically, total thyroidectomy (TT) has been recommended for WDTC ≥1 cm in size. However, recent NCCN and draft ATA guidelines recognize unilateral thyroid lobectomy as a viable alternative for 1-4 cm cancers due to their otherwise favorable prognosis, with TT remaining the preferred option for tumors with unfavorable pathological characteristics. We sought to determine how often a completion TT would be recommended based on these guidelines if lobectomy was initially performed in our patients with 1-4 cm WDTC without preoperatively known risk factors. Methods We retrospectively reviewed our patients who underwent thyroidectomy for 1-4 cm WDTC (January 2000 to January 2010). We excluded patients with preoperatively known high risk characteristics, including gross extra-thyroidal extension on preoperative imaging, clinically apparent lymph node metastases, distant metastases, history of radiation and positive family history. We evaluated the pathology specimens from the cancer-containing lobe for features that would lead to a recommendation for TT based on current guidelines, including aggressive histology, vascular invasion, microscopic extra-thyroidal extension (ETE), positive margins and any positive lymph nodes within the specimen. Results Of 1000 consecutive patients operated for WDTC, 287 would have been eligible for lobectomy as the initial operation. The mean age in this cohort was 45 years, and 80% were women. Aggressive tall cell variant histology was found in 1 patients (0.5%), angio-invasion in 34 (12%), ETE in 48 (17%), positive margins in 51 (18%), and positive lymph nodes in 49 (18%). Completion TT would have been recommended in 122/287 (43%) patients. Even in those with 1-2 cm cancers, completion TT would have been recommended in 52/143 (36%). Conclusions Nearly half of patients with 1-4 cm WDTC who are eligible for lobectomy under current guidelines would require completion TT based on pathological characteristics of the initial lobe. Surgeons, endocrinologists, and patients need to balance the relative benefits, risks, and costs of initial TT versus the possible need for reoperative completion TT.

PMID: 27083216 [PubMed - as supplied by publisher]

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Exogenous gene can be integrated into Nosema bombycis genome by mediating with a non-transposon vector

Abstract

Nosema bombycis, a microsporidium, is a pathogen of pebrine disease of silkworms, and its genomic DNA sequences had been determined. Thus far, the research of gene functions of microsporidium including N. bombycis cannot be performed with gain/loss of function. In the present study, we targeted to construct transgenic N. bombycis. Therefore, hemocytes of the infected silkworm were transfected with a non-transposon vector pIZT/V5-His vector in vivo, and the blood, in which the hemocyte with green fluorescence could be observed, was added to the cultured BmN cells. Furthermore, normal BmN cells were infected with germinated N. bombycis, and the infected cells were transfected with pIZT/V5-His. Continuous fluorescence observations exposed that there were N. bombycis with green fluorescence in some N. bombycis-infected cells, and the extracted genome from the purified N. bombycis spore was used as templates. PCR amplification was carried out with a pair of primers for specifically amplifying the green fluorescence protein (GFP) gene; a specific product representing the gfp gene could be amplified. Expression of the GFP protein through Western blotting also demonstrated that the gfp gene was perfectly inserted into the genome of N. bombysis. These results illustrated that exogenous gene can be integrated into N. bombycis genome by mediating with a non-transposon vector. Our research not only offers a strategy for research on gene function of N. bombycis but also provides an important reference for constructing genetically modified microsporidium utilized for biocontrol of pests.

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Accipiter hawks ( Accipitridae ) confirmed as definitive hosts of Sarcocystis turdusi , Sarcocystis cornixi and Sarcocystis sp. ex Phalacrocorax carbo

Abstract

Sarcocystis is a large genus of protozoan parasites with complex heteroxenous life cycles. For many species, either the intermediate or the definitive host is still unknown. In this study, 116 Accipiter hawks (Eurasian sparrowhawks and northern goshawks) were investigated for the presence of Sarcocystis spp. in their intestinal tract or their faeces. To gain a wide distribution, samples were collected throughout Germany within 2 years. It was possible to detect Sarcocystis-like oocysts in 65 samples. Sequencing of the ITS region or species-specific PCR identified 33 samples as Sarcocystis turdusi/Sarcocystis sp. ex A. nisus (18), Sarcocystis calchasi (6), Sarcocystis columbae (3), Sarcocystis cornixi (3) and Sarcocystis sp. ex Phalacrocorax carbo (3). Besides the known infestation with S. columbae, S. sp. ex A. nisus and S. calchasi the Accipiter hawks were thereby confirmed as definitive host of S. turdusi, S. cornixi and S. sp. ex Phalacrocorax carbo for the first time.

