Τετάρτη 6 Σεπτεμβρίου 2017
Guidelines for Contributing Authors
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Expression of transcription factors in MEN1-associated pancreatic neuroendocrine tumors
MEN1-associated pancreatic neuroendocrine tumors (pNETs) may potentially express distinct hormones, but the mechanism has not been elucidated. Transcription factors such as MafA and Pdx1 have been identified to lead to beta cell differentiation, while Arx and Brn4 to alpha cell differentiation in developing pancreas. We hypothesized those transcription factors are important to produce specific hormones in pNETs, similarly to developing pancreas, and examined the expression of transcription factors in a case of MEN1 who showed immunohistological coexistence of several hormone-producing pNETs including insulinoma. A 70-year-old woman was found to manifest hypoglycemia with non-suppressed insulinemia and hypercalcemia with elevated PTH level. She was diagnosed as MEN1 based on the manifestation of primary hyperparathyroidism, pituitary adenoma and insulinoma, with genetic variation of MEN1 gene. She had pylorus-preserving pancreaticoduodenectomy because CT scan and SACI test indicated that insulinoma was localized in the head of the pancreas. Histopathological finding was MEN1-associated NET, G1. Interestingly, immunohistological examination of the resected pancreas revealed that two insulinomas, a glucagon-positive NET and a multiple hormone-positive NET coexisted. Hence, we examined the expression of transcription factors immunohistochemically to elucidate the role of the transcription factors in MEN1-associated hormone-producing pNETs. We observed homogeneous expressions of MafA and Pdx1 in insulinomas and Arx in glucagon-positive NET, respectively. Moreover, multiple hormone-positive NETs expressed several transcription factors heterogeneously. Collectively, our results suggested that transcription factors could play important roles in the production of specific hormones in MEN1-associated pNETs, similar to islet differentiation.
Learning points:To date, it has been shown that different hormone-producing tumors coexist in MEN1-associated pNETs; however, the underlying mechanism of the hormone production in MEN1-associated pNETs has not been well elucidated.
Although this case presented symptomatic hypoglycemia, several hormone-producing pNETs other than insulinoma also coexisted in the pancreas.
Immunohistochemical analysis showed MafA and Pdx1 expressions distinctly in insulinoma, and Arx expression particularly in a glucagon-positive NET, while a multiple hormone-positive NET expressed MafA, Pdx1 and Arx.
Collectively, clinicians should consider that several hormone-producing pNETs may coexist in a MEN1 case and examine both endocrinological and histopathological analysis of pNETs, regardless of whether symptoms related to the excess of hormones are observed or not.
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Indeterminate dendritic cell neoplasm of the skin: A 2-case report and review of the literature
Indeterminate dendritic cell neoplasm (IDCN) is an exceedingly rare and mostly cutaneous histiocytosis, frequently associated with other hematopoietic malignancies. We report 2 cases of multilesional cutaneous IDCN. A 55-year-old male with no associated malignancy and complete response to ultraviolet light therapy; and a 72-year-old male with chronic myelomonocytic leukemia (CMML). Both cases showed histiocytoid cytology, positivity for CD1a and no expression of Langerin or BRAFV600E. With our patients, the literature describes 79 cases of IDCNs, including 65 (82%) with only skin involvement, 7 cases (9%) with involvement of skin and a second site, 5 cases (6%) involving lymph nodes only, 1 splenic lesion and 1 systemic disease. Seventeen cases (22%) were associated with other hematopoietic malignancies, most commonly CMML (6 cases), follicular lymphoma (4 cases) and acute myeloid leukemia (3 cases). All IDCNs associated with myeloid malignancies were limited to the skin, while most cases associated with lymphoma were limited to lymph nodes. Reported responses of cutaneous lesions to ultraviolet light therapy are encouraging, while systemic chemotherapy is appropriate for clinically aggressive cases and treatment of associated malignancies. Recognition of the clinico-morphologic spectrum of IDCNs should prevent misdiagnoses and prompt investigation of possible associated neoplasms.
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TIMP-3 mRNA expression levels positively correlates with levels of miR-21 in in situ BC and negatively in PR positive invasive BC
Publication date: Available online 6 September 2017
Source:Pathology - Research and Practice
Author(s): Nina Petrovic, Ahmad Sami, Jelena Martinovic, Marina Zaric, Irina Nakashidze, Silvana Lukic, Snezana Jovanovic-Cupic
BackgroundBreast carcinomas (BC) belong to a heterogeneous group of malignant diseases. Correct categorization of BC based on molecular biomarkers has a very important role in deciding the proper course of therapy for each patient. It has been already shown that the decrease of TIMP metalloproteinase inhibitor 3 (TIMP-3) together with overexpression of microRNA-21 (miR-21) might be involved in the process of BC invasion. This is the first study that examined relationship among miR-21, TIMP-3 mRNA and TIPM-3 protein levels in BC groups formed according to invasiveness.MethodsIn this study, we used 46 breast cancer samples. Estrogen and progesterone receptor (ER, PR) protein levels were evaluated by immunohistochemistry (IHC) method. TIMP-3 mRNA expression was examined by two-step real-time quantitative PCR (qRT-PCR). Western blot analysis was performed for 16 samples.ResultsStatistically significant differences in TIMP-3 expression levels between invasive groups were discovered in ER positive (ER+) (p=0.015), Her-2 negative (p=0.026) subgroups, and patients without lymph-node metastasis (p=0.039). Interestingly, significant positive correlation was detected between miR-21 and TIMP-3 mRNA levels (P<0.001, ρ=0.949) in the group of in situ tumors. TIMP-3 mRNA expression levels highly negatively correlated with levels of miR-21 in PR+ invasive BCs (p=0.007, ρ=−0.641). TIMP-3 protein levels negatively correlated with miR-21 levels in pure invasive BCs.ConclusionThese data suggest that signaling pathways involved in formation and progression of BCs in groups formed according to invasiveness might be different. Our findings propose that TIMP-3 mRNA expression levels could be significant prognostic parameter, but within specific BC subtypes.
