Surgical management of bisphosphonate-related osteonecrosis of the jaws: literature review

Abstract

Purpose

Surgical management of bisphosphonate-related osteonecrosis of the jaws (BRONJ) has been performed in an attempt to increase healing rates of the affected cases. This literature review aimed to identify clinical studies of surgical management of bisphosphonate-related osteonecrosis of the jaws (BRONJ) in order to assess their surgical treatment modalities, outcome and the follow-up.

Methods

A search in the PubMed (Medline) database using specific terms and/or phrases as "bisphosphonate-related osteonecrosis" or "jaw osteonecrosis", and "surgical treatment" or "surgical management" was conducted in order to identify clinical trials and cases of surgical treatment of BRONJ. The review search covered the time period from 2004 to 2014. All studies identified in the search were selected according to the inclusion criteria. Relevant information was recorded according to the following items: author, year, number of patients, BRONJ clinical stage, surgical treatment modality, clinical success, and follow-up.

Results

The initial database search yielded 345 titles. After filtering, 67 abstracts were selected culminating in 67 full text articles. A variety of surgical approach was found in this review: debridement, sequestrectomy bone resection, and bone reconstruction. Adjunctive therapies included hyperbaric oxygen, laser therapy, growth factors, and ozone.

Conclusion

Although there are many indexed studies about BRONJ, well-documented reports concerning surgical therapeutically techniques are scarce, resulting from a lack of well-established protocols. Considerable differences were found regarding sample size, surgical treatment modalities and outcomes. Clinical studies with larger number of patients and longer follow-up are required to provide best information for each surgical treatment modality and its outcomes.

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Results of a Multicenter, Randomized, Double-Masked, Placebo-Controlled Clinical Study of the Efficacy and Safety of Visomitin Eye Drops in Patients with Dry Eye Syndrome

Abstract

Introduction

This article presents the results of an international, multicenter, randomized, double-masked, placebo-controlled clinical study of Visomitin (Mitotech LLC, Moscow, Russian Federation) eye drops in patients with dry eye syndrome (DES). Visomitin is the first registered (in Russia) drug with a mitochondria-targeted antioxidant (SkQ1) as the active ingredient.

Methods

In this multicenter (10 sites) study of 240 subjects with DES, study drug (Visomitin or placebo) was self-administered three times daily (TID) for 6 weeks, followed by a 6-week follow-up period. Seven in-office study visits occurred every 2 weeks during both the treatment and follow-up periods. Efficacy measures included Schirmer's test, tear break-up time, fluorescein staining, meniscus height, and visual acuity. Safety measures included adverse events, slit lamp biomicroscopy, tonometry, blood pressure, and heart rate. Tolerability was also evaluated.

Results

This clinical study showed the effectiveness of Visomitin eye drops in the treatment of signs and symptoms of DES compared with placebo. The study showed that a 6-week course of TID topical instillation of Visomitin significantly improved the functional state of the cornea; Visomitin increased tear film stability and reduced corneal damage. Significant reduction of dry eye symptoms (such as dryness, burning, grittiness, and blurred vision) was also observed.

Conclusion

Based on the results of this study, Visomitin is effective and safe for use in eye patients with DES for protection from corneal damage.

Funding

Mitotech LLC.

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Pharmacotherapy for Pediatric Generalized Anxiety Disorder: A Systematic Evaluation of Efficacy, Safety and Tolerability

Abstract

Background

Randomized controlled trials consistently support the efficacy of antidepressants in treating youth with generalized anxiety disorder (GAD), although integrated examinations of efficacy, safety, and tolerability of psychotropic medications in GAD, specifically, are rare. With this in mind, we sought to describe the efficacy, safety, and tolerability of psychopharmacologic interventions in pediatric patients with GAD.

Methods

Randomized, double-blind, placebo-controlled, prospective trials of psychopharmacologic interventions in youth with GAD were identified through a PubMed/Medline (1966–2015) search. Both authors manually reviewed trials and, to evaluate comparative efficacy and tolerability across medications, numbers needed to treat (NNT) [based on Pediatric Anxiety Rating Scale (PARS) remission criteria (PARS ≤8)] and number needed to harm (NNH) for selected treatment-emergent adverse events (TEAEs) were calculated. Finally, treatment-emergent suicidality and taper-emergent/post-study adverse events are reported descriptively.

Results

Five trials that involved 1186 patients and evaluated four medications were reviewed and efficacy data were extracted with regard to dimensional measures of anxiety. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) demonstrated efficacy in the reduction of anxiety symptoms with NNTs ranging from 2.8 to 9.3. TEAEs varied considerably between studies but tended to be mild and generally did not lead to discontinuation.

Conclusions

Data from five trials of SSRI/SNRI in youth with GAD, many of whom had co-occurring separation and social anxiety disorders, suggest superiority to placebo and favorable tolerability profiles.

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Extracellular Toxoplasma gondii tachyzoites metabolize and incorporate unnatural sugars into cellular proteins

Publication date: Available online 11 December 2015
Source:Microbes and Infection
Author(s): Lidia A. Nazarova, Roxanna J. Ochoa, Krysten A. Jones, Naomi S. Morrissette, Jennifer A. Prescher
Toxoplasma gondii is an obligate intracellular parasite that infects all nucleated cell types in diverse warm-blooded organisms. Many of the surface antigens and effector molecules secreted by the parasite during invasion and intracellular growth are modified by glycans. Glycosylated proteins in the nucleus and cytoplasm have also been reported. Despite their prevalence, the complete inventory and biological significance of glycosylated proteins in Toxoplasma remains unknown. In this study, we aimed to globally profile parasite glycoproteins using a bioorthogonal chemical reporter strategy. This strategy involves the metabolic incorporation of unnatural functional groups (i.e., "chemical reporters") into Toxoplasma glycans, followed by covalent labeling with visual probes or affinity tags. The two-step approach enables the visualization and identification of newly biosynthesized glycoconjugates in the parasite. Using a buffer that mimics intracellular conditions, extracellular Toxoplasma tachyzoites were found to metabolize and incorporate unnatural sugars (equipped with bioorthogonal functional groups) into diverse proteins. Covalent chemistries were used to visualize and retrieve these labeled structures. Subsequent mass spectrometry analysis revealed 89 unique proteins. This survey identified novel proteins as well as previously characterized proteins from lectin affinity analyses.



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CD1a+ and CD83+ Langerhans cells are reduced in lower lip squamous cell carcinoma

Background

Actinic cheilitis (AC) is a potentially malignant lesion diagnosed in the lip of patients chronically exposed to the sun that may give rise to a fully invasive lower lip squamous cell carcinoma (LLSCC). It is known that ultraviolet radiation causes dendritic cells (DCs) depletion in the epidermis, but the role of this cellular population in lip cancer progression remains uncertain. Therefore, this study investigated the distribution of DCs in normal, dysplastic and neoplastic tissues of the lower lip.

Methods

Thirteen cases of lower lip mucocele, 42 of ACs and 21 of LLSCC were retrieved and original diagnoses confirmed by two oral pathologists, who further classified ACs as low- and high-risk lesions. Immunoreactions against CD1a and CD83 identified immature and mature DCs, respectively.

Results

Immature CD1a+ Langerhans cells (LCs) were significantly decreased in LLSCC when compared to morphologically normal (P < 0.009) and dysplastic epitheliums (P < 0.003), whereas mature CD83+ LCs were significantly decreased in LLSCC when compared to normal epithelium (P = 0.038). There was no significant difference between low- and high-risk ACs regarding CD1a+ and CD83+ LCs (P > 0.05), but ACs demonstrated a lower concentration of CD1a+ LCs than normal epithelium (P < 0.009). There was no significant difference in the distribution of CD1a+ and CD83+ interstitial dendritic cells (IDCs) in the connective tissue among the studied groups (P > 0.05).

Conclusion

These results suggest that depletion of epithelial LCs, but not IDCs in the connective tissue, would represent an important step for lip cancer development.

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mTOR pathway protein immunoexpression as a prognostic factor for survival in head and neck cancer patients: a systematic review and meta-analysis

Background

Several mTOR pathway proteins are involved in the regulation of cellular anabolism, growth, proliferation, and survival. Activated proteins in the mTOR pathway are deregulated in multiple types of cancers and could influence prognosis. However, it is unclear whether deregulation of mTOR pathway proteins serves a prognostic role in patients with head and neck cancer (HNC). Furthermore, proteins in the mTOR pathway may be important targets for anticancer therapy. The aim of this study was to summarize existing cohort studies to determine whether immunoexpression of mTOR pathway proteins are important prognostic factors for survival in patients with HNC.

Materials and methods

A systematic review was performed using the Cochrane, Lilacs, PubMed, ScienceDirect, Scopus, and Web of Science databases (up to 23 January 2015). A meta-analysis was conducted to measure the frequency of protein expression in head and neck cancer patient samples and the prognostic value of mTOR pathway proteins for overall survival (OS) and disease-free survival (DFS).

Results

Twelve studies were included in our final analysis. The meta-analysis revealed that the frequency of overall expression of mTOR pathway proteins was 74.42% (CI: 63.3 to 84.0, P < 0.001, n = 2016 samples). The survival meta-analysis showed a pooled hazard ratio for OS and DFS of 1.44 (95% confidence interval [95% CI] 1.14–1.73) and 1.18 (95% CI 0.71–1.64), respectively.