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Molecular characterization of serine protease inhibitor isoform 3, SmSPI, from Schistosoma mansoni

Abstract

Serine protease inhibitors, known as serpins, are pleiotropic regulators of endogenous and exogenous proteases, and molecule transporters. They have been documented in animals, plants, fungi, bacteria, and viruses; here, we characterize a serpin from the trematode platyhelminth Schistosoma mansoni. At least eight serpins have been found in the genome of S. mansoni, but only two have characterized molecular properties and functions. Here, the function of S. mansoni serpin isoform 3 (SmSPI) was analyzed, using both computational and molecular biological approaches. Phylogenetic analysis showed that SmSPI was closely related to Schistosoma haematobium serpin and Schistosoma japonicum serpin B10. Structure determined in silico confirmed that SmSPI belonged to the serpin superfamily, containing nine α-helices, three β-sheets, and a reactive central loop. SmSPI was highly expressed in schistosomules, predominantly in the head gland, and in adult male and female with intensive accumulation on the spines, which suggests that it may have a role in facilitating intradermal and intravenous survival. Recombinant SmSPI was overexpressed in Escherichia coli; the recombinant protein was of the same size (46 kDa) as the native protein. Immunological analysis suggested that mice infected with S. mansoni responded to rSmSPI at 8 weeks postinfection (wpi) but not earlier. The inhibitory activity of rSmSPI was specific to chymotrypsin but not trypsin, neutrophil elastase, and porcine pancreatic elastase. Elucidating the biological and physiological functions of SmSPI as well as other serpins will lead to further understanding of host-parasite interaction machinery that may provide novel strategies to prevent and control schistosomiasis in the future.

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First molecular identification and report of genetic diversity of Strongyloides stercoralis , a current major soil-transmitted helminth in humans from Lao People’s Democratic Republic

Abstract

Strongyloidiasis is a major soil-transmitted helminth (STH) disease that affects people worldwide. We present updated data on prevalence in the Lao People's Democratic Republic (Lao PDR) in 2015, arising from a community cross-sectional helminthiasis survey. Fecal samples were collected from 327 individuals across three provinces in Lao PDR (Luang Prabang in the north, Khammouane in the center, and Champasack in the south). Agar plate culture and Kato-Katz methods were used to examine duplicate stool samples from each participant to detect Strongyloides stercoralis and co-infecting helminths. Overall prevalences of S. strercoralis human hookworm, Taenia spp., Trichuris trichiura, Ascaris lumbricoides, and Enterobius vermicularis were 41.0, 28.1, 4.9, 4.0, 1.5, and 0.9 %, respectively. The prevalence of miscellaneous trematodiases (including opisthorchiasis) was 37.9 % and of Schistosoma mekongi infection was 0.3 %. Strongyloidiasis is a current major STH disease in Lao PDR. We also report the molecular-phylogenetic identification of S. stercoralis adult males collected from 40 representative human strongyliodiasis fecal samples. DNA was extracted, amplified, and sequenced from a portion of the mitochondrial cox1 gene and the nuclear 18S ribosomal DNA. Phylogenetic analyses indicated that all specimens sequenced belonged to S. stercoralis (Bavay, 1876) Stiles and Hassall, 1902. The cox1 sequences exhibited great diversity (24 haplotypes) in Lao PDR. This is the first molecular identification and report of genetic diversity of S. stercoralis in humans from Lao PDR. An effective parasite control program is needed to reduce the serious health impacts.

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The temporal dynamics of the distractor in the global effect

Abstract

In the global effect, saccades are displaced towards a distractor if the latter is near to the target, an effect thought to reflect spatial averaging in neurons of the superior colliculus. The temporal dynamics of the global effect have not been well studied, however. We had twelve subjects perform horizontal saccades to a target in trials in which there were either no distractor or a distractor stimulus located 20° above or below the target. The distractor appeared either simultaneously with the target or preceded it by an interval of between 100 and 800 ms, and was either flashed for only 100 ms or remained visible until the subject responded with a saccade. Both flashed and persistent distractors reduced saccadic latency if they preceded target onset, indicating that subjects could use this cue to prepare saccades in advance. Saccadic endpoint was displaced towards a flashed distractor only if it was simultaneous with the target. However, persistent distractors produced a global effect for both simultaneous presentation and distractor–target intervals of 100 ms, but not for longer intervals. We conclude that the global effect requires of the distractor both a recent onset and persistence of the distractor, and that distractor-related activity decays rapidly within 300 ms.