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Perceptual Differences between Novice and Professional Music Theater Singers
Publication date: Available online 6 September 2017
Source:Journal of Voice
Author(s): Lynn Maxfield, Brian Manternach
ObjectiveResearch examining contemporary commercial music styles of singing has increased significantly over the last 10 years. While acoustic analysis has helped determine which characteristics define various vocal genres, a discrepancy still exists in how those acoustic characteristics are perceived, described, and evaluated.MethodsThe current study recorded seven novice and four professional musical theater singers performing belt, legit, and mix vocal samples. Novice singers were defined as first- and second-year students in an undergraduate musical theater program, while professional singers were defined as having played at least one major role in a music theater production in regional Equity theaters. Five regional Equity casting directors listened to the recordings and rated each sample on the basis of style (belt versus legit) and tone quality (brassy versus fluty and bright versus dark). Results were compared across experience level (novice/professional) and pitch. Additionally, relationships between style (belt/legit) and quality (brassy/fluty, bright/dark) were examined.ResultsThe statistically significant correlation emerged between the raters' perceived singing style and the singers' indicated singing style. Auditors identified the style (belt/legit) more reliably for the professional singers than for novice singers, and ratings of other qualities varied significantly between raters.ConclusionsThe singers were successfully able to produce voicing styles that matched the perceptual expectations of the casting directors. Not surprisingly, professional singers were somewhat more successful in this regard than were the novices. There appears to be little consensus among the auditors, however, about which acoustical qualities define a belt, mix, or legit style.
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Testosterone inhibits the growth of prostate cancer xenografts in nude mice
Abstract
Background
Traditional beliefs of androgen's stimulating effects on the growth of prostate cancer (PCa) have been challenged in recent years. Our previous in vitro study indicated that physiological normal levels of androgens inhibited the proliferation of PCa cells. In this in vivo study, the ability of testosterone (T) to inhibit PCa growth was assessed by testing the tumor incidence rate and tumor growth rate of PCa xenografts on nude mice.
Methods
Different serum testosterone levels were manipulated in male nude/nude athymic mice by orchiectomy or inserting different dosages of T pellets subcutaneously. PCa cells were injected subcutaneously to nude mice and tumor incidence rate and tumor growth rate of PCa xenografts were tested.
Results
The data demonstrated that low levels of serum T resulted in the highest PCa incidence rate (50%). This PCa incidence rate in mice with low T levels was significantly higher than that in mice treated with higher doses of T (24%, P < 0.01) and mice that underwent orchiectomy (8%, P < 0.001). Mice that had low serum T levels had the shortest tumor volume doubling time (112 h). This doubling time was significantly shorter than that in the high dose 5 mg T arm (158 h, P < 0.001) and in the orchiectomy arm (468 h, P < 0.001).
Conclusion
These results indicated that low T levels are optimal for PCa cell growth. Castrate T levels, as seen after orchiectomy, are not sufficient to support PCa cell growth. Higher levels of serum T inhibited PCa cell growth.
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Proanthocyanidins prevent ethanol-induced cognitive impairment by suppressing oxidative and inflammatory stress in adult rat brain.
Excessive chronic alcohol consumption enhances brain oxidative and inflammatory stress, resulting in cognitive deficit. This study investigated the potential alleviating effects of proanthocyanidins (PACs) on ethanol-induced cognitive impairment and stress in brain regions including the prefrontal cortex, hippocampus, and amygdala. Adult male rats were administered saline, PACs, ethanol, or combinations of ethanol with different doses of PACs for 8 weeks. Then, the Morris water-maze test was performed. Thiobarbituric acid-reactive substances, superoxide dismutase activity, total antioxidant capacity, and nitric oxide were chosen as parameters of oxidative stress, whereas tumor necrosis factor-[alpha] and interleukin-1[beta] chosen as parameters of inflammatory stress. The results indicated that ethanol led to cognitive impairment along with enhanced oxidative and inflammatory stress in brain regions, whereas PACs per se had no significant effects. Moreover, coadministration with PACs in ethanol-treated rats dose dependently rescued cognitive impairment accompanied by suppressed oxidative and inflammatory stress in brain regions. Thus, the protective effects of PACs on ethanol-induced cognitive impairments may be because of their antioxidant and anti-inflammatory activities. (C) 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Treadmill exercise modifies dopamine receptor expression in the prefrontal cortex of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease.
Parkinson's disease (PD) is the second most common neurodegenerative disorder for which there is no cure. PD is a dopamine (DA)-deficit disorder marked by progressive motor and nonmotor disturbances, including cognitive impairment. Executive function (EF) is the most common subtype of cognitive impairment in PD and consists of deficits in number of processes including behavioral flexibility. The prefrontal cortex (PFC) is an important brain region subserving EF. Furthermore, DA plays a key neuromodulatory role in the PFC and altered DA neurotransmission is believed to contribute toward EF deficits in PD. The mechanisms underlying PFC dysfunction are not fully understood and there are no effective treatments for EF deficits in PD. Exercise is a promising therapeutic strategy that may exert beneficial effects on PFC function in PD. Our previous work suggests that exercise improves motor function and restores striatal DA-D2 receptor (DA-D2R) expression after DA depletion. This study builds upon our previous work by exploring whether exercise modulates PFC function, specifically DA levels and DA receptor expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mouse model of DA depletion. We found that exercise restores PFC DA levels, reverses the MPTP-induced increase in DA-D1R and decrease in DA-D4R, and exerts differential effects on D2Rs. The modest effect of exercise in PFC function may suggest that other types of exercise, such as those that are more skill based, would be required to target these cognitive behavioral circuits. (C) 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Abnormal modification of histone acetylation involved in depression-like behaviors of rats induced by chronically unpredicted stress.
Depression is a complex multifactorial mental disorder. Its etiology involves many factors such as social environments, genetics, and psychology. Recent studies have shown that epigenetic modification may be associated with depression. Histone acetylation is one of the main mechanisms of epigenetic modification and plays an important role in genetic expression. In this study, we investigated the role of histone acetylation in the depression-like behaviors of rats undergoing chronically unpredicted stress (CUS) by detecting the mRNA and protein expression of histone deacetylase 5, cAMP-response element-binding protein, and the level of histone acetylated modification of H3K14, H3K23, and H4K16 in the prefrontal cortex and hippocampus of the rats. The results showed that significantly increasing depression-like behaviors were observed with a decreasing histone acetylated modification level, especially on acytelated-H3K14, acytelated-H3K23, and acytelated-H4K16, upregulating histone deacetylase 5 expression and downregulating cAMP-response element-binding protein expression in CUS rats, compared with control rats. The results indicate that the decrease in the histone acetylation modification level may be partly involved in the mechanism of depression-like behaviors of rats induced by CUS. (C) 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Activation of [beta]-adrenoceptor facilitates active avoidance learning through enhancement of glutamate levels in the hippocampal dentate gyrus.