Conclusion

This systematic review and meta-analysis support evidence that mTOR pathway proteins can be used as predictive markers for survival in patients with HNC because their expression was significantly associated with poor OS and short DFS.

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Intrathecal fentanyl abolishes the exaggerated blood pressure response to cycling in hypertensive men

Abstract

Hypertensive patients present an exaggerated increase in blood pressure and elevated cardiovascular risk during exercise. Although controversial, human studies suggest that group III and IV skeletal muscle afferents might have a contribution to this abnormal response. Here, we evaluated whether attenuation of the group III and IV muscle afferent signal of hypertensive men eliminates the exaggerated increase in blood pressure during exercise. Eight hypertensive men performed two sessions of 5-min cycling exercise at 40 W. Between sessions, the subjects were provided with lumbar intrathecal injection of fentanyl, a μ-opioid receptor agonist, to attenuate the central projection of opioid-sensitive group III and IV muscle afferent nerves. The cardiovascular response to exercise of these subjects was compared to that of six normotensive men. During cycling, the hypertensive group demonstrated an exaggerated increase in blood pressure compared to the normotensive group (+17 ± 3 vs. +8 ± 1 mmHg, respectively; P < 0.05), while the increase in heart rate, stroke volume, cardiac output, and vascular conductance was similar (P > 0.05). Fentanyl inhibited blood pressure response to exercise in the hypertensive group (+11 ± 2 mmHg) to a level comparable to that of the normotensive group (P > 0.05). Moreover, fentanyl increased the responses of vascular conductance and stroke volume to exercise (P < 0.05), while heart rate response was attenuated (P < 0.05) and cardiac output response was maintained (P > 0.05). This study shows that attenuation of the exercise pressor reflex normalizes blood pressure response to cycling exercise in hypertensive individuals.

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Endothelin regulates intermittent hypoxia-induced lipolytic remodelling of adipose tissue and phosphorylation of hormone-sensitive lipase

Abstract

Obstructive sleep apnea syndrome (OSA) is characterized by repetitive episodes of upper airway collapse during sleep resulting in chronic intermittent hypoxia (IH). OSA, through IH, promotes cardiovascular and metabolic disorders. Endothelin-1 (ET-1) secretion is upregulated by IH, and is able to modulate adipocyte metabolism. Therefore, our goal was to characterize the role of ET-1 in the metabolic consequences of IH on adipose tissue in vivo and in vitro. Wistar rats were submitted to 14 days of IH-cycles (30 s 21% FiO₂ - 30 s 5% FiO₂, 8 h day⁻¹) or normoxia (air-air cycles) and were treated or not with bosentan, a dual type A and B endothelin receptor (ETA-R and ETB-R) antagonist. Bosentan treatment decreased plasma FFA and triglycerides levels, and inhibited IH-induced lipolysis in adipose tissue. Moreover, IH induced a 2-fold increase in ET-1 transcription and ETA-R expression in adipose tissue that was reversed by bosentan. In 3T3-L1 adipocytes, ET-1 upregulated its own and its ETA-R transcription and this effect was abolished by bosentan. Moreover, ET-1 induced glycerol release and inhibited insulin-induced glucose uptake. Bosentan and BQ123 inhibited these effects. Bosentan also reversed the ET-1-induced phosphorylation of hormone-sensitive lipase (HSL) on Ser⁶⁶⁰. Finally, ET-1-induced lipolysis and HSL phosphorylation were also observed under hypoxia. Altogether, these data suggest that ET-1 is involved in IH-induced lipolysis in Wistar rats, and that upregulation of ET-1 production and ETA-R expression by ET-1 itself under IH could amplify its effects. Moreover, ET-1-induced lipolysis could be mediated through ETA-R and the activation of HSL by Ser⁶⁶⁰ phosphorylation.

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Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne Muscular Dystrophy

Abstract

Duchenne Muscular Dystrophy (DMD) is a fatal muscle wasting disease for which there is no widely available cure. Whilst the mechanism of loss of muscle function in DMD and the mdx mouse model are not fully understood, disruptions in intracellular calcium homeostasis, inflammation and oxidative stress are implicated. We have shown that protein thiol oxidation is increased in mdx muscle, and that the indirect thiol antioxidant L-2-Oxothiazolidine-4-Carboxylate (OTC), which increases cysteine availability, decreases pathology and increases in vivo strength. We propose that the protective effects of OTC are a consequence of conversion of cysteine to taurine, which has itself been shown to be beneficial to mdx pathology. This study compares the efficacy of taurine with OTC in decreasing dystropathology in mdx mice by measuring in vivo and ex vivo contractile function and measurements of inflammation and protein thiol oxidation. Increasing the taurine content of mdx muscle improved both in vivo and ex vivo muscle strength and function, potentially via anti-inflammatory and antioxidant effects of taurine. OTC treatment increased taurine synthesis in the liver and taurine content of mdx muscle, improved muscle function and decreased inflammation. However, OTC was less effective than taurine treatment, with OTC also decreasing body and EDL muscle weights, suggesting that OTC had some detrimental effects. These data support continued research into the use of taurine as a therapeutic intervention for DMD, and suggest that increasing dietary taurine is the better strategy for increasing taurine content and decreasing severity of dystropathology.

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Microglia modulate brainstem serotonergic expression following neonatal sustained hypoxia exposure: implications for Sudden Infant Death Syndrome

Abstract

We showed previously that the end of the second postnatal week (P11-15 days) represents a period of development during which the respiratory neural control system exhibits a heightened vulnerability to sustained (SH, 11% O₂, 5 days) hypoxia exposure. In the current study, we investigated whether the vulnerability to SH during the same developmental time period is associated with changes in brainstem serotonin (5-HT) expression and whether it can be prevented by the microglia inhibitor, minocycline. Using whole-body plethysmography SH attenuated the acute (5 min) hypoxic ventilatory response (HVR) and caused a high incidence of mortality compared to normoxia rats. SH also increased microglia cell numbers and decreased 5-HT immuno-reactivity in the nucleus of the solitary tract (nTS) and dorsal motor nucleus of the vagus (DMNV). The attenuated HVR, mortality, and changes in nTS and DMNV immuno-reactivity was prevented by minocycline (25 mg kg⁻¹/2days during SH). These data demonstrate that the 5-HT abnormalities in distinct respiratory neural control regions can be initiated by prolonged hypoxia exposure and may be modulated by microglia activity. These observations share several commonalities with the risk factors thought to underlie the etiology of Sudden Infant Death Syndrome (SIDS), including: 1) a vulnerable neonate; 2) a critical period of development; 3) evidence of hypoxia; 4) brainstem gliosis (particularly the nTS and DMNV); and 5) 5-HT abnormalities.

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Factors associated with having less than 20 natural teeth in rural adults: a cross-sectional study

Abstract

Background

Some systematic reviews have consistently indicated a positive link between Metabolic syndrome, impairedfasting glucose, all-cause or circulatory disease-related mortality, general health, periodontitis, and toothloss. This study was to examine the prevalence of number of remaining teeth <20 and associated risk factors among adults in a rural area of Taiwan.

Methods

A community-based, cross-sectional study was conducted in southwestern coastal Taiwan in 2013; 6680 residents aged 20–64 years were studied. Oral hygiene, substance use, dietary habits, and metabolic syndrome were explored as potential risk factors for number of remaining teeth <20 using logistic regression analysis.

Results

The mean number of remaining teeth was 24.6 (SD = 7.4), and 16.3 % (n = 1085) of the participants had number of remaining teeth <20. Men had significantly less frequent use of dental floss, unhealthy dietary habits, more substance use and metabolic syndrome than did women (p <0.001). However, women tended to have fewer teeth than men (p <0.001). After adjusting for potential confounders, older age (odds ratio [OR] = 4.56, 95 % confidence interval [CI]: 3.74–5.55), female (OR = 1.88, 95 % CI: 1.56–2.25), less education (OR = 2.40, 95 % CI: 1.90–3.02), infrequent use of dental floss (OR = 1.94, 95 % CI: 1.66–2.27), substance use (OR = 1.32, 95 % CI: 1.09–1.59), and number of metabolic syndrome components (OR = 1.10, 95 % CI: 1.04–1.16) were independently associated with a higher risk of number of remaining teeth <20.

Conclusions

Number of remaining teeth <20 was highly prevalent among rural adults. In addition to unmodifiable factors, infrequent use of dental floss, substance use, and metabolic syndrome were risk factors associated with tooth loss.