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Proton Beam Reirradiation for Recurrent Head and Neck Cancer: Multi-institutional Report on Feasibility and Early Outcomes.

Proton Beam Reirradiation for Recurrent Head and Neck Cancer: Multi-institutional Report on Feasibility and Early Outcomes.

Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):386-95

Authors: Romesser PB, Cahlon O, Scher ED, Hug EB, Sine K, DeSelm C, Fox JL, Mah D, Garg MK, Han-Chih Chang J, Lee NY

Abstract
PURPOSE: Reirradiation therapy (re-RT) is the only potentially curative treatment option for patients with locally recurrent head and neck cancer (HNC). Given the significant morbidity with head and neck re-RT, interest in proton beam radiation therapy (PBRT) has increased. We report the first multi-institutional clinical experience using curative-intent PBRT for re-RT in recurrent HNC.
METHODS AND MATERIALS: A retrospective analysis of ongoing prospective data registries from 2 hybrid community practice and academic proton centers was conducted. Patients with recurrent HNC who underwent at least 1 prior course of definitive-intent external beam radiation therapy (RT) were included. Acute and late toxicities were assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively. The cumulative incidence of locoregional failure was calculated with death as a competing risk. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were calculated with the Kaplan-Meier method.
RESULTS: Ninety-two consecutive patients were treated with curative-intent re-RT with PBRT between 2011 and 2014. Median follow-up among surviving patients was 13.3 months and among all patients was 10.4 months. The median time between last RT and PBRT was 34.4 months. There were 76 patients with 1 prior RT course and 16 with 2 or more courses. The median PBRT dose was 60.6 Gy (relative biological effectiveness, [RBE]). Eighty-five percent of patients underwent prior HNC RT for an oropharynx primary, and 39% underwent salvage surgery before re-RT. The cumulative incidence of locoregional failure at 12 months, with death as a competing risk, was 25.1%. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were 84.0% and 65.2%, respectively. Acute toxicities of grade 3 or greater included mucositis (9.9%), dysphagia (9.1%), esophagitis (9.1%), and dermatitis (3.3%). There was 1 death during PBRT due to disease progression. Grade 3 or greater late skin and dysphagia toxicities were noted in 6 patients (8.7%) and 4 patients (7.1%), respectively. Two patients had grade 5 toxicity due to treatment-related bleeding.
CONCLUSIONS: Proton beam re-RT of the head and neck can provide effective tumor control with acceptable acute and late toxicity profiles likely because of the decreased dose to the surrounding normal, albeit previously irradiated, tissue, although longer follow-up is needed to confirm these findings.

PMID: 27084656 [PubMed - in process]

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Clinical Outcomes and Patterns of Disease Recurrence After Intensity Modulated Proton Therapy for Oropharyngeal Squamous Carcinoma.

Clinical Outcomes and Patterns of Disease Recurrence After Intensity Modulated Proton Therapy for Oropharyngeal Squamous Carcinoma.

Int J Radiat Oncol Biol Phys. 2016 May 1;95(1):360-7

Authors: Gunn GB, Blanchard P, Garden AS, Zhu XR, Fuller CD, Mohamed AS, Morrison WH, Phan J, Beadle BM, Skinner HD, Sturgis EM, Kies MS, Hutcheson KA, Rosenthal DI, Mohan R, Gillin MT, Frank SJ

Abstract
PURPOSE: A single-institution prospective study was conducted to assess disease control and toxicity of proton therapy for patients with head and neck cancer.
METHODS AND MATERIALS: Disease control, toxicity, functional outcomes, and patterns of failure for the initial cohort of patients with oropharyngeal squamous carcinoma (OPC) treated with intensity modulated proton therapy (IMPT) were prospectively collected in 2 registry studies at a single institution. Locoregional failures were analyzed by using deformable image registration.
RESULTS: Fifty patients with OPC treated from March 3, 2011, to July 2014 formed the cohort. Eighty-four percent were male, 50% had never smoked, 98% had stage III/IV disease, 64% received concurrent therapy, and 35% received induction chemotherapy. Forty-four of 45 tumors (98%) tested for p16 were positive. All patients received IMPT (multifield optimization to n=46; single-field optimization to n=4). No Common Terminology Criteria for Adverse Events grade 4 or 5 toxicities were observed. The most common grade 3 toxicities were acute mucositis in 58% of patients and late dysphagia in 12%. Eleven patients had a gastrostomy (feeding) tube placed during therapy, but none had a feeding tube at last follow-up. At a median follow-up time of 29 months, 5 patients had disease recurrence: local in 1, local and regional in 1, regional in 2, and distant in 1. The 2-year actuarial overall and progression-free survival rates were 94.5% and 88.6%.
CONCLUSIONS: The oncologic, toxicity, and functional outcomes after IMPT for OPC are encouraging and provide the basis for ongoing and future clinical studies.