Long-term potentiation (LTP) is widely accepted as the best studied model for neurophysiological mechanisms that could underlie learning and memory formation. Despite a number of studies indicating that [beta]-adrenoceptors in the hippocampal dentate gyrus (DG) is involved in the modulation of learning and memory as well as LTP, few studies have used glutamate release as a visual indicator in awake animals to explore the role of [beta]-adrenoceptors in learning-dependent LTP. Therefore, in the present study, the effects of propranolol (an antagonist of [beta]-adrenoceptor) and isoproterenol (an agonist of [beta]-adrenoceptor) on extracellular concentrations of glutamate and amplitudes of field excitatory postsynaptic potential were measured in the DG region during active avoidance learning in freely moving conscious rats. In the control group, the glutamate level in the DG was significantly increased during the acquisition of active avoidance behavior and returned to basal level following extinction training. In propranolol group, antagonism of [beta]-adrenoceptors in the DG significantly reduced the change in glutamate level, and the acquisition of the active avoidance behavior was significantly inhibited. In contrast, the change in glutamate level was significantly enhanced by isoproterenol, and the acquisition of the active avoidance behavior was significantly accelerated. Furthermore, in all groups, the changes in glutamate level were accompanied by corresponding changes in field excitatory postsynaptic potential amplitude and active avoidance behavior. Our results suggest that activation of [beta]-adrenoceptors in the hippocampal DG facilitates active avoidance learning by modulations of glutamate level and synaptic efficiency in rats. (C) 2017 Wolters Kluwer Health | Lippincott Williams & Wilkins
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Tests of the sorption and olfactory 'fovea' hypotheses in the mouse.
The spatial distribution of receptors within sensory epithelia (e.g. retina and skin) is often markedly non-uniform to gain efficiency in information capture and neural processing. By contrast, odors, unlike visual and tactile stimuli, have no obvious spatial dimension. What need then could there be for either nearest-neighbor relationships or non-uniform distributions of receptor cells in the olfactory epithelium (OE)? Adrian (1942; 1950) provided the only widely debated answer to this question when he posited that the physical properties of odors, such as volatility and water solubility, determine a spatial pattern of stimulation across the OE that could aid odor discrimination. Unfortunately, despite its longevity, few critical tests of the 'sorption hypothesis' exist. Here we test the predictions of this hypothesis by mapping mouse OE responses using the electroolfactogram (EOG) and comparing these response 'maps' to computational fluid dynamics (CFD) simulations of airflow and odorant sorption patterns in the nasal cavity. CFD simulations were performed for airflow rates corresponding to quiet breathing and sniffing. Consistent with predictions of the sorption hypothesis, water soluble odorants tended to evoke larger EOG responses in the central portion of the OE than the peripheral portion. However, sorption simulation patterns along individual nasal turbinates for particular odorants did not correlate with their EOG response gradients. Indeed, the most consistent finding was a rostral-greater to caudal-lesser response gradient for all the odorants tested that is un explained by sorption patterns. The viability of the sorption and related olfactory 'fovea' hypotheses are discussed in light of these findings.
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Constitutive activity of 5-HT2c receptors is present following incomplete spinal cord injury but is not modified after chronic SSRI or baclofen treatment
Following spinal cord injury (SCI), reflexes become hyperexcitable, leading to debilitating muscle spasms and compromised motor function. Previous work has described adaptations in spinal systems that might underlie this hyperexcitability, including an increase in constitutively active 5-HT2C receptors in spinal motoneurons. That work, however, examined adaptations following complete transection SCI, whereas SCI in humans is usually anatomically and functionally incomplete. We therefore evaluated whether constitutive activity of 5-HT2C receptors contributes to reflex hyperexcitability in an incomplete compression model of SCI and to spasms in vitro and in vivo. Our results confirm that 5-HT2C receptor constitutive activity contributes to reflex excitability following incomplete SCI. We also evaluated whether constitutive activity could be altered by manipulating neural activity levels following SCI, testing the hypothesis that it reflects homeostatic processes acting to maintain spinal excitability. We decreased neural activity following SCI by administering baclofen and increased activity by administering the SSRI fluoxetine. We found that drug administration produced minimal alterations in in vivo locomotor function or reflex excitability. Similarly, we found that neither baclofen nor fluoxetine altered the contribution of constitutively active 5-HT2C receptors to reflexes following SCI, although the contribution of 5-HT2C receptors to reflex activity was altered following SSRIs. These results confirm the importance of constitutively activity in 5-HT2C receptors to spinal hyperexcitability following SCI in the clinically relevant case of incomplete SCI, but suggest that this activity is not driven by homeostatic processes that act to maintain overall levels of spinal excitability.
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The effect of prior knowledge and intelligibility on the cortical entrainment response to speech
It has been suggested that cortical entrainment plays an important role in speech perception by helping to parse the acoustic stimulus into discrete linguistic units (Giraud & Poeppel, 2012). However, the question of whether the entrainment response to speech depends on the intelligibility of the stimulus remains open. Studies addressing this question of intelligibility have, for the most part, significantly distorted the acoustic properties of the stimulus to degrade the intelligibility of the speech stimulus, making it difficult to compare across "intelligible" and "unintelligible" conditions. To avoid these acoustic confounds, we follow Millman et al. (2015) and use priming to manipulate the intelligibility of vocoded speech. We use EEG to measure the entrainment response to vocoded target sentences that are preceded by natural-speech (non-vocoded) prime sentences that are either valid (match the target) or invalid (do not match the target). For unintelligible speech, valid primes have the effect of restoring intelligibility (Remez et al., 1980). We compared the effect of priming on the entrainment response for both 3-channel (unintelligible) and 16-channel (intelligible) speech (Loizou et al., 1999). We observed a main effect of priming, suggesting that the entrainment response depends on prior knowledge, but not a main effect of vocoding (16-channel vs. 3-channel). Furthermore, we found no difference in the effect of priming on the entrainment response to 3-channel and 16-channel vocoded speech, suggesting that for vocoded speech entrainment response does not depend on intelligibility.
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Integra® as a single-stage dermal regeneration template in reconstruction of large defects of the scalp
Publication date: Available online 6 September 2017
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): G. Vithlani, P. Santos Jorge, E. Brizman, K. Mitsimponas
Dermal regeneration templates may be used in the reconstruction of large defects after the excision of cutaneous malignancies. We describe the successful use of Integra® (Integra Lifesciences Corporation, Plainsboro, NJ, USA) as a single-stage regeneration template after the excision of multiple lesions of the scalp with a surface area of 96.7cm2. Second-stage epidermal autografting was precluded because of an unforeseen deterioration in the patient's condition, and the wound re-epithelialised over a period of six months. To the best of our knowledge there are no published reports on the use of this procedure after excision of cutaneous malignancies of the scalp of similar dimensions, without subsequent epidermal autografting (Johnson and Wong, 2016).1
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Acupuncture for temporomandibular joint syndrome
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): W. Rodgers
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Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study
Summary
Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF V600E mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF V600 mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.