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The Effect on Sodium/Iodide Symporter and Pendrin in Thyroid Colloid Retention Developed by Excess Iodide Intake

Abstract

It is well known that excess iodide can lead to thyroid colloid retention, a classic characteristic of iodide-induced goiter. However, the mechanism has not been fully unrevealed. Iodide plays an important role in thyroid function at multiple steps of thyroid colloid synthesis and transport among which sodium/iodide symporter (NIS) and pendrin are essential. In our study, we fed female BALB/c mice with different concentrations of high-iodine water including group A (control group, 0 μg/L), group B (1500 μg/L), group C (3000 μg/L), group D (6000 μg/L), and group E (12,000 μg/L). After 7 months of feeding, we found that excess iodide could lead to different degrees of thyroid colloid retention. Besides, NIS and pendrin expression were downregulated in the highest dose group. The thyroid iodide intake function detected by urine iodine assay and thyroidal ¹²⁵I experiments showed that the urine level of iodine increased, while the iodine intake rate decreased when the concentration of iodide used in feeding water increased (all p < 0.05 vs. control group). In addition, transmission electron microscopy (TEM) indicated a reduction in the number of intracellular mitochondria of thyroid cells. Based on these findings, we concluded that the occurrence of thyroid colloid retention exacerbated by excess iodide was associated with the suppression of NIS and pendrin expression, providing an additional insight of the potential mechanism of action of excess iodide on thyroid gland.

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Transient spurious intrathecal immunoglobulin synthesis in neurological patients after therapeutic apheresis

Abstract

Background

The analysis of cerebrospinal fluid (CSF) is usually done under steady-state conditions, when proteins (e.g., immunoglobulins) reach diffusion equilibrium between blood and CSF. However, little data has been published on CSF analysis under non-steady-state conditions after therapeutic apheresis. By reducing serum proteins (e.g., immunoglobulins), while leaving CSF unchanged, therapeutic apheresis might cause spuriously altered intrathecal immunoglobulin fractions.

Methods

Based on the incidental finding of plasma exchange-induced increased intrathecal immunoglobulin fractions in a cohort of 12 unsystematically selected patients with various neurological disorders, we retrospectively investigated CSF results that had been raised during routine diagnostic work-up from 41 consecutive neurological patients (predominantly Guillain-Barré syndrome and autoimmune encephalitis) treated with plasmapheresis or immunoadsorption in a tertiary care university hospital in whom lumbar puncture (LP) was performed after a varying number of treatments of therapeutic apheresis.

Results

Only when LP was performed 1 day after therapeutic apheresis, spurious quantitative intrathecal immunoglobulin (Ig) synthesis of at least one subclass (IgG, IgA and/or IgM) was found in 68.4 % of the patients, irrespective of the number of treatments, in all age groups and independent of other previous immunotherapies (e.g., steroids). This phenomenon occurred only transiently and was almost always accompanied by an elevation of the IgG index. In one patient, an elevated IgG index was noticed even 2 days after plasmapheresis. Neither quantitative Ig synthesis, nor elevated IgG index was observed when the LP was performed three or more days after therapeutic apheresis.

Conclusions

Spurious quantitative intrathecal Ig synthesis and increased IgG index are common findings shortly after plasmapheresis or immunoadsorption due to altered serum immunoglobulin levels. Knowledge of this phenomenon is needed for clinicians to prevent false interpretations leading to unnecessary diagnostic and therapeutic procedures. Misdiagnoses can be avoided by considering the characteristic CSF constellation including absence of oligoclonal bands and the close temporal relation to therapeutic apheresis.

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Validation of the Chinese version of the FOUR score in the assessment of neurosurgical patients with different level of consciousness

Abstract

Background

The Glasgow Coma Scale (GCS) is currently the most widely used scoring system for comatose patients. A decade ago, the Full Outline of Unresponsiveness (FOUR) score was devised to better capture four functional aspects of consciousness (eye, motor responses, brainstem reflexes, and respiration). This study aimed to validate the Chinese version of the FOUR score in patients with different levels of consciousness.

Methods

The study had two phases: (1) translation of the FOUR score, and (2) assessment of its reliability and validity. The Chinese version of the FOUR score was developed according to a standardized protocol. One hundred-twenty consecutive patients with acute brain damage, admitted to Nanfang Hospital (Southern Medical University, Guangdong, China) from November 2014 to February 2015, were enrolled. The inter-rater agreement for the FOUR score and GCS was evaluated using intraclass correlation coefficient (ICC). Receiver operating characteristic (ROC) curves were established to determine the scales' abilities to predict outcome.

Results

The rater agreement was excellent both for FOUR (ICC = 0.970; p < 0.001) and GCS (ICC = 0.958; p < 0.001). The FOUR score yielded an excellent test-retest reliability (ICC = 0.930; p < 0.001). Spearman's correlation coefficients between GCS and the FOUR score were high: r = 0.932, first rating; r = 0.887, second rating (all p < 0.001). Areas under the curve (AUC) for mortality were 0.834 (95 % CI, 0.740–0.928) and 0.815 (95 % CI, 0.723–0.908) for the FOUR score and GCS, respectively.

Conclusions

The Chinese version of the FOUR score is a reliable scale for evaluating the level of consciousness in patients with acute brain injury.

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IJMS, Vol. 16, Pages 29772-29786: Microtubule-Associated Protein SBgLR Facilitates Storage Protein Deposition and Its Expression Leads to Lysine Content Increase in Transgenic Maize Endosperm

Maize (Zea mays) seed is deficient in protein and lysine content. Many studies have been made to improve the nutritional quality of maize seeds. Previously, we reported the role of a natural lysine-rich protein gene SBgLR in increasing protein and lysine content. However, how the SBgLR improves lysine and protein content remains unclear. Here, the reasons and possible mechanism for SBgLR in protein and lysine improvement have been analyzed and discussed. Through seed-specific expression of SBgLR, we obtained transgenic maize with the simultaneously increased lysine and protein contents. High-protein and high-lysine characters were stably inherited across generations. The expression of SBgLR in maize kernels increased the accumulation of both zeins and non-zein proteins. Transmission electron microscopy showed that the number of protein bodies (PBs) was increased obviously in SBgLR transgenic immature endosperms with the morphology and structure of PBs unchanged. The proteinaceous matrix was more abundant in transgenic mature endosperms under scanning electron microscopy. The stabilities of zein and lysine-rich non-zein genes were also increased in transgenic endosperms. Finally, the potential application of SBgLR in maize nutrient improvement was evaluated. This study shows that a cytoskeleton-associated protein has potential applicable value in crop nutrient improving, and provided a feasible strategy for improvement of maize grain quality.

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MMP2 and MMP7 at the invasive front of gastric cancer are not associated with mTOR expression

Background: Regulation of MMP expression by activation of mTOR signalling has been demonstrated for several tumor types, but has thus far not been confirmed in gastric cancer.FindingsThe study compromised 128 patients who underwent gastric resection for cancer (66.4 % male; 86 intestinal, 42 diffuse type). Immunohistochemical staining of MMPs was performed to analyse the topographical pattern of MMP expression at the tumor center and the invasive front, respectively. MMP2 showed higher expression at the invasive front compared to the tumor center, whereas MMP7 staining scores were higher in the tumor center, and there was no difference for MMP9. The expression of p-mTOR was higher in the tumor center than at the invasive front, with a similar trend for mTOR. For intestinal type gastric cancer there was a weak correlation of MMP9 with expression of mTOR in the tumor center. Otherwise, there was no correlation of the MMPs with mTOR. By treatment of MKN45 gastric cancer cells with rapamycin, a reduction of p-mTOR in the Western blot was achieved; however, expression of MMPs remained unaffected. Conclusions: Expression of MMP2 and MMP7 in gastric cancer is not associated with mTOR, MMP9 expression might be related to mTOR signalling in a subset of tumors.

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Carcinosarcoma of the larynx consisting of squamous cell carcinoma and inflammatory myofibroblastic tumor components

Publication date: Available online 11 December 2015
Source:Auris Nasus Larynx
Author(s): Shinsuke Suzuki, Kyoshi Hanata, Satoshi Toyoma, Hiroshi Nanjo, Hidekazu Saito, Nobuko Iikawa, Kazuo Ishikawa
ObjectiveCarcinosarcoma is a rare malignant tumor with both carcinomatous and sarcomatous components. Carcinosarcoma can appear in various organs, but its occurrence in the head and neck, particularly larynx, is extremely rare. Furthermore, its response to treatment has not been well established.MethodsWe report the case of a 79-year-old man with a 6-month history of hoarseness who presented with a mass having a polypoid appearance at the anterior commissure of the larynx. Further analyses revealed carcinosarcoma in the larynx that consisted of squamous cell carcinoma and an inflammatory myofibroblastic tumor (IMT).ResultsThe tumor was excised at the first hospital visited. Because pathological examination revealed an IMT and positive margin, the patient was referred to our hospital. A front lateral vertical partial laryngectomy was performed for further treatment. Histological examination demonstrated a biphasic component, consisting of squamous cell carcinoma (SCC) and IMT.ConclusionsIMT rarely occurs in the head and neck region. Moreover, to best of our knowledge, no carcinosarcoma cases consisting of SCC and IMT in the larynx have been reported in the literature. The prognosis of carcinosarcoma is considered to be dependent on the type of malignant mesenchyme, and surgical excision with wide margins is generally used to treat IMT. Therefore, the treatment of laryngeal carcinosarcoma consisting of IMT can be best accomplished with complete excision of the tumor.