PMID: 27084653 [PubMed - in process]

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Age of onset differentially influences the progression of regional dysfunction in sporadic amyotrophic lateral sclerosis.

Age of onset differentially influences the progression of regional dysfunction in sporadic amyotrophic lateral sclerosis.

J Neurol. 2016 Apr 15;

Authors: Yokoi D, Atsuta N, Watanabe H, Nakamura R, Hirakawa A, Ito M, Watanabe H, Katsuno M, Izumi Y, Morita M, Taniguchi A, Oda M, Abe K, Mizoguchi K, Kano O, Kuwabara S, Kaji R, Sobue G, JaCALS

Abstract
The clinical courses of sporadic amyotrophic lateral sclerosis (ALS) show extensive variability. Our objective was to elucidate how age of onset influences the progression of regional symptoms and functional losses in sporadic ALS. We included 648 patients with sporadic ALS from a multicenter prospective ALS cohort. We investigated the distribution of initial symptoms and analyzed the time from onset to events affecting activities of daily living (ADL) as well as the longitudinal changes in each regional functional rating score among four groups with different ages of onset. The frequencies of dysarthria and dysphagia as initial symptoms were higher in the older age groups, whereas weakness of upper limbs was the most common initial symptom in the youngest age group. The survival times and the times from onset to loss of speech and swallowing were significantly shorter in the older age group (p < 0.001), although the times from onset to loss of upper limb function were not significantly different among the age groups. According to joint modeling analysis, the bulbar score declined faster in the older age groups (<50 vs. 60-69 years: p = 0.029, <50 vs. ≥70 years: p < 0.001), whereas there was no significant correlation between the age of onset and decline in the upper limb score. Our results showed that age of onset had a significant influence on survival time and the progression of bulbar symptoms, but had no influence on upper limb function in sporadic ALS.

PMID: 27083563 [PubMed - as supplied by publisher]

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Gastric metastasis from salivary duct carcinoma mimicking primary gastric cancer.

Gastric metastasis from salivary duct carcinoma mimicking primary gastric cancer.

Int J Surg Case Rep. 2016 Apr 7;23:36-39

Authors: Yamashita K, Takeno S, Nimura S, Sugiyama Y, Sueta T, Maki K, Kayashima Y, Shiwaku H, Kato D, Hashimoto T, Sasaki T, Yamashita Y

Abstract
INTRODUCTION: We present a very rare case of gastric metastasis mimicking primary gastric cancer in a patient who had undergone surgery for salivary duct carcinoma.
PRESENTATION OF CASE: A 67-year-old man had been diagnosed as having right parotid cancer and had undergone a right parotidectomy and lymph node dissection. The histological diagnosis was salivary duct carcinoma. One year after the surgery, a positron emission tomography-computed tomography scan using fluorodeoxyglucose (FDG) revealed an abnormal uptake of FDG in the left cervical, mediastinal, paraaortic, and cardiac lymph nodes; stomach; and pancreas. On gastroduodenoscopy, there was a huge, easily bleeding ulcer mimicking primary gastric cancer at the upper body of the stomach. Biopsy revealed poorly differentiated adenocarcinoma. Therefore, we were unable to differentiate between the primary gastric cancer and the metastatic tumor using gastroduodenoscopy and biopsy. Because of the uncontrollable bleeding from the gastric cancer, we performed an emergency palliative total gastrectomy. On histological examination, the gastric lesion was found to be metastatic carcinoma originating from the salivary duct carcinoma.
DISCUSSION: In the presented case, we could not diagnose the gastric metastasis originating from the salivary duct carcinoma even by endoscopic biopsy. This is because the histological appearance of salivary duct carcinoma is similar to that of high-grade adenocarcinoma, thus, resembling primary gastric cancer.
CONCLUSION: When we perform endoscopic examination of patients with malignant neoplasias, a possibility of metastatic gastric cancer should be taken into consideration.

PMID: 27085106 [PubMed - as supplied by publisher]

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p53: out of Africa.

p53: out of Africa.