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Perceptual Differences between Novice and Professional Music Theater Singers
Source:Journal of Voice
Author(s): Lynn Maxfield, Brian Manternach
ObjectiveResearch examining contemporary commercial music styles of singing has increased significantly over the last 10 years. While acoustic analysis has helped determine which characteristics define various vocal genres, a discrepancy still exists in how those acoustic characteristics are perceived, described, and evaluated.MethodsThe current study recorded seven novice and four professional musical theater singers performing belt, legit, and mix vocal samples. Novice singers were defined as first- and second-year students in an undergraduate musical theater program, while professional singers were defined as having played at least one major role in a music theater production in regional Equity theaters. Five regional Equity casting directors listened to the recordings and rated each sample on the basis of style (belt versus legit) and tone quality (brassy versus fluty and bright versus dark). Results were compared across experience level (novice/professional) and pitch. Additionally, relationships between style (belt/legit) and quality (brassy/fluty, bright/dark) were examined.ResultsThe statistically significant correlation emerged between the raters' perceived singing style and the singers' indicated singing style. Auditors identified the style (belt/legit) more reliably for the professional singers than for novice singers, and ratings of other qualities varied significantly between raters.ConclusionsThe singers were successfully able to produce voicing styles that matched the perceptual expectations of the casting directors. Not surprisingly, professional singers were somewhat more successful in this regard than were the novices. There appears to be little consensus among the auditors, however, about which acoustical qualities define a belt, mix, or legit style.
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Effects of low-to-moderate alcohol supplementation on urinary estrogen metabolites in postmenopausal women in a controlled feeding study
Abstract
Heavy alcohol drinking is associated with increased breast cancer risk, but associations with low-to-moderate alcohol consumption are less clear and the biological mechanisms are not well defined. The objective of this study was to evaluate the effects of 8 weeks of low (15 g/d) and moderate (30 g/d) alcohol ingestion on concentrations of 15 urinary estrogen metabolites (EMs) in postmenopausal women (n = 51) in a controlled feeding study with a randomized crossover design. Compared to no alcohol, 15 g/day for 8 weeks had no effect on urinary EMs. However, compared to no alcohol, 30 g/day for 8 weeks decreased urinary 2-hydroestrone (2-OHE1) by 3.3% (P = 0.055) and increased 16-epiestriol (16-EpiE3) by 26.6% (P = 0.037). Trends for reduced urinary 2-OHE1 (P = 0.045), reduced ratio of 2-OH:16OH pathways (P = 0.008), and increased 16-EpiE3 (P = 0.035) were observed as alcohol ingestion increased from 0 g to 15 g to 30 g/d. Moderate alcohol consumption for 8 weeks had modest effects on urinary concentrations of 2-OHE1 and 16-EpiE3 among postmenopausal women in a carefully controlled feeding study.
Recent evidence indicates that postmenopausal breast cancer risk increases with higher levels of 16-EpiE3 and decreases with lower levels of 2-OHE1 in different prospective cohorts. Since moderate alcohol consumption in our study of postmenopausal women increased 16-EpiE3 and lowered 2-OHE1, these results imply that moderate drinking may have dual effects on later breast cancer development, but this finding needs confirmation.
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miR-199a-3p and miR-214-3p improve the overall survival prediction of muscle-invasive bladder cancer patients after radical cystectomy
Abstract
To improve the clinical decision-making regarding further treatment management and follow-up scheduling for patients with muscle-invasive bladder cancer (MIBC) after radical cystectomy (RC), a better prediction accuracy of prognosis for these patients is urgently needed. The objective of this study was to evaluate the validity of differentially expressed microRNAs (miRNAs) based on a previous study as prognostic markers for overall survival (OS) after RC in models combined with clinicopathological data. The expression of six miRNAs (miR-100-5p, miR-130b-3p, miR-141-3p, miR-199a-3p, miR-205-5p, and miR-214-3p) was measured by RT-qPCR in formalin-fixed, paraffin-embedded tissue samples from 156 MIBC patients who received RC in three urological centers. Samples from 2000 to 2013 were used according to their tissue availability, with follow-up until June 2016. The patient cohort was randomly divided into a training (n = 100) and test set (n = 56). Seventy-three samples from adjacent normal tissue were used as controls. Kaplan–Meier, univariate and multivariate Cox regression, and decision curve analyses were carried out to assess the association of clinicopathological variables and miRNAs to OS. Both increased (miR-130b-3p and miR-141-3p) and reduced (miR-100-5p, miR-199a-3p, and miR-214-3p) miRNA expressions were found in MIBC samples in comparison to nonmalignant tissue samples (P < 0.0001). miR-199a-3p and miR-214-3p were independent markers of OS in Cox regression models with the significant clinicopathological variables age, tumor status, and lymph node status. The prediction model with the clinicopathological variables was improved by these two miRNAs in both sets. The predictive benefit was confirmed by decision curve analysis. In conclusion, the inclusion of both miRNAs into models based on clinical data for the outcome prediction of MIBC patients after RC could be a valuable approach to improve prognostic accuracy.
This study demonstrated the usefulness of the microRNAs miR-199a-3p and miR-214-3p in formalin-fixed, paraffin-embedded tissue samples from patients with muscle-invasive bladder cancer after radical cystectomy as predictive biomarkers of overall survival. In this aspect, the miRNAs combined with traditional clinicopathological factors improved the prediction accuracy for overall survival and could be useful to facilitate clinical decision making for further treatment strategies.
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Long-term outcomes in patients treated with proton therapy for localized prostate cancer
Abstract
The aim of this retrospective study was to report long-term clinical outcomes in patients treated with proton therapy (PT) for localized prostate cancer. Between 2001 and 2014, 1375 consecutive patients were treated with PT. Patients were classified into prognostic risk groups based on the National Comprehensive Cancer Network criteria. Freedom from biochemical relapse (FFBR), cancer-specific survival (CSS) and incidence of late gastrointestinal (GI)/genitourinary (GU) toxicities were calculated. Multivariate analysis was performed to identify clinical prognostic factors for FFBR and late toxicities. The median follow-up period was 70 months (range, 4–145 months). In total, 99% of patients received 74 Gy (relative biologic effectiveness [RBE]); 56% of patients received neoadjuvant androgen deprivation therapy. For the low-, intermediate-, high-, and very high-risk groups, 5-year FFBR was 99% (95% confidence intervals [CI], 96–100%), 91% (95% CI, 88–93%), 86% (95% CI, 82–89%), and 66% (95% CI, 53–76%), respectively, and 5-year CSS was 100% (95% CI, 100–100%), 100% (95% CI, 100–100%) , 99% (95% CI, 97–100%), and 95% (95% CI, 94–98%), respectively. Patient age, T classification, Gleason score, prostate-specific antigen, and percentage of positive cores were significant prognostic factors for FFBR. Grade 2 or higher GI and GU toxicities were 3.9% and 2.0%. Patient age was a prognostic factor for both late GI and GU toxicities. This study represents the largest cohort of patients treated with PT for localized prostate cancer, with the longest follow-up to date. Our results demonstrate that the biochemical control of PT is favorable particularly for high- and very high-risk patients with lower late genitourinary toxicity and indicates the necessity of considering patient age in the treatment protocols.