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Head and neck cancers: a clinico-pathological profile and management challenges in a resource-limited setting

Background: Head and neck cancer (HNC) is one of the most common cancers worldwide and its incidence is reported to be increasing in resource-limited countries. There is a paucity of published data regarding head and neck cancers in Tanzania, and Bugando Medical Centre in particular. This study describes the clinicopathological profile of HNC in our local setting and highlights the challenges in the management of this disease. Methods: This was a retrospective study of histopathologically confirmed cases of head and neck cancers treated at Bugando Medical Center between January 2009 and December 2013. Results: A total of 346 patients (M:F = 2.1:1) were studied representing 9.5 % of all malignancies. The median age of patients was 42 years. Cigarette smoking (76.6 %) and heavy alcohol consumption (69.9 %) were the most frequently identified risk factors for head and neck cancer. The majority of patients (95.9 %) presented late with advanced stages. Twenty-five (7.2 %) patients were HIV positive with a median CD4+ count of 244 cells/μl. The oral cavity (37.3 %) was the most frequent anatomical site affected. The most common histopathological type was carcinomas (59.6 %) of which 75.7 % were squamous cell carcinoma. A total of 196 (56.6 %) patients underwent surgical procedures for HNC. Radiotherapy and chemotherapy was reported in 9.5 and 16.8 % of patients, respectively. Only 2 (0.6 %) patients received chemo-radiation therapy. The mortality rate was 24.4 %. The overall 5-year survival rate (5-YSR) was 20.6 %. The predictors of overall 5-YSR were age of patient at diagnosis, stage of disease, extent of lymph node involvement, HIV seropositivity and CD4+ count <200 cells/μl (P < 0.001). Local recurrence was reported in 22 (23.4 %) patients and this was significantly associated with positive resection margins, stage of the tumor and presence of metastasis at diagnosis and non-adherence to adjuvant therapy (P < 0.001). Conclusion: Head and neck cancers are not uncommon at Bugando Medical Centre and show a trend towards a relative young age at diagnosis and the majority of patients present late with advanced stage cancer. Therefore, public enlightenment, early diagnosis, and effective cost-effective treatment and follow-up are urgently needed to improve outcomes of these patients in our environment.

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The use of intraoperative triggered electromyography to detect misplaced pedicle screws: a systematic review and meta-analysis

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECT Insertion of instruments or implants into the spine carries a risk for injury to neural tissue. Triggered electromyography (tEMG) is an intraoperative neuromonitoring technique that involves electrical stimulation of a tool or screw and subsequent measurement of muscle action potentials from myotomes innervated by nerve roots near the stimulated instrument. The authors of this study sought to determine the ability of tEMG to detect misplaced pedicle screws (PSs). METHODS The authors searched the US National Library of Medicine, the Web of Science Core Collection database, and the Cochrane Central Register of Controlled Trials for PS studies. A meta-analysis of these studies was performed on a per-screw basis to determine the ability of tEMG to detect misplaced PSs. Sensitivity, specificity, and receiver operating characteristic (ROC) area under the curve (AUC) were calculated overall and in subgroups. RESULTS Twenty-six studies were included in the systematic review. The authors analyzed 18 studies in which tEMG was used during PS placement in the meta-analysis, representing data from 2932 patients and 15,065 screws. The overall sensitivity of tEMG for detecting misplaced PSs was 0.78, and the specificity was 0.94. The overall ROC AUC was 0.96. A tEMG current threshold of 10–12 mA (ROC AUC 0.99) and a pulse duration of 300 µsec (ROC AUC 0.97) provided the most accurate testing parameters for detecting misplaced screws. Screws most accurately conducted EMG signals (ROC AUC 0.98). CONCLUSIONS Triggered electromyography has very high specificity but only fair sensitivity for detecting malpositioned PSs.

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Scoliosis may increase the risk of recurrence of lumbar disc herniation after microdiscectomy

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECT The aim of this paper was to investigate the risk of recurrence of lumbar disc herniation (LDH) in patients with scoliosis who underwent microdiscectomy. METHODS A series of consecutive patients who underwent microdiscectomy for LDH was retrospectively reviewed. The inclusion criteria were young adults younger than 40 years who received microdiscectomy for symptomatic 1-level LDH. An exclusion criterion was any previous spinal surgery, including fusion or correction of scoliosis. The patients were divided into 2 groups: those with scoliosis and those without scoliosis. The demographic data in the 2 groups were similar. All medical records and clinical and radiological evaluations were reviewed. RESULTS A total of 58 patients who underwent 1-level microdiscectomy for LDH were analyzed. During the mean follow-up of 24.6 months, 6 patients (10.3%) experienced a recurrence of LDH with variable symptoms. The recurrence rate was significantly higher among the scoliosis group than the nonscoliosis group (33.3% vs 2.3%, p = 0.001). Furthermore, the recurrence-free interval in the scoliosis group was short. CONCLUSIONS Young adults (< 40 years) with uncorrected scoliosis are at higher risk of recurrent LDH after microdiscectomy.

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The role of obesity in the biomechanics and radiological changes of the spine: an in vitro study

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECT The effects of obesity on lumbar biomechanics are not fully understood. The aims of this study were to analyze the biomechanical differences between cadaveric L4–5 lumbar spine segments from a large group of nonobese (body mass index [BMI] < 30 kg/m2) and obese (BMI ≥ 30 kg/m2) donors and to determine if there were any radiological differences between spines from nonobese and obese donors using MR imaging. METHODS A total of 168 intact L4–5 spinal segments (87 males and 81 females) were tested using pure-moment loading, simulating flexion-extension, lateral bending, and axial rotation. Axial compression tests were performed on 38 of the specimens. Sex, age, and BMI were analyzed with biomechanical parameters using 1-way ANOVA, Pearson correlation, and multiple regression analyses. MR images were obtained in 12 specimens (8 from obese and 4 from nonobese donors) using a 3-T MR scanner. RESULTS The segments from the obese male group allowed significantly greater range of motion (ROM) than those from the nonobese male group during axial rotation (p = 0.018), while there was no difference between segments from obese and nonobese females (p = 0.687). There were no differences in ROM between spines from obese and nonobese donors during flexion-extension or lateral bending for either sex. In the nonobese population, the ROM during axial rotation was significantly greater for females than for males (p = 0.009). There was no significant difference between sexes in the obese population (p = 0.892). Axial compressive stiffness was significantly greater for the obese than the nonobese population for both the female-only group and the entire study group (p < 0.01); however, the difference was nonsignificant in the male population (p = 0.304). Correlation analysis confirmed a significant negative correlation between BMI and resistance to deformation during axial compression in the female group (R = −0.65, p = 0.004), with no relationship in the male group (R = 0.03, p = 0.9). There was also a significant negative correlation between ROM during flexion-extension and BMI for the female group (R = −0.38, p = 0.001), with no relationship for the male group (R = 0.06, p = 0.58). Qualitative analysis using MR imaging indicated greater facet degeneration and a greater incidence of disc herniations in the obese group than in the control group. CONCLUSIONS Based on flexibility and compression tests, lumbar spinal segments from obese versus nonobese donors seem to behave differently, biomechanically, during axial rotation and compression. The differences are more pronounced in women. MR imaging suggests that these differences may be due to greater facet degeneration and an increased amount of disc herniation in the spines from obese individuals.

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The rise and fall of the craniocervical junction relative to the hard palate: a lifetime story

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECT Endoscopic approaches to the anterior craniocervical junction are increasing in frequency. Choice of oral versus endoscopic endonasal approach to the odontoid often depends on the relationship of the C1–2 complex to the hard palate. However, it is not known how this relevant anatomy changes with age. We hypothesize that there is a dynamic relationship of C-2 and the hard palate, which changes with age, and potentially affects the choice of surgical approach. The aim of this study was to characterize the relationship of C-2 relative to the hard palate with respect to age and sex. METHODS Emergency department billing and trauma records from 2008 to 2014 were reviewed for patients of all ages who underwent cervical or maxillofacial CT as part of a trauma evaluation for closed head injury. Patients who had a CT scan that allowed adequate visualization of the hard palate, opisthion, and upper cervical spine (C-1 and C-2) were included. Patients who had cervical or displaced facial/skull base fractures, a history of rheumatoid arthritis, or craniofacial anomalies were excluded. The distance from McGregor's palatooccipital line to the midpoint of the inferior endplate of C-2 (McL–C2) was measured on midsagittal CT scans. Patients were grouped by decile of age and by sex. A 1-way ANOVA was performed with each respective grouping. RESULTS Ultimately, 483 patients (29% female) were included. The mean age was 46 ± 24 years. The majority of patients studied were in the 2nd through 8th decades of life (85%). Significant variation was found between McL–C2 and decile of age (p < 0.001) and sex (p < 0.001). The mean McL–C2 was 27 mm in the 1st decade of life compared with the population mean of 37 mm. The mean McL–C2 was also noted to be smaller in females (mean difference 4.8 mm, p < 0.0001). Both decile of age (p = 0.0009) and sex (p < 0.0001) were independently correlated with McL–C2 on multivariate analysis. CONCLUSIONS The relationship of C-2 and the hard palate significantly varies with respect to age and sex, descending relative to the hard palate a full centimeter on average in adulthood. These findings may have relevance in determining optimal surgical approaches for addressing pathology involving the anterior craniocervical junction.