Genes Dev. 2016 Apr 15;30(8):876-7

Authors: Lane D

Abstract
Somatic mutations in the tumor suppressor gene p53 occur in more than half of all human cancers. Rare germline mutations result in the Li-Fraumeni cancer family syndrome. In this issue ofGenes&Development, Jennis and colleagues (pp. 918-930) use an elegant mouse model to examine the affect of a polymorphism, P47S (rs1800371), in the N terminus of p53 that is found in Africans as well as more than a million African Americans. Remarkably, the single nucleotide change causes the mice to be substantially tumor-prone compared with littermates, suggesting that this allele causes an increased risk of developing cancer. The defect in p53 function is traced to a restriction in downstream gene regulation that reduces cell death in response to stress.

PMID: 27083994 [PubMed - in process]

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Professional Conduct and Social Media

Our personal, portable electronic communication devices are with us everywhere: in the workplace, in the classroom, in committee meetings, and in clinical settings. We are using texting and e-mail to accomplish our work more efficiently. The use of apps has revolutionized the way we provide health care, with clinical guidelines at our fingertips and at the point of care. We also turn to social media sites to communicate with friends, as well as with colleagues and professional groups.

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Table of Contents

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Information for Readers

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Position Statement on Nurse Practitioner Prescriptive Privileges

The National Association of Pediatric Nurse Practitioners (NAPNAP) advocates that all nurse practitioners (NPs) have full prescriptive authority and dispensing privileges based on their education, training, licensure, and certification. Pediatric nurse practitioners (PNPs) have completed a formal educational program in pediatric health care and have met their state board's regulations that govern advanced practice nursing (American Nurses Association, NAPNAP, & Society of Pediatric Nurses, 2015).

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Society

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Summer-Safe, Trauma-Wise: Advocating for Preventative Legislation

Advocacy remains an extremely important role of the pediatric health care provider. Pediatric nurse practitioners are challenged to focus on supporting the most critical policies that govern child health, especially in the areas of safety and injury prevention within their own states and neighborhoods. The summer months of June through August are considered "trauma season," a time of year when children are most likely to sustain injuries on the road as pedestrians or occupants of motor vehicles; in the sports arena; and as a result of participating in activities like swimming or hiking.

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Continuing Education Posttest

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Letter to the Editor

In the article entitled "First We Have to Engage Them: A Mixed Methods Assessment of Low-Income Parents' Preferences for and Barriers to Receiving Child Health Promotion Information" (Davis et al., 2015), the authors conclude that "new health information delivery methods are needed that take into account the barriers associated with parenting in the context of poverty." However, several examples of new delivery methods do exist.

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Nonsuicidal Self-Injury

Nonsuicidal self-injury (NSSI) is a serious and prevalent problem within the adolescent population. NSSI is associated with a variety of psychiatric diagnoses and behavioral concerns. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, has recognized NSSI as its own separate diagnosis. Although there are unique differences between NSSI and suicidal behaviors, a link exists between these behaviors. It is crucial that pediatric nurse practitioners who provide care for adolescents possess a thorough understanding of NSSI.

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Position Statement on Reimbursement for Nurse Practitioner Services

Nurse practitioners (NPs) provide comprehensive, cost-effective, high-quality health care services in diverse settings across the care and age continuum (Institute of Medicine, 2010; Newhouse et al., 2011). The National Association of Pediatric Nurse Practitioners (NAPNAP) believes that NPs must receive equitable reimbursement from all payers in order to provide the communities they serve with the full scope of health care services. NAPNAP understands the unique contribution that NPs make to the U.S.

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Editorial Board

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IEEE SCM deadline extrended

The SMC Special Session on Medical CPS deadline has been extended! Make sure you do not miss the final, May 1 deadline.

Important Dates
April 15 May 1, 2016: Deadline for submission of full-length papers
May 25, 2016: Acceptance/Rejection Notification.
July 9, 2016: Final camera-ready papers due in electronic form.

Submission   
Manuscripts for a Special Session should NOT be submitted in duplication to any other regular or special sessions and should be submitted to SMC2016 main conference online submission system on SMC2016 conference website.
All submitted papers of Special Sessions have to undergo the same review process (three completed reviews per paper).  The technical reviewers for each Special Session paper will be members of the SMC2016 Program Committee and qualified peer-reviewers to be nominated by the Special Session organizers.

There are other relevant Special Sessions as well, such as the SMC TC on Robotics and Intelligent Sensing's on "Robotics, Human-Machine Interface and Haptics." We welcome paper submissions covering your recent advancements and results in these areas.