Proton therapy for localized prostate cancer demonstrates favorable biochemical control particularly for high- and very high-risk patients and a lower incidence of late genitourinary toxicity. Our findings indicate the necessity of considering patient age in the treatment protocols.
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Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992–2011
Abstract
Women diagnosed with cutaneous melanoma have a survival advantage compared to men, which has been hypothesized to be due to difference in behavior and/or biology (sex hormones). It remains controversial whether this advantage is dependent on age or stage of disease. We sought to compare melanoma-specific survival between females in pre, peri, and postmenopausal age groups to males in the same age group, adjusting for stage of disease. This is a retrospective population-based cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed from 1 January 1992 through 31 January 2011 with primary invasive cutaneous melanoma were included in our cohort. Melanoma-specific survival was the main outcome studied. Of the 106,511 subjects that were included, 45% were female. Females in all age groups (18–45, 46–54, and ≥55) with localized and regional disease, were less likely to die from melanoma compared to males in the same age group. Among patients with localized and regional disease, the relative risk of death due to melanoma increased with advancing age at diagnosis; this increase was more pronounced among females than males. In contrast, we observed no female survival advantage among patients with distant disease and no effect of age on relative risk of death from melanoma. Females with localized and regional melanoma have a decreased risk of death compared to males within all age groups. Our data show no differences in survival between men and women with metastatic melanoma, indicating that the influence of sex on survival is limited to early stage disease but not confined to pre or perimenopausal age groups.
In local and regional cutaneous melanoma, women of all ages have a significant survival benefit over men. However, data from the SEER registry indicate that this female survival advantage is decreased when the disease is metastatic, suggesting an unknown protective biology is lost in distant disease.
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Prognostic effect of parotid area lymph node metastases after preliminary diagnosis of nasopharyngeal carcinoma: a propensity score matching study
Abstract
Parotid area lymph node (PLN) metastasis in nasopharyngeal carcinoma (NPC) is rare, and its prognosis remains largely unknown. Our study aimed to investigate the prognostic value and staging categories of PLN metastasis in patients with NPC and treated with intensity-modulated radiation therapy (IMRT), to provide a reference for clinical treatment for NPC with PLN metastasis. Records for 1616 untreated NPC patients without distant metastasis was retrospectively reviewed. All patients underwent magnetic resonance imaging (MRI) examination prior to treatment and then received IMRT as their primary treatment. Forty-five NPC patients (2.8%) showed initial PLN metastasis on follow-up MRI. PLN metastasis was significantly associated with the N classification and clinical stage. Univariate analysis showed that PLN metastasis had an unfavorable influence on overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and regional relapse-free survival (RRFS) in NPC patients. Using propensity score matching (PSM) to calibrate selection bias and confounding bias, it was observed that PLN metastasis remained an adverse prognostic factor for OS, PFS, DMFS, and RRFS. Furthermore, the 5-year DMFS and RRFS curves for PLN metastasis were significantly separated from that for N2 disease but crossed that for N3 disease. Therefore, PLN metastasis was found to be an adverse prognostic factor for NPC and to be associated with the same DMFS as N3 disease. Therefore, more aggressive therapeutic strategies consistent with those for N3 disease are recommended for NPC with PLN metastasis to reduce distant metastasis.
PLN metastasis was found to be an adverse prognostic factor for NPC and to be correlated with the same DMFS as N3 disease.
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Prevention of Mandible Reconstruction Plate Exposure by Costal Cartilage Wrapping
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Optimizing Aesthetic Outcomes in Delayed Breast Reconstruction
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Reply: What Is the Ideal Neophallus? Response to Frey et al. (2017): An Update on Genital Reconstruction Options for the Female-to-Male Transgender Patient: A Review of the Literature
Patient-Reported Disability Measures Do Not Correlate with Electrodiagnostic Severity in Carpal Tunnel Syndrome
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Double-Pedicled Free Deep Inferior Epigastric Perforator Flap for the Coverage of Thigh Soft-Tissue Defect
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Meta-Analysis of Long Thoracic Nerve Decompression and Neurolysis Versus Muscle and Tendon Transfer Operative Treatments of Winging Scapula
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Wide Awake Trapeziectomy for Thumb Basal Joint Arthritis
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Dual Vascular Free Anterolateral Thigh Flap
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Acellular Dermal Matrix: Treating Periocular Melanoma in a Patient with Xeroderma Pigmentosa
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Deltopectoral and Pectoralis Musculocutaneous Flap Technique for Cervical Esophageal Reconstruction after Free-Jejunal-Flap Necrosis
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Interosseous Membrane Release for Long-Standing Upper Limb Lymphedema: A Procedure Often Neglected
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Evaluation of a Novel Hybrid Viable Bioprosthetic Mesh in a Model of Mesh Infection
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Mastectomy Flap Thickness and Complications in Nipple-Sparing Mastectomy: Objective Evaluation using Magnetic Resonance Imaging
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Optimization of an Arterialized Venous Fasciocutaneous Flap in the Abdomen of the Rat
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Aesthetic Female-to-Male Chest Transformation: Power of Combining Modified Mastectomy with a Pectoral Implant
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Mucosal Perfusion Preservation by a Novel Shapeable Tissue Expander for Oral Reconstruction
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Carpal Tunnel Syndrome in the Setting of Mucopolysaccharidosis II (Hunter Syndrome)
Background: Carpal tunnel syndrome (CTS) is a rare finding in children, but heavily represented in pediatric patients with mucopolysaccharidoses. Diagnosis is a challenge due to lack of the stereotypical symptomatic complaints and relies on examination and objective nerve conduction studies. Methods: We present a case of delayed presentation of CTS in a 12-year-old boy with Hunter syndrome, followed by a review of the literature. Results: Patient Z.D. presented with minimal reported CTS symptoms but advanced median nerve damage on electromyography. He underwent bilateral carpal tunnel release with median nerve neurolysis and flexor tenosynovectomies. Intraoperative examination demonstrated the presence of a "waist sign" of the median nerve and moderate flexor tenosynovial hypertrophy bilaterally. Parents reported mild subjective improvement of dexterity and fine motor skills postoperatively. Conclusion: To optimize functional outcome, routine screening for CTS and intervention at an early age are emphasized in the mucopolysaccharidoses population.