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Preoperative retrolisthesis as a risk factor of postdecompression lumbar disc herniation

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECT In this study, the authors aimed to identify specific risk factors for postdecompression lumbar disc herniation (PDLDH) in patients who have not undergone discectomy and/or fusion. METHODS Between 2007 and 2012, 493 patients with lumbar spinal stenosis underwent bilateral partial laminectomy without discectomy and/or fusion in a single hospital. Eighteen patients (herniation group [H group]: 15 men, 3 women; mean age 65.1 years) developed acute sciatica as a result of PDLDH within 2 years after surgery. Ninety patients who did not develop postoperative acute sciatica were selected as a control group (C group: 75 men, 15 women; mean age 65.4 years). Patients in the C group were age and sex matched with those in the H group. The patients in the groups were also matched for decompression level, number of decompression levels, and surgery date. The radiographic variables measured included percentage of slippage, intervertebral angle, range of motion, lumbar lordosis, disc height, facet angle, extent of facet removal, facet degeneration, disc degeneration, and vertebral endplate degeneration. The threshold for PDLDH risk factors was evaluated using a continuous numerical variable and receiver operating characteristic curve analysis. The area under the curve was used to determine the diagnostic performance, and values greater than 0.75 were considered to represent good performance. RESULTS Multivariate analysis revealed that preoperative retrolisthesis during extension was the sole significant independent risk factor for PDLDH. The area under the curve for preoperative retrolisthesis during extension was 0.849; the cutoff value was estimated to be a retrolisthesis of 7.2% during extension. CONCLUSIONS The authors observed that bilateral partial laminectomy, performed along with the removal of the posterior support ligament, may not be suitable for lumbar spinal stenosis patients with preoperative retrolisthesis greater than 7.2% during extension.

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Economic value of treating lumbar disc herniation in Brazil

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECT Lumbar discectomy is one of the most common surgical spine procedures. In order to understand the value of this surgical care, it is important to understand the costs to the health care system and patient for good results. The objective of this study was to evaluate for the first time the cost-effectiveness of spine surgery in Latin America for lumbar discectomy in terms of cost per quality-adjusted life year (QALY) gained for patients in Brazil. METHODS The authors performed a prospective cohort study involving 143 consecutive patients who underwent open discectomy for lumbar disc herniation (LDH). Patient-reported outcomes were assessed utilizing the SF-6D, which is derived from a 12-month variation of the SF-36. Direct medical costs included medical reimbursement, costs of hospital care, and overall resource consumption. Disability losses were considered indirect costs. A 4-year horizon with 3% discounting was applied to health-utilities estimates. Sensitivity analysis was performed by varying utility gain by 20%. The costs were expressed in Reais (R$) and US dollars ($), applying an exchange rate of 2.4:1 (the rate at the time of manuscript preparation). RESULTS The direct and indirect costs of open lumbar discectomy were estimated at an average of R$3426.72 ($1427.80) and R$2027.67 ($844.86), respectively. The mean total cost of treatment was estimated at R$5454.40 ($2272.66) (SD R$2709.17 [$1128.82]). The SF-6D utility gain was 0.044 (95% CI 0.03197–0.05923, p = 0.017) at 12 months. The 4-year discounted QALY gain was 0.176928. The estimated cost-utility ratio was R$30,828.35 ($12,845.14) per QALY gained. The sensitivity analysis showed a range of R$25,690.29 ($10,714.28) to R$38,535.44 ($16,056.43) per QALY gained. CONCLUSIONS The use of open lumbar discectomy to treat LDH is associated with a significant improvement in patient outcomes as measured by the SF-6D. Open lumbar discectomy performed in the Brazilian supplementary health care system provides a cost-utility ratio of R$30,828.35 ($12,845.14) per QALY. The value of acceptable cost-effectiveness will vary by country and region.

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Letter to the Editor: Alternative approach in Type II hangman fractures

Journal of Neurosurgery: Spine, Ahead of Print.


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Prevalence and type of cervical deformities among adults with Parkinson's disease: a cross-sectional study

Journal of Neurosurgery: Spine, Ahead of Print.
OBJECT To identify the characteristics of cervical deformities in Parkinson's disease (PD) and the role of severity of PD in the development of cervical spine deformities, the authors investigated the prevalence of the cervical deformities, cervical kyphosis (CK), and cervical positive sagittal malalignment (CPSM) in patients with PD. They also analyzed the association of severity of cervical deformities with the stage of PD in the context of global sagittal spinopelvic alignment. METHODS This study was a prospective assessment of consecutively treated patients (n = 89) with PD. A control group of the age- and sex-matched patients was selected from patients with degenerative cervical spine disease but without PD. Clinical and demographic parameters including age, sex, duration of PD, and Hoehn and Yahr (H&Y) stage were collected. Full-length standing radiographs were used to assess spinopelvic parameters. CK was defined as a C2–7 Cobb angle < 0°. CPSM was defined as C2–7 sagittal vertical axis (SVA) > 4 cm. RESULTS A significantly higher prevalence of CPSM (28% vs 1.1%, p < 0.001), but not CK (12% vs 10.1%, p = 0.635), was found in PD patients compared with control patients. Among patients with PD, those with CK were younger (62.1 vs 69.0 years, p = 0.013) and had longer duration of PD (56.4 vs 36.2 months, p = 0.034), but the severity of PD was not significantly different. Logistic regression analysis revealed that the presence of CK was associated with younger age, higher mismatch between pelvic incidence and lumbar lordosis, and lower C7–S1 SVA. The patients with CPSM had significantly greater thoracic kyphosis (TK) (p < 0.001) and a trend toward more advanced H&Y stage (p = 0.05). Logistic regression analysis revealed that CPSM was associated with male sex, greater TK, and more advanced H&Y stage. CONCLUSIONS Patients with PD have a significantly higher prevalence of CPSM compared with age- and sex-matched control patients with cervical degenerative disease but without PD. Among patients with PD, CK is not associated with the severity of PD but is associated with overall global sagittal malalignment. In contrast, the presence of CPSM is associated more with the severity of PD than it is with the presence of global sagittal malalignment. Collectively, these data suggest that the neuromuscular pathogenesis of PD may affect the development of CPSM more than of CK.

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App-assisted external ventricular drain insertion

Journal of Neurosurgery, Ahead of Print.
The freehand technique for insertion of an external ventricular drain (EVD) is based on fixed anatomical landmarks and does not take individual variations into consideration. A patient-tailored approach based on augmented-reality techniques using devices such as smartphones can address this shortcoming. The Sina neurosurgical assist (Sina) is an Android mobile device application (app) that was designed and developed to be used as a simple intraoperative neurosurgical planning aid. It overlaps the patient's images from previously performed CT or MRI studies on the image seen through the device camera. The device is held by an assistant who aligns the images and provides information about the relative position of the target and EVD to the surgeon who is performing EVD insertion. This app can be used to provide guidance and continuous monitoring during EVD placement. The author describes the technique of Sina-assisted EVD insertion into the frontal horn of the lateral ventricle and reports on its clinical application in 5 cases as well as the results of ex vivo studies of ease of use and precision. The technique has potential for further development and use with other augmented-reality devices.

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Effectiveness of 2-methoxyestradiol in alleviating angiogenesis induced by intracranial venous hypertension

Journal of Neurosurgery, Ahead of Print.
OBJECT Intracranial dural arteriovenous fistulas (DAVFs) are complex intracranial vascular malformations that can lead to hemorrhage. The authors recently found that chronic local hypoperfusion seems to be the main cause of angiogenesis in the dura mater, which leads to the formation of DAVFs. As a natural derivative of estradiol, 2-methoxyestradiol (2-ME) has an antiangiogenic effect and can be used safely in patients with advanced carcinoid tumors. This study was conducted to examine the antiangiogenic effects of 2-ME on a rat DAVF model. METHODS Male Sprague-Dawley rats (n = 72) were used in the experiments. Intracranial venous hypertension was induced for modeling, and 2-ME was used in the early or late stage for treatment. The effects were examined by immunohistochemistry, Western blot analysis, and quantitative real-time polymerase chain reaction assays. RESULTS 2-Methoxyestradiol significantly reduced angiogenesis in the dura in early- and late-intervention treatment groups, as proven by the results of immunohistochemical staining, Western blotting, real-time polymerase chain reaction assays, and microvessel density counts. The antiangiogenic effect even lasted for up to 2 weeks after 2-ME cessation. CONCLUSIONS These data collectively suggest that 2-ME can reduce the angiogenic effect caused by venous hypertension in a rat DAVF model, mainly by suppressing the inhibitor of differentiation 1 (ID-1) and hypoxia-inducible factor 1α (HIF-1α) pathways.