More info: IEEE SMC 2016

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Doppler ultrasound in kidney diseases: a key parameter in clinical long-term follow-up

Abstract

Doppler ultrasound has been extensively used in detecting reno-vascular diseases, showing to be a non-invasive, safe, low cost and repeatable tool. The Renal Resistive Index (RRI) [(peak systolic velocity − end diastolic velocity)/peak systolic velocity] is a semi-quantitative index derived by Doppler evaluation of renal vascular bed. Normally RRI is in the range of 0.47–0.70, it increases with aging and, usually, it shows a difference between the two kidneys less than 5–8 %. RRI is an important prognostic marker in chronic kidney diseases (CKD), both in diabetic and non-diabetic kidney diseases, because, in longitudinal prospective studies, it significantly correlated with hemodynamic (ABPM, SBP, DBP, pulse pressure) and histopathological parameters (glomerular sclerosis, arteriolosclerosis, interstitial fibrosis/tubular atrophy, interstitial infiltration). In acute kidney injury (AKI) RI is a valid tool in differentiating between pre-renal and renal failure and in predicting renal response to vaso-active agents. In addition a RRI >0.74 can predict the onset of AKI in septic patients. Renal Resistive Index is a useful marker in allograft diseases because it has been widely showed a correlation with histological lesions during worsening of renal function, both in acute rejection and in chronic allograft nephropathy. Recent studies suggest its role in the risk of new onset diabetes after transplantation and it could be one of the parameters to evaluate to shift or withdrawal immunological and/or hypertensive therapy.

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Use of Lumbar Perforator Recipient Vessels for Salvage Chest Wall Reconstruction: A Case Report

Summary: Abdominal-based free flaps are commonly used for breast reconstruction, and the internal mammary or thoracodorsal vessels are typically used as recipient sites. Conversely, free tissue transfer is less commonly used for chest wall reconstruction in the setting of chest wall recurrence, in part, because of a paucity of recipient vessels. Here, we describe a case of a 68-year-old female smoker with metastatic breast cancer, who presented with a chest wall recurrence. There was a large area of chronic ulceration with foul smelling drainage, in addition to radiation-induced tissue injury, and palliative resection was performed. The area was reconstructed with a free transverse rectus abdominis myocutaneous flap using lumbar perforators as recipient vessels, because conventional recipient sites were unavailable because of scarring from radiation and residual tumor. This case demonstrates that uncommon recipient vessels such as lumbar perforators may allow for successful palliative chest wall reconstruction. We hypothesize that the tumor burden, previous surgeries, and radiation may have rendered the recipient field relatively ischemic, thereby inducing hypertrophy of the lumbar perforators, similar to a delay phenomenon.

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Whole Exome Sequencing Reveals Homozygous Mutations in RAI1, OTOF, and SLC26A4 Genes Associated with Nonsyndromic Hearing Loss in Altaian Families (South Siberia)

by Alexander Y. Сhurbanov, Tatiana M. Karafet, Igor V. Morozov, Valeriia Yu. Mikhalskaia, Marina V. Zytsar, Alexander A. Bondar, Olga L. Posukh

Hearing loss (HL) is one of the most common sensorineural disorders and several dozen genes contribute to its pathogenesis. Establishing a genetic diagnosis of HL is of great importance for clinical evaluation of deaf patients and for estimating recurrence risks for their families. Efforts to identify genes responsible for HL have been challenged by high genetic heterogeneity and different ethnic-specific prevalence of inherited deafness. Here we present the utility of whole exome sequencing (WES) for identifying candidate causal variants for previously unexplained nonsyndromic HL of seven patients from four unrelated Altaian families (the Altai Republic, South Siberia). The WES analysis revealed homozygous missense mutations in three genes associated with HL. Mutation c.2168A>G (SLC26A4) was found in one family, a novel mutation c.1111G>C (OTOF) was revealed in another family, and mutation c.5254G>A (RAI1) was found in two families. Sanger sequencing was applied for screening of identified variants in an ethnically diverse cohort of other patients with HL (n = 116) and in Altaian controls (n = 120). Identified variants were found only in patients of Altaian ethnicity (n = 93). Several lines of evidences support the association of homozygosity for discovered variants c.5254G>A (RAI1), c.1111C>G (OTOF), and c.2168A>G (SLC26A4) with HL in Altaian patients. Local prevalence of identified variants implies possible founder effect in significant number of HL cases in indigenous population of the Altai region. Notably, this is the first reported instance of patients with RAI1 missense mutation whose HL is not accompanied by specific traits typical for Smith-Magenis syndrome. Presumed association of RAI1 gene variant c.5254G>A with isolated HL needs to be proved by further experimental studies.