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A Proposal for Updated Standards of Photographic Documentation in Aesthetic Medicine
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Lymphedema of the Lower Extremities due to Refractory Malignant Lymphoma Treated by Lymphaticovenous Anastomosis
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Prioritization for Plastic Surgery Procedures Aimed to Improve Quality of Life: Moral Considerations
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Anxiety and pain related to mandibular block injections: comparison of self-reported measures and physiological response.
Publication date: Available online 6 September 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Jacco G. Tuk, Jerome A. Lindeboom, Linda Hoogendoorn, Byron W. Taylor, Arjen van Wijk
ObjectiveThe aim of this study was to determine whether patients with a pain score ≥7 (high pain group) after a mandibular block injection had a higher physiological response than patients with scores <7 (low pain group).Study Design: Prior to oral surgery, patients (n = 66) filled out questionnaires to measure anxiety and expected pain. Questionnaires also assessed the patients' experiences with dental injections and dental anxiety, as well as their emotional state and intensity of anxiety. Before, during, and after the injection, physiological responses were measured using the Nexus-10. Patients were then asked about the pain and anxiety they experienced.ResultsThe mean score for pain experienced was 3.45 (SD 2.17) on an 11-point rating scale. Eight patients (12.1%) experienced high injection pain. There was a significant increase in mean sweat secretion and a significant decrease in mean respiration between the relaxing and injection phases. There was a significant positive relationship between experienced anxiety and mean heart rate during the injection phase. No significant difference was found in physiological response between patients who experienced high vs. low pain.ConclusionReported pain was not associated with the physiological response of patients receiving mandibular block injections.
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Radiation-related caries assessment through the international caries detection and assessment system and the post-radiation dental index
Publication date: Available online 6 September 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Natalia Rangel Palmier, Ana Carolina Prado Ribeiro, Jéssica Montenegro Fonsêca, João Victor Salvajoli, Pablo Agustin Vargas, Marcio Ajudarte Lopes, Thaís Bianca Brandão, Alan Roger Santos-Silva
Purpose: Although radiation-related caries (RRC) are a well-known toxicity of head and neck radiotherapy, a clinical classification system for RRC has not yet been clinically validated. Therefore, the aim of this study was to assess if the International Caries Detection and Assessment System (ICDAS) and the Post-Radiation Dental Index (PRDI) were viable methods for the assessment of RRC. Methods: Clinicopathological data and intraoral digital photographs of 60 patients (833 teeth) affected by RRC were assessed and classified according to the ICDAS and PRDI criteria. Results: A total of 814 (97.7%) teeth presented RRC lesions ranging from early stage to complete tooth destruction. Mean scores for the whole sample were 5 for ICDAS and 3 for PRDI, indicating that RRC were diagnosed predominately in late stages. ICDAS and PRDI criteria underestimate the clinical expressivity of RRC by not including the whole qualitative clinical spectrum of RRC, such as enamel cracks, delamination, dental crown amputation, surface color alterations, and atypical lesions topography (incisal/cuspal caries). Conclusion: ICDAS and PRDI may not be considered viable for the assessment of RRC. The development of a specific clinical classification system is urgently needed to help clinicians recognize the peculiar patterns of RRC, particularly in incipient cases.
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23 year-old female with a painless left mandibular swelling
Publication date: Available online 6 September 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Alia Khan, Scott M. Peters, Chang Han, Angela J. Yoon, Elizabeth M. Philipone
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AAOM clinical practice statement
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
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Mandibular embryonal rhabdomyosarcoma with cartilaginous metaplasia: report of a case and review of literature
Publication date: Available online 6 September 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Scott M. Peters, Tim Kunkle, Michael A. Perrino, Elizabeth M. Philipone, Angela J. Yoon
Rhabdomyosarcoma (RMS) is a malignant tumor of the skeletal muscle origin that frequently involves the head and neck region. It represents the second most common pediatric soft tissue sarcoma, and accounts for 3% of all childhood cancers. Herein, we report a case of embryonal rhabdomyosarcoma presenting as a right sided facial swelling in a 7-year-old boy. Histologically, the tumor consisted of classic embryonal rhabdosarcomatous areas with metaplastic cartilage both in the initial biopsy and final resection specimen. Cartilaginous metaplasia arising in the background of RMS is a rare finding, thereby raising a diagnostic challenge. To the best of our knowledge, this represents the first case of a RMS with cartilaginous metaplasia in the oral cavity.
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Virtual Reality: The Next Frontier of Audiology
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Embracing Robotics for CIs
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Symptom: Failed Cochlear Implant
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Advancing Tinnitus Awareness Through Animation
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Heroes With Hearing Loss®
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Animal-Assisted Interventions in Audiology
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Feel the Vibrations: Understanding the Hearing-Emotion Connection
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Diffusion Tensor Imaging of the ‘Auditory Connectome’
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Tips for Traveling With Hearing Loss
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Barriers And Opportunities in Rural Hearing Health
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Preventive Care for Dementia and Hearing Loss
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Preparing for Relational Audiology: Things I Wish Someone Told Me Before I Started Working in Pediatric Audiology
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Humanitarian Outreach in Otology
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Hearing Loss and Misunderstandings
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Manufacturers News
Primary epithelioid hemangioendothelioma of the dorsal spine: A review
Neurology India 2017 65(5):1180-1186
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Memorable clinical experiences, all in one year at Queen Square, London, United Kingdom (1968-1969): A tribute to Neurology legends
Neurology India 2017 65(5):944-947
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Magnetic resonance imaging findings in heat stroke-related encephalopathy
Neurology India 2017 65(5):1146-1148
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Dr. Harry M. Zimmerman (1901 – 1995): Neuropathologist who autopsied Dr. Harvey Cushing, and his interactions with Indian colleagues
Neurology India 2017 65(5):948-963
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MRI findings in a fetus with a tight cord around the neck
Neurology India 2017 65(5):1130-1131
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The Knowledge of South African Men Relating to Cervical Cancer and Cervical Cancer Screening
Abstract
Cervical cancer is the second most common cancer in South African women, but the most common cancer in Black women. Despite having a national cervical cancer screening programme, most women present with advanced disease. Men play a role in cervical cancer as the HPV, the major cause of cervical cancer, is sexually transmitted. The purpose of our study was to describe the knowledge men, living in Muldersdrift, had about cervical cancer, cervical cancer screening and the cervical cancer screening programme and how they preferred to be taught about these health issues. We used a survey design and convenience sampling to select 101 men older than 18 years (n = 101). A pretested self-developed questionnaire was used as the data collection instrument, and the data were analyzed using the SPSS version 22-computer program and quantitative content analyses. The Fischer's exact test measured associations between variables (p = 0.05). The ages of the sample (n = 101) ranged from 18 to 92 years; most were from the Zulu cultural group, unemployed and unmarried. The majority (66.3%, n = 67) had not heard of cervical cancer, the cervical cancer screening programme (60.4%, n = 61) or the Pap smear (67.3%, n = 68). Age and educational level did not influence having ever heard of these health issues. HPV infection was the most well-known risk factor, and the very late symptoms of cervical cancer were the least known. Most men preferred to be educated in a group, which provided a practical, feasible and cost effective way of educating men living in this community about these health issues.