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Neuropsychological outcomes of subtemporal selective amygdalohippocampectomy via a small craniotomy

Journal of Neurosurgery, Ahead of Print.
OBJECT The objectives of this study were to describe a novel minimal-access subtemporal approach for selective resection of the amygdala and hippocampus in patients with medically refractory mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis, and to analyze the related outcomes. METHODS The authors analyzed data from all cases involving patients with unilateral MTLE due to hippocampal sclerosis who were treated with selective amygdalohippocampectomy via the posterior subtemporal approach through a relatively small craniotomy, without a neuronavigation system, at their institution during the period from September 2010 to September 2012. Data were obtained on baseline characteristics, preoperative evaluations of unilateral mesial temporal sclerosis, surgical complications, and Engel class seizure outcomes. All patients underwent memory testing, IQ testing, and language testing. RESULTS The mean duration of follow-up was 33.6 months (range 24–48 months). There were no deaths and no cases of significant postoperative morbidity. One patient had a mild complication. At 2-year follow-up, 19 patients were seizure free (Engel Class I outcome). Verbal memory scores obtained at 3 months and at 2 years after surgery were significantly lower than preoperative scores for patients who underwent surgery on the left side of the brain (p < 0.05). Pictorial memory scores were higher following surgery compared with before surgery regardless of whether patients underwent left- or right-sided brain surgery. There was also improvement in performance IQ and total IQ following surgery in both groups. For patients who underwent right-sided brain surgery, verbal comprehension and semantic fluency testing scores were significantly higher at both 3 months and 2 years after surgery than before surgery. For patients who underwent left-sided brain surgery, scores on all language tests were significantly lower at 3 months after surgery than before surgery. Verbal comprehension testing scores returned to the preoperative level at 2 years after surgery. CONCLUSIONS The posterior subtemporal approach through a relatively small craniotomy allows adequate exposure and safe resection of mesial temporal structures and effectively reduces medically intractable MTLE. It preserves IQ but may have a detrimental effect on verbal memory and language ability.

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The safety of Pipeline flow diversion in fusiform vertebrobasilar aneurysms: a consecutive case series with longer-term follow-up from a single US center

Journal of Neurosurgery, Ahead of Print.
OBJECT Pessimism exists regarding flow diversion for posterior circulation aneurysms because of reports of perforator territory infarcts and delayed ruptures. The authors report the results of patients who underwent Pipeline Embolization Device (PED) flow diversion using novel strategies for treatment of fusiform posterior circulation aneurysms, and compare these results with those from previously reported series. METHODS The authors conducted a retrospective review of data from consecutive patients with fusiform vertebrobasilar artery aneurysms treated with the PED. RESULTS This review resulted in the identification of 12 such patients (mean [± SD] age 55.1 ± 14.1 years). Eleven patients had symptoms; 1 had a dissecting aneurysm identified on imaging for neck pain. The average aneurysm size was 13.25 ± 4.5 mm. None of the aneurysms were ruptured or previously treated. The average clinical follow-up duration was 22.1 ± 10.7 months and radiological follow-up was 14.5 ± 11.1 months from the index PED treatment. One patient suffered a perforator stroke and had a modified Rankin Scale (mRS) score of 4 at last follow-up. Another patient had a retained stent pusher requiring retrieval via surgical cut-down but recovered to an mRS score of 0 at last follow-up. Eleven (91.7%) of 12 patients recovered to an mRS score of 0 or 1. Two patients had aneurysmal remnants at 7 and 10 months, respectively, after the index PED, which were retreated with PEDs. At last follow-up, all 12 aneurysms were occluded and PEDs were patent. The minimum follow-up duration was 12 months from the index PED treatment; no patient experienced delayed hemorrhage, stroke, or in-stent stenosis. CONCLUSIONS Flow diversion with selective adjunctive techniques is evolving to become a safer treatment option for posterior circulation aneurysms. This is the longest clinical follow-up duration reported for a single-center experience of flow-diversion treatment of these aneurysms.

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Sonographic findings associated with stenosis progression and vascular complications in moyamoya disease

Journal of Neurosurgery, Ahead of Print.
OBJECT The progression of arterial stenosis in patients with moyamoya disease (MMD) has variable courses and an unclear mechanism. The authors hypothesized that elevated wall shear stress (WSS) at the terminal internal carotid artery (ICA) and proximal middle cerebral artery (MCA) may facilitate MMD progression. They indirectly evaluated the relative magnitude of WSS (WSS value [WSSV]) with MR angiography (MRA) and transcranial Doppler to determine its predictive value for stenosis progression (SP) and the development of vascular complications. METHODS Thirty-one medically treated patients (58 hemispheres and 95 nonoccluded vessels) were analyzed with serial MRA (median follow-up 23 months). The parameters studied were SP, SP rates (SPRs) for individual ICAs/MCAs, and their mean values from the ipsilateral hemispheres as mean SP (MSP) and MSP rates (MSPRs). Significant progression was defined as decrements of ≥ 20% for SP and MSP and ≥ 10%/year for SPR and MSPR. The development of vascular complications in relevant hemispheres was also recorded. The WSSV (dyne/cm2) was defined as the shear rate multiplied by blood viscosity. RESULTS After adjusting the initial stenosis degree and MRA stage of MMD, an SP of ≥ 20% and an SPR of ≥ 10%/year were associated with the highest-quartile WSSVs for all individual vessels and for MCAs and ICAs separately. For each hemisphere, an MSP of ≥ 20% and an MSPR of ≥ 10%/year were associated with the highest-quartile mean WSSVs. Furthermore, significant SP was highly correlated with vascular complications, and the highest-quartile mean WSSV was independently associated with vascular complications in relevant hemispheres. CONCLUSIONS An elevated WSSV is an independent predictor for SP and vascular complications in nonoccluded MMD.

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Origin of craniopharyngiomas: implications for growth pattern, clinical characteristics, and outcomes of tumor recurrence

Journal of Neurosurgery, Ahead of Print.
OBJECT Craniopharyngiomas are associated with a high rate of recurrence. The surgical management of recurrent lesions has been among the most challenging neurosurgical procedures because of the craniopharyngioma's complex topographical relationship with surrounding structures. The aim of this study was to define the determinative role of the site of origin on the growth pattern and clinical features of recurrent craniopharyngiomas. METHODS The authors performed a retrospective analysis of 52 patients who had undergone uniform treatment by a single surgeon. For each patient, data concerning symptoms and signs, imaging features, hypothalamic-pituitary function, and recurrence-free survival rate were collected. RESULTS For children, delayed puberty was more frequent in the group with Type I (infradiaphragmatic) craniopharyngioma than in the group with Type TS (tuberoinfundibular and suprasellar extraventricular) lesions (p < 0.05). For adults, blindness was more frequent in the Type I group than in the Type TS group (p < 0.05). Nausea or vomiting, delayed puberty, and growth retardation were more frequent in children than in adults (p < 0.05). Overall clinical outcome was good in 48.07% of the patients and poor in 51.92%. Patients with Type TS recurrent tumors had significantly worse functional outcomes and hypothalamic function than patients with the Type I recurrent tumors but better pituitary function especially in children. CONCLUSIONS The origin of recurrent craniopharyngiomas significantly affected the symptoms, signs, functional outcomes, and hypothalamic-pituitary functions of patients undergoing repeated surgery. Differences in tumor growth patterns and site of origin should be considered when one is comparing outcomes and survival across treatment paradigms in patients with recurrent craniopharyngiomas.

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Identifying preoperative language tracts and predicting postoperative functional recovery using HARDI q-ball fiber tractography in patients with gliomas

Journal of Neurosurgery, Ahead of Print.
OBJECT Diffusion MRI has uniquely enabled in vivo delineation of white matter tracts, which has been applied to the segmentation of eloquent pathways for intraoperative mapping. The last decade has also seen the development from earlier diffusion tensor models to higher-order models, which take advantage of high angular resolution diffusion-weighted imaging (HARDI) techniques. However, these advanced methods have not been widely implemented for routine preoperative and intraoperative mapping. The authors report on the application of residual bootstrap q-ball fiber tracking for routine mapping of potentially functional language pathways, the development of a system for rating tract injury to evaluate the impact on clinically assessed language function, and initial results predicting long-term language deficits following glioma resection. METHODS The authors have developed methods for the segmentation of 8 putative language pathways including dorsal phonological pathways and ventral semantic streams using residual bootstrap q-ball fiber tracking. Furthermore, they have implemented clinically feasible preoperative acquisition and processing of HARDI data to delineate these pathways for neurosurgical application. They have also developed a rating scale based on the altered fiber tract density to estimate the degree of pathway injury, applying these ratings to a subset of 35 patients with pre- and postoperative fiber tracking. The relationships between specific pathways and clinical language deficits were assessed to determine which pathways are predictive of long-term language deficits following surgery. RESULTS This tracking methodology has been routinely implemented for preoperative mapping in patients with brain gliomas who have undergone awake brain tumor resection at the University of California, San Francisco (more than 300 patients to date). In this particular study the authors investigated the white matter structure status and language correlation in a subcohort of 35 subjects both pre- and postsurgery. The rating scales developed for fiber pathway damage were found to be highly reproducible and provided significant correlations with language performance. Preservation of the left arcuate fasciculus (AF) and the temporoparietal component of the superior longitudinal fasciculus (SLF-tp) was consistent in all patients without language deficits (p < 0.001) at the long-term follow-up. Furthermore, in patients with short-term language deficits, the AF and/or SLF-tp were affected, and damage to these 2 pathways was predictive of a long-term language deficit (p = 0.005). CONCLUSIONS The authors demonstrated the successful application of q-ball tracking in presurgical planning for language pathways in brain tumor patients and in assessing white matter tract integrity postoperatively to predict long-term language dysfunction. These initial results predicting long-term language deficits following tumor resection indicate that postoperative injury to dorsal language pathways may be prognostic for long-term clinical language deficits. Study results suggest the importance of dorsal stream tract preservation to reduce language deficits in patients undergoing glioma resection, as well as the potential prognostic value of assessing postoperative injury to dorsal language pathways to predict long-term clinical language deficits.