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Central Nervous Activity upon Systemic Salicylate Application in Animals with Kanamycin-Induced Hearing Loss - A Manganese-Enhanced MRI (MEMRI) Study

by Moritz Gröschel, Romy Götze, Susanne Müller, Arne Ernst, Dietmar Basta

This study investigated the effect of systemic salicylate on central auditory and non-auditory structures in mice. Since cochlear hair cells are known to be one major target of salicylate, cochlear effects were reduced by using kanamycin to remove or impair hair cells. Neuronal brain activity was measured using the non-invasive manganese-enhanced magnetic resonance imaging technique. For all brain structures investigated, calcium-related neuronal activity was increased following systemic application of a sodium salicylate solution: probably due to neuronal hyperactivity. In addition, it was shown that the central effect of salicylate was not limited to the auditory system. A general alteration of calcium-related activity was indicated by an increase in manganese accumulation in the preoptic area of the anterior hypothalamus, as well as in the amygdala. The present data suggest that salicylate-induced activity changes in the auditory system differ from those shown in studies of noise trauma. Since salicylate action is reversible, central pharmacological effects of salicylate compared to those of (permanent) noise-induced hearing impairment and tinnitus might induce different pathophysiologies. These should therefore, be treated as different causes with the same symptoms.

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Synthesis and Quantitative Structure-activity Relationships Study for Arylpropenamide Derivatives as Inhibitors of Hepatitis B Virus Replication

Abstract

A series of new arylpropenamide derivatives containing different aryl groups were synthesized, characterized and evaluated for their anti-hepatitis B virus (HBV) activities. A new high accuracy QSAR model of arylpropenamide was constructed based on a more completely activities data and calculation parameter. The 2D-QSAR equations, by using DFT and multiple linear regression analysis methods, revealed that higher value of total energy (TE) and lower entropy (S^ө) increase the anti-HBV activities of the arylpropenamide molecules. Predictive 3D-QSAR models were established by SYBYL multifit molecular alignment rule. The optimum models were all statistically significant with cross-validated and conventional coefficients, indicating that they were reliable enough for activity prediction.

This article is protected by copyright. All rights reserved.

The new arylpropenamide derivatives were synthesized, characterized and evaluated for their anti-HBV activities. A high accuracy 2D and 3D-QSAR models of arylpropenamide were constructed and utilized to predict the activities.

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Novel N-allyl/propargyl tetrahydroquinolines: Synthesis via three-component cationic imino Diels-Alder reaction, binding prediction and evaluation as cholinesterase inhibitors

Abstract

New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels-Alder reaction (70-95%). All compounds were tested in vitro as dual acetylcholinesterase (AChE) and butyryl-cholinesterase (BChE) inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G), respectively. The compound 4af (IC₅₀= 72 μM) presented the most effective inhibition against AChE despite its poor selectivity (SI= 2), while the best inhibitory activity on BChE was exhibited by compound 4ae (IC₅₀= 25.58 μM) with considerable selectivity (SI=0.15). Molecular docking studies indicated that the most active compounds fit in the reported AChE and BChE active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets.

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N-allyl/propargyl tetrahydroquinolines showed inhibitory activity against cholinesterases.

Synthesis of tetrahydroquinolines proceeds via a three-component cationic imino Diels-Alder reaction

The mechanism of enzymatic inhibition was determined by kinetic assays

The computer calculations are consistent with the experimental results.

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Identification of damaging nsSNVs in humanERCC2 gene

Abstract

The hERCC2 gene is an important DNA repair molecule for initiating Cutaneous melanoma (CM). Therefore, it is advisable to study the possible functional SNVs in hERCC2. To achieve this goal, we collected total 2, 253 SNVs in hERCC2from the EMBL website, out of which 303 are nonsynonymous single nucleotide variants (nsSNVs). Then, SIFT and PolyPhen were used to predict the damaging nsSNVs, and four nsSNVs (rs368866996, rs377739017, rs370819591, and rs121913022) were suggested to be damaging mutations. Since I-Mutant2.0 showed a decrease in stability for the mutants containing each of the four nsSNVs, a 3D protein structure was modeled. Based on the comparison of the energy after minimization, RMSD and stabilizing residues between the native and mutant proteins' structure, rs121913022 was proposed to be the most damaging variant among the nsSNVs in hERCC2 gene by decreasing the stability of protein. The mutant G713R of hERCC2 protein caused by rs121913022 was found to have less expression level than native hERCC2 protein in melanoma cells. These results suggest that rs121913022 may have potentially important clinical and drug target implications.

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Cutaneous melanoma is a malignant cancer involved with ERCC2 gene. The roles of comprehensive nsSNP in ERCC2 have been studied. Based on the comparison of 3D structure information between the native and mutant proteins, the mutant G713R of ERCC2 protein caused by the rs121913022 is proposed to be the most damaging variant and validated to have less expression level than native ERCC2 in melanoma cells.