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Carvacrol Induces Reactive Oxygen Species (ROS)-mediated Apoptosis Along with Cell Cycle Arrest at G0/G1 in Human Prostate Cancer Cells.
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Carvacrol Induces Reactive Oxygen Species (ROS)-mediated Apoptosis Along with Cell Cycle Arrest at G0/G1 in Human Prostate Cancer Cells.
Nutr Cancer. 2017 Sep 05;:1-13
Authors: Khan F, Khan I, Farooqui A, Ansari IA
Abstract
Carvacrol, a major monoterpenoid phenol from Origanum and Thymus species, has been shown to exhibit antiproliferative and anticancer properties in a few recent studies. Nevertheless, detailed mechanism of the action of this compound in prostate cancer has not been elucidated yet. Therefore, in the current study, we examined the anticancer activity and mechanism of the action of carvacrol against human prostate cancer cells. It was found that the treatment of DU145 cells with carvacrol decreased cell viability in a concentration and time-dependent manner. The antiproliferative action of carvacrol leads to induction of apoptosis as confirmed by nuclear condensation, Annexin V-FITC/PI positive cells, and caspase-3 activation. In addition, carvacrol augmented reactive oxygen species generation and disruption in the mitochondrial membrane potential which has not been reported in the previous studies of carvacrol with prostate cancer. Moreover, carvacrol-induced apoptosis of prostate cancer cells was also accompanied by significant amount of growth arrest at the G0/G1 phase of the cell cycle which has also not been documented previously. To sum up, this study has established that carvacrol could be a promising chemotherapeutic agent and could have a direct practical implication and translational relevance to prostate cancer patients as Origanum consumption may retard prostate cancer progression.
PMID: 28872904 [PubMed - as supplied by publisher]
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In vitro Biological Effects of Sulforaphane (SFN), Epigallocatechin-3-gallate (EGCG), and Curcumin on Breast Cancer Cells: A Systematic Review of the Literature.
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In vitro Biological Effects of Sulforaphane (SFN), Epigallocatechin-3-gallate (EGCG), and Curcumin on Breast Cancer Cells: A Systematic Review of the Literature.
Nutr Cancer. 2017 Sep 05;:1-10
Authors: Gianfredi V, Nucci D, Vannini S, Villarini M, Moretti M
Abstract
Much of the recent research in neoplasia has been focusing on the epigenetics of cancer cells, particularly as regards the search for potential molecular biomarkers that could be used for early diagnosis, effective treatment, and prognosis of several types of cancer. Carcinogenesis often starts with mutations in oncogenes and tumor suppressor genes, and it leads to anomalies in cellular processes as vital as cell cycle regulation and apoptosis. Because malignant changes arise as a result of genetic as well as epigenetic mechanisms, one possible means of intervention involves reprogramming gene expression, so as to-at least in part-revert the molecular alterations. DNA methylation and demethylation, acetylation and deacetylation of histones, and microRNAs are a few examples of the epigenetic mechanisms responsible for tumor development and progression. Many biologically active compounds present in food-including sulforaphane, curcumin, and epigallocatechin-have been found to modulate those processes. We here systematically review information on the effects of such bioactive dietary compounds on human breast cancer cell lines, and explore the mechanisms underlying those effects with a view to their potential therapeutic application.
PMID: 28872903 [PubMed - as supplied by publisher]
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Developing Item Response Theory-Based Short Forms to Measure the Social Impact of Burn Injuries
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Molly Marino, Emily C. Dore, Pengsheng Ni, Colleen M. Ryan, Jeff C. Schneider, Amy Acton, Alan M. Jette, Lewis E. Kazis
ObjectiveTo develop self-reported short forms for the LIBRE Profile.DesignParticipants were selected for inclusion in the short forms based upon the item parameters of discrimination and average difficulty. Test information function, as well as floor and ceiling effects, were evaluated for both the full item bank and the short forms.SettingParticipants were recruited were from the Phoenix Society (a support network for burn survivors), peer support networks, social media, and mailings.Participants601 burn survivors over 18 years of age in North America.InterventionsnoneMain Outcome MeasuresThe LIBRE-ProfileResultsTen-item short forms were developed to cover the six LIBRE Profile scales: Relationships with Family & Friends, Social Interactions, Social Activities, Work & Employment, Romantic Relationships, and Sexual Relationships. Ceiling effects were ≤15% for all scales; floor effects were all <1%. The marginal reliability of the short forms ranged from 0.85-0.89.ConclusionsThe LIBRE Profile-Short Forms demonstrated credible psychometric properties. The short form version provides a viable alternative to administering the LIBRE Profile when resources do not allow for computer/internet access. The full item bank, Computerized Adaptive Test, and short forms are all scored along the same metric and therefore scores are comparable regardless of mode of administration.