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Dynamic telescopic craniotomy: a cadaveric study of a novel device and technique

Journal of Neurosurgery, Ahead of Print.
OBJECT The authors assessed the feasibility of the dynamic decompressive craniotomy technique using a novel cranial fixation plate with a telescopic component. Following a craniotomy in human cadaver skulls, the telescopic plates were placed to cover the bur holes. The plates allow constrained outward movement of the bone flap upon an increase in intracranial pressure (ICP) and also prevent the bone flap from sinking once the ICP normalizes. The authors compared the extent of postcraniotomy ICP control after an abrupt increase in intracranial volume using the dynamic craniotomy technique versus the standard craniotomy or hinge craniotomy techniques. METHODS Fixation of the bone flap after craniotomy was performed in 5 cadaver skulls using 3 techniques: 1) dynamic telescopic craniotomy, 2) hinge craniotomy, and 3) standard craniotomy with fixed plates. The ability of each technique to allow for expansion during intracranial hypertension was evaluated by progressively increasing intracranial volume. Biomechanical evaluation of the telescopic plates with load-bearing tests was also undertaken. RESULTS Both the dynamic craniotomy and the hinge craniotomy techniques provided significant control of ICP during increases in intracranial volume as compared with the standard craniotomy technique. With the standard craniotomy, ICP increased from a mean of 11.4 to 100.1 mm Hg with the addition of 120 ml of intracranial volume. However, with the dynamic craniotomy, the addition of 120 ml of intracranial volume increased the ICP from a mean of 2.8 to 13.4 mm Hg, maintaining ICP within the normal range as compared with the standard craniotomy (p = 0.04). The dynamic craniotomy was also superior in controlling ICP as compared with the hinge craniotomy, providing expansion for an additional 40 ml of intracranial volume while maintaining ICP within a normal range (p = 0.008). Biomechanical load-bearing tests for the dynamic telescopic plates revealed rigid restriction of bone-flap sinking as compared with standard fixation plates and clamps. CONCLUSIONS The dynamic telescopic craniotomy technique with the novel cranial fixation plate provides superior control of ICP after an abrupt increase in intracranial volume as compared with the standard craniotomy and hinge craniotomy techniques.

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Prospective comparison of sinonasal outcomes after microscopic sublabial or endoscopic endonasal transsphenoidal surgery for nonfunctioning pituitary adenomas

Journal of Neurosurgery, Ahead of Print.
OBJECT Both endoscopic and microscopic transsphenoidal approaches are accepted techniques for the resection of pituitary adenomas. Although studies have explored patient outcomes for each technique individually, none have prospectively compared sinonasal and quality of life outcomes in a concurrent series of patients at the same institution, as has been done in the present study. METHODS Patients with nonfunctioning adenomas undergoing transsphenoidal surgery were assessed for sinonasal function, quality of life, and pain using the Sino-Nasal Outcome Test-20 (SNOT-20), the short form of the Nasal Obstruction Symptom Evaluation (NOSE) instrument, the SF-36, and a headache scale. Eighty-two patients undergoing either endoscopic (47 patients) or microscopic (35 patients) surgery were surveyed preoperatively and at 24–48 hours, 2 weeks, 4 weeks, 8 weeks, and 1 year after surgery. RESULTS Patients who underwent endoscopic and microscopic transsphenoidal surgery experienced a similar recovery pattern, showing an initial increase in symptoms during the first 2 weeks, followed by a return to baseline by 4 weeks and improvement beyond baseline functioning by 8 weeks. Patients who underwent endoscopic surgery experienced better sinonasal outcomes at 24–48 hours (SNOT total p = 0.015, SNOT rhinologic subscale [ssRhino] p < 0.001), 2 weeks (NOSE p = 0.013), and 8 weeks (SNOT total p = 0.032 and SNOT ssRhino p = 0.035). By 1 year after surgery, no significant differences in sinonasal outcomes were observed between the 2 groups. Headache scales at 1 year improved in all dimensions except duration for both groups (total result 73%, p = 0.004; severity 46%, p < 0.001; frequency 53%, p < 0.001), with 80% of either microscopic or endoscopic patients experiencing improvement or resolution of headache symptoms. Endoscopic and microscopic patients experienced reduced vitality preoperatively compared with US population norms and remained low postoperatively. By 8 weeks after surgery, both groups experienced significant improvements in mental health (13%, p = 0.005) and vitality (15%, p = 0.037). By 1 year after surgery, patients improved significantly in mental health (14%, p = 0.03), role physical (14%, p = 0.036), social functioning (16%, p = 0.009), vitality (22%, p = 0.002), and SF-36 total (10%, p = 0.024) as compared with preoperative measures. There were no significant differences at any time point between the 2 groups for the total SF-36 or for any of the 8 subscales. CONCLUSIONS Patients who underwent either an endoscopic or a microscopic approach experienced the greatest nasal symptoms at 2 weeks postoperatively and exhibited similar time courses of recovery in nasal, headache, and quality of life assessments. Although patients who underwent endoscopic surgery experienced significantly fewer nasal symptoms during the first 8 weeks, by 1 year after surgery, there were no significant differences between the 2 groups.

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Application of contrast-enhanced T1-weighted MRI-based 3D reconstruction of the dural tail sign in meningioma resection

Journal of Neurosurgery, Ahead of Print.
OBJECT The goal of this study was to investigate the significance of contrast-enhanced T1-weighted (T1W) MRI-based 3D reconstruction of dural tail sign (DTS) in meningioma resection. METHODS Between May 2013 and August 2014, 18 cases of convexity and parasagittal meningiomas showing DTS on contrast-enhanced T1W MRI were selected. Contrast-enhanced T1W MRI-based 3D reconstruction of DTS was conducted before surgical treatment. The vertical and anteroposterior diameters of DTS on the contrast-enhanced T1W MR images and 3D reconstruction images were measured and compared. Surgical incisions were designed by referring to the 3D reconstruction and MR images, and then the efficiency of the 2 methods was evaluated with assistance of neuronavigation. RESULTS Three-dimensional reconstruction of DTS can reveal its overall picture. In most cases, the DTS around the tumor is uneven, whereas the DTS around the dural vessels presents longer extensions. There was no significant difference (p > 0.05) between the vertical and anteroposterior diameters of DTS measured on the contrast-enhanced T1W MR and 3D reconstruction images. The 3D images of DTS were more intuitive, and the overall picture of DTS could be revealed in 1 image, which made it easier to design the incision than by using the MR images. Meanwhile, assessment showed that the incisions designed using 3D images were more accurate than those designed using MR images (ridit analysis by SAS, F = 7.95; p = 0.008). Pathological examination showed that 34 dural specimens (except 2 specimens from 1 tumor) displayed tumor invasion. The distance of tumor cell invasion was 1.0–21.6 mm (5.4 ± 4.41 mm [mean ± SD]). Tumor cell invasion was not observed at the dural resection margin in all 36 specimens. CONCLUSIONS Contrast-enhanced T1W MRI-based 3D reconstruction can intuitively and accurately reveal the size and shape of DTS, and thus provides guidance for designing meningioma incisions.

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Treatment of ruptured complex and large/giant ruptured cerebral aneurysms by acute coiling followed by staged flow diversion

Journal of Neurosurgery, Ahead of Print.
OBJECT Flow-diversion treatment has been shown to be associated with high rates of angiographic obliteration; however, the treatment is relatively contraindicated in the acute phase following subarachnoid hemorrhage (SAH) as these patients require periprocedural dual antiplatelet therapy. Acute coiling followed by flow diversion has emerged as an intriguing and feasible treatment option for ruptured complex and giant aneurysms. In this study the authors report outcomes and complications of patients with ruptured aneurysms undergoing coiling in the acute phase followed by planned delayed flow diversion. METHODS This case series includes patients from 2 institutions. All patients underwent standard endovascular coiling in the acute phase after SAH with the intention and plan to proceed with flow diversion at a later date. Outcomes studied included angiographic occlusion, procedure-related complications, and long-term clinical outcome as measured using the modified Rankin Scale. RESULTS A total of 31 patients underwent coiling in the acute phase with the intention to undergo flow diversion at a later date. The mean aneurysm size was 15.8 ± 7.9 mm. Of the 31 patients undergoing coiling, 4 patients could not undergo further flow-diverter therapy: 3 patients (9.7%) died of complications of subarachnoid hemorrhage and 1 patient had permanent morbidity as a result of perioperative ischemic stroke (3.1%). Twenty-seven patients underwent staged placement of flow diverters after adequate recovery. The median time to treatment was 16 weeks. There was one case of aneurysm rebleeding following coil treatment. There were no cases of permanent morbidity or mortality resulting from flow-diverter treatment. Twenty-four patients underwent imaging follow-up; 18 of these patients had aneurysms that were completely or nearly completely occluded (58.1% on an intent-to-treat basis). At last follow-up (mean 18.3 months), 25 patients had mRS scores ≤ 2 (80.6% on an intent-to-treat basis). CONCLUSIONS Staged treatment of ruptured complex and giant intracranial aneurysms with coiling in the acute phase and flow-diverter treatment following recovery from SAH is both safe and effective. In this series, no cases of rebleeding occurred during the interval between coiling and flow diversion. This strategy should be considered as a valid option in patients presenting with these challenging ruptured aneurysms.