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Novel Alginate–Chitosan Composite Microspheres for implant delivery of vancomycin and in vivo evaluation

Abstract

In this study, vancomycin loaded alginate–chitosan composite microspheres were developed by emulsion crosslinking method. The in vitro and vivo characterizations were done to evaluate the feasibility of application. Our experimental results showed that the emulsification cross-linking technique appeared to be a feasible method for the preparation of alginate–chitosan composite microspheres. The microspheres were spherical in shape and the mean particle size and drug loading were 25.3 ± 5.4 μm and 18.5% ± 2.3%, respectively. A sustained vancomycin release was realized i.e. the amount of cumulative release increased in a time frame of 24 hours to reach an amount i.e. ~ 68%. The model that fit best for vancomycin released from the microspheres was the Higuchi kinetic model with a correlation coefficient r=0.9996. In vivo results showed that the application of microspheres not only reduced the toxicity, but also maintained effective drug concentration. In addition, no severe signs of epithelial necrosis and sloughing of epithelial cells were detected in histological studies.

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Vancomycin loaded alginate–chitosan composite microspheres were developed by emulsion crosslinking method. The microspheres were spherical in shape and the mean particle size and drug loading were 25.3 ± 5.4 μm and 18.5% ± 2.3%. In vivo results showed that the application of microspheres not only reduced the toxicity, but also maintained effective drug concentration.

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Antibacterial activity of imidazolium-based ionic liquids investigated by QSAR modeling and experimental studies

Abstract

Predictive QSAR models for the inhibitors of B. subtilis and Ps. aeruginosa among imidazolium-based ionic liquids were developed using literary data. The regression QSAR models were created through Artificial Neural Network and k-Nearest Neighbor procedures. The classification QSAR models were constructed using WEKA-RF (Random Forest) method. The predictive ability of the models was tested by 5-fold cross-validation; giving q²=0.77-0.92 for regression models and accuracy 83-88% for classification models.

20 synthesized samples of 1,3-dialkylimidazolium ionic liquids with predictive value of activity level of antimicrobial potential were evaluated. For all asymmetric 1,3-dialkylimidazolium ionic liquids, only compounds containing at least one radical with alkyl chain length of 12 carbon atoms showed high antibacterial activity. However, the activity of symmetric 1,3-dialkylimidazolium salts was found to have opposite relationship with the length of aliphatic radical being maximum for compounds based on 1,3-dioctylimidazolium cation.

The obtained experimental results suggested that the application of classification QSAR models is more accurate for the prediction of activity of new imidazolium-based ILs as potential antibacterials.

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The developed QSAR models can be used to search for a new active symmetric and asymmetric 1,3-dialkylimidazolium ionic liquids against B. subtilis and Ps. aeruginosa bacterial strains.

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Effects of oral motor exercises and laser therapy on chronic temporomandibular disorders: a randomized study with follow-up

Abstract

This study investigated the efficacy of combining low-level laser therapy (LLLT) with oral motor exercises (OM-exercises) for rehabilitation of patients with chronic temporomandibular disorders (TMDs). Eighty-two patients with chronic TMD and 20 healthy subjects (control group) participated in the study. Patients were randomly assigned to treatment groups: GI (LLLT + OM exercises), GII (orofacial myofunctional therapy—OMT—which contains pain relief strategies and OM-exercises), and GIII (LLLT placebo + OM-exercises) and GIV (LLLT). LLLT (AsGaAl; 780-nm wavelength; average power of 60 mW, 40 s, and 60 ± 1.0 J/cm²) was used to promote analgesia, while OM-exercises were used to reestablish the orofacial functions. Evaluations at baseline (T1), after treatment immediate (T2), and at follow-up (T3) were muscle and joint tenderness to palpation, TMD severity, and orofacial myofunctional status. There was a significant improvement in outcome measures in all treated groups with stability at follow-up (Friedman test, P < 0.05), but GIV did not show difference in orofacial functions after LLLT (P > 0.05). Intergroup comparisons showed that all treated groups had no difference in tenderness to palpation of temporal muscle compared to GC at follow-up (Kruskal-Wallis test, P < 0.01). Moreover, GI, GII, and GIII showed no difference from GC in orofacial functional condition (T2 and T3) while they differed significantly from GIV (P < 0.01). In conclusion, LLLT combined with OM-exercises was more effective in promoting TMD rehabilitation than LLLT alone was. Similar treatment results were verified with the OMT protocol.

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