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A cadaveric microanatomical study of the fascicular topography of the brachial plexus

Journal of Neurosurgery, Ahead of Print.
OBJECT Mapping of the fascicular anatomy of the brachial plexus could provide the nerve surgeon with knowledge of fascicular orientation in spinal nerves of the brachial plexus. This knowledge might improve the surgical outcome of nerve grafting in brachial plexus injuries by anastomosing related fascicles and avoiding possible axonal misrouting. The objective of this study was to map the fascicular topography in the spinal nerves of the brachial plexus. METHODS The entire right-sided brachial plexus of 25 adult male cadavers was dissected, including all 5 spinal nerves (C5–T1), from approximately 5 mm distal to their exit from the intervertebral foramina, to proximal 1 cm of distal branches. All spinal nerves were tagged on the cranial aspect of their circumference using 10-0 nylon suture for orientation. The fascicular dissection of the C5–T1 spinal nerves was performed under microscopic magnification. The area occupied by different nerve fascicles was then expressed as a percentage of the total cross-sectional area of a spinal nerve. RESULTS The localization of fascicular groups was fairly consistent in all spinal nerves. Overall, 4% of the plexus supplies the suprascapular nerve, 31% supplies the medial cord (comprising the ulnar nerve and medial root of the median nerve [MN]), 27.2% supplies the lateral cord (comprising the musculocutaneous nerve and lateral root of the MN), and 37.8% supplies the posterior cord (comprising the axillary and radial nerves). CONCLUSIONS The fascicular dissection and definitive anatomical localization of fascicular groups is feasible in plexal spinal nerves. The knowledge of exact fascicular location might be translatable to the operating room and can be used to anastomose related fascicles in brachial plexus surgery, thereby avoiding the possibility of axonal misrouting and improving the results of plexal reconstruction.

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EP24.15 as a potential regulator of Kisspeptin within the Neuroendocrine Hypothalamus

Endocrinology, Early Release.


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Research-focused isolation of human islets from donors with and without diabetes at the Alberta Diabetes Institute IsletCore

Endocrinology, Early Release.


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Activation of medulla-projecting perifornical neurons modulates the adrenal sympathetic response to hypoglycemia: involvement of orexin type 2 (OX2-R) receptors

Endocrinology, Early Release.


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Nodal promotes functional luteolysis via downregulation of progesterone and prostaglandins E2 and promotion of PGF2 alpha synthetic pathways in mare corpus luteum

Endocrinology, Early Release.


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Post stroke hemi-dystonia in children: a neglected area of research

Abstract

Background

Childhood arterial ischemic stroke (CAIS) is increasingly recognized as an important cause of significant long-term morbidity in the pediatric population. Post stroke movement disorders, above all hemi-dystonias, are much more common in children after stroke compared to adults. However, research in this field is largely lacking. By highlighting some important knowledge gaps, we aim to encourage future collaborative research projects in this particular field.

Findings

Post stroke-dystonia seems to be much more common among children than adults. However, no reliable epidemiological data of post-stroke movement disorders in childhood are available, and differentiation between spasticity and dystonia can be challenging. Pharmacotherapy for dystonia is limited by lack of effect, especially in the long-term treatment. The pathophysiology of dystonia is complex and incompletely understood. Recent findings from functional imaging studies suggest that dystonia does not result from a single lesion but rather network dysfunctions and abnormalities in functional connectivity. However, very few patients with post stroke dystonia have been studied, and it is not clear to what extent pathophysiology of primary and post stroke ischemia shares common characteristics on network level. In general, progress in understanding the nature of childhood dystonia lags far behind adult onset CNS diseases.

Conclusions

Dystonia after CAIS is a common yet insufficiently understood and poorly studied clinical challenge. Studies to improve our understanding of the underlying pathophysiology and consequently the development of instruments for early prediction as well as targeted treatment of dystonia should become a high priority in collaborative childhood stroke research.

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Salting-out-assisted liquid–liquid extraction as a suitable approach for determination of methoxetamine in large sets of tissue samples

Abstract

A new designer drug, a dissociative anesthetic, and a putative N-methyl-d-aspartate receptor antagonist, methoxetamine (MXE) noted by the EU Early Warning System has been already identified as a cause of several fatalities worldwide. The primary objective of this work was to develop a suitable sample preparation method allowing for isolation of MXE and its main metabolites in high yields from rat brain, liver, and lungs. For the purpose of the project, MXE and five metabolites were synthesized in-house, specifically O-desmethyl-normethoxetamine, O-desmethylmethoxetamine, dihydro-O-desmethylmethoxetamine, normethoxetamine, and dihydromethoxetamine. A sample preparation procedure consisted in the homogenization of the tissue applying salting-out-assisted liquid–liquid extraction (SALLE). A subsequent liquid chromatography-mass spectrometry (LC-MS) analysis was based on reversed-phased chromatography hyphenated with a triple quad MS system in a positive electrospray mode. Multiple reaction monitoring (MRM) was used for qualification and quantification of the analytes. The quantification was based on the application of an isotopically labeled internal standard, normethoxetamine-d₃. The matrix-matched calibrations were prepared for each type of matrix with regression coefficients 0.9943–1.0000. The calibration curves were linear in the concentration range of 2.5–250 ng g⁻¹. Limits of quantification (LOQs) were estimated as 2.5 and 5 ng g⁻¹, respectively. Recovery (80–117 %) and matrix effect (94–110 %) at 100 ng g⁻¹ and intra- and inter-day accuracy and precision at low (2.5 ng g⁻¹), middle (25 ng g⁻¹), and upper (250 ng g⁻¹) concentration levels for all the analytes in all three types of tissues were also determined. The developed analytical method was applied to a set of real samples gathered in toxicological trials on rats and MXE, and its metabolites were determined successfully.

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Downscaling the in vitro test of fungal bioremediation of polycyclic aromatic hydrocarbons: methodological approach

Abstract

The miniaturization and optimization of a white rot fungal bioremediation experiment is described in this paper. The optimized procedure allows determination of the degradation kinetics of anthracene. The miniaturized procedure requires only 2.5 ml of culture medium. The experiment is more precise, robust, and better controlled comparing it to classical tests in flasks. Using this technique, different parts, i.e., the culture medium, the fungi, and the cotton seal, can be analyzed. A simple sample preparation speeds up the analytical process. Experiments performed show degradation of anthracene up to approximately 60 % by Irpex lacteus and up to approximately 40 % by Pleurotus ostreatus in 25 days. Bioremediation of anthracene by the consortium of I. lacteus and P. ostreatus shows the biodegradation of anthracene up to approximately 56 % in 23 days. At the end of the experiment, the surface tension of culture medium decreased comparing it to the blank, indicating generation of surfactant compounds.

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Cervical Cancer Prevention in Malaysia: Knowledge and Attitude of Undergraduate Pharmacy Students Towards Human Papillomavirus Infection, Screening and Vaccination in Malaysia

Abstract

This study was conducted to evaluate knowledge of undergraduate pharmacy students about human papillomavirus infection and their attitude towards its prevention. A cross-sectional survey was conducted in 270 undergraduate pharmacy students using a validated questionnaire to assess knowledge about human papillomavirus infection and cervical cancer and their attitudes towards human papillomavirus vaccines. Eighty-one percent of the respondents knew that human papillomavirus is a cause of cervical cancer, and 87.8 % knew that this infection is preventable. The gender of the respondents showed the strongest correlations with human papillomavirus knowledge. There were no significant correlations between the ethnic group of the respondents and their human papillomavirus-related knowledge. Higher perceptions of risk were associated with relationship status, and respondents who were in a relationship showed greater interest in vaccinating themselves; relationship status emerged as a unique predictor. The results indicated a moderately high level of knowledge and positive attitude towards human papillomavirus vaccination with few disagreements. The results of this study will help to develop and plan appropriate education campaigns for pharmacy students that aim to reduce human papillomavirus infection and, consequently, the incidence of and mortality caused by cervical cancer in Malaysia.

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Local cryosurgery and imiquimod: A successful combination for the treatment of locoregional cutaneous metastasis of melanoma: A case series

Abstract

Locoregional cutaneous metastases of melanoma (LCMM) represent a therapeutic challenge. Many treatment options are available with varying results. The combination of cryotherapy and imiquimod, two treatments with a possible synergistic effect, has not yet been described for treating this disease. In this paper, we aimed to show the response of LCMM to cryotherapy combined with topical imiquimod 5%. A retrospective review of 20 patients diagnosed with LCMM and treated with cryotherapy combined with topical imiquimod 5% between November 2000 and May 2014 at three institutions was performed. The locoregional cutaneous response was evaluated. After a mean of five sessions, 13 patients (65%) responded to treatment, eight (40%) of these completely and five (25%) partially. Systemic disease progressed in 16 (80%) patients. Cryotherapy followed by topical imiquimod 5% is simple to apply, has minimal adverse effects and provides response rates similar to other, more complex treatment options.

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Blistering disease associated with diffuse large B-cell lymphoma but without autoantibodies

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Spontaneous remission of aleukemic cutaneous myeloid sarcoma followed by crisis of acute monoblastic leukemia

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Kissing tumors of sebaceous carcinoma on the eyelids in collision with melanocytic nevus: A case report

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