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Ulnar Nerve Cross-sectional Area for the Diagnosis of Cubital Tunnel Syndrome: A Meta-analysis of Ultrasonographic Measurements
Publication date: Available online 6 September 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Ke-Vin Chang, Wei-Ting Wu, Der-Sheng Han, Levent Özçakar
ObjectiveThis meta-analysis aimed to examine the performance of sonographic cross-sectional area (CSA) measurements, in the diagnosis of cubital tunnel syndrome (CuTS).Data sourceElectronic databases, comprising of PubMed and Embase, were searched for the pertinent literature before July 2017.Study selectionFourteen trials comparing the ulnar nerve CSA measurements between participants, with and without CuTS, were included.Data extractionStudy design, participants' demographics, diagnostic reference of CuTS and methods of CSA measurement.Data synthesisAmong different elbow levels, the between-group difference in CSA was the largest at the medial epicondyle [6.0 mm2 (95% confidence interval [CI]: 4.5-7.4)]. The pooled mean CSA from the healthy participants was 5.5 mm2 (95%CI: 4.4-6.6) at the arm level, 7.4 mm2 (95% CI: 6.7-8.1) at the cubital tunnel inlet, 6.6 mm2 at the medial epicondyle (95% CI: 5.9-7.2), 7.3 mm2 (95%CI: 5.6-9.0) at the cubital tunnel outlet, and 5.5 mm2 (95% CI: 4.7-6.3) at the forearm level. The sensitivity, specificity, and diagnostic odds ratios pooled from 5 studies, using 10 mm2 as the cut-off point, were 0.85 (95% CI: 0.78-0.90), 0.91 (95% CI: 0.86-0.94), and 53.96 (95% CI: 14.84-196.14), respectively.ConclusionThe ulnar nerve CSA measured by US imaging is useful for the diagnosis of CuTS, and is most significantly different between patients and controls at the medial epicondyle. As the ulnar nerve CSA in normal subjects, at various locations, rarely exceeds 10 mm2, this value can be considered as a cut-off point to diagnose ulnar nerve entrapment at the elbow region.
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Comparative NMR and NIRS Analysis of Oxygen Dependent Metabolism in Exercising Finger Flexor Muscles
Muscle contraction requires the physiology to adapt rapidly to meet the surge in energy demand. To investigate the shift in metabolic control, especially between oxygen and metabolism, researchers often depend on near infrared spectroscopy (NIRS) to measure non-invasively the tissue O2. Because NIRS detects the overlapping myoglobin (Mb) and hemoglobin (Hb) signals in muscle, interpreting the data as an index of cellular or vascular O2 requires deconvoluting the relative contribution. Currently, many in the NIRS field ascribe the signal to Hb. In contrast, 1H NMR has only detected the Mb signal in contracting muscle, and comparative NIRS and NMR experiments indicate a predominant Mb contribution. The present study has examined the question of the NIRS signal origin by measuring simultaneously the 1H, 31P NMR, and NIRS signals in finger flexor muscles during the transition from rest to contraction, recovery, ischemia, and reperfusion. The experiment results confirm a predominant Mb contribution to the NIRS signal from muscle. Given the NMR and NIRS corroborated changes in the intracellular O2, the analysis shows that at the onset of muscle contraction, O2 declines immediately and reaches new steady states as contraction intensity rises. Moreover, lactate formation increases even under quite aerobic condition.
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The in vitro zebrafish heart as a model to investigate the chronotropic effects of vapor anesthetics
In addition to their intended clinical actions, all general anesthetic agents in common use have detrimental intra- and post-surgical side effects on organs and systems including the heart. The major cardiac side effect of anesthesia is bradycardia, which increases the probability of insufficient systemic perfusion during surgery. These side effects also occur in all vertebrate species so far examined, but the underlying mechanisms are not clear. The zebrafish heart is a powerful model for studying cardiac electrophysiology, employing the same pacemaker system and neural control as do mammalian hearts. In this study isolated zebrafish hearts were significantly bradycardic during exposure to the vapor anesthetics sevoflurane (SEVO), desflurane (DES) and isoflurane (ISO). Bradycardia induced by DES and ISO continued during pharmacological blockade of the intracardiac portion of the autonomic nervous system, but the chronotropic effect of SEVO was eliminated during blockade. Bradycardia evoked by vagosympathetic nerve stimulation was augmented during DES and ISO exposure; nerve stimulation during SEVO exposure had no effect. Together these results support the hypothesis that the cardiac chronotropic effect of SEVO occurs via a neurally mediated mechanism while DES and ISO act directly upon cardiac pacemaker cells via an as yet unknown mechanism.
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Insulin Sensitivity, Leptin, Adiponectin, Resistin, and Testosterone in Adult Male and Female Rats After Maternal-Neonatal Separation and Environmental Stress
Care of premature infants often requires parental and caregiver separation particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented with external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]), plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults with prior neonatal hypoxia allowing spontaneous hypothermia Exposure of neonates to daily hypoxia while preventing spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines, and that our rat model of prematurity with hypoxia with the prevention of hypothermia alters adult testosterone dynamics.
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Circadian variability of body temperature responses to methamphetamine
Vital parameters of living organisms exhibit circadian rhythmicity. Although rats are nocturnal animals, most of the studies involving rats are performed during the day. The objective of this study was to examine the circadian variability of the body temperature responses to methamphetamine (Meth). Body temperature was recorded in male Sprague-Dawley rats received Meth (1 or 5 mg/kg) or saline at 10am or 10pm. The baseline body temperature at night was 0.8ºC higher than during the day. Both during the day and at night 1 mg/kg of Meth induced monophasic hyperthermia. However, the maximal temperature increase at night was 50% smaller than during the daytime. Injection of 5 mg/kg of Meth during the daytime caused a delayed hyperthermic response. In contrast, the same dose at night produced responses with a tendency towards a decrease of body temperature. Using mathematical modeling, we previously showed that the complex dose-dependence of the daytime temperature responses to Meth results from an interplay between inhibitory and excitatory drives. Here, using the model, we explain the suppression of the hyperthermia in response to Meth at night. First, we found that the baseline activity of the excitatory drive is greater at night. It appears partially saturated, and, thus, is additionally activated by Meth to a lesser extent. Therefore, the excitatory component causes lesser hyperthermia or becomes overpowered by the inhibitory drive in response to the higher dose. Second, at night the injection of Meth results in reduction of the equilibrium body temperature leading to gradual cooling counteracting hyperthermia.
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Hemoglobin polymerization via disulfide bond formation in the hypoxia-tolerant turtle Trachemys scripta: implications for antioxidant defense and O2 transport
The ability of many reptilian hemoglobins (Hbs) to form high-molecular weight polymers, albeit known for decades, has not been investigated in detail. Given that turtle Hbs often contain a high number of cysteine (Cys), potentially contributing to the red blood cell defense against reactive oxygen species, we have examined whether polymerization of Hb could occur via intermolecular disulfide bonds in red blood cells of freshwater turtle Trachemys scripta, a species that is highly tolerant of hypoxia and oxidative stress. We find that one of the two Hb isoforms of the hemolysate, HbA, is prone to polymerization in vitro into linear flexible chains of different size that are visible by electron microscopy, but not the HbD isoform. Polymerization of purified HbA is favored by hydrogen peroxide, a main cellular reactive oxygen species and a thiol oxidant, and inhibited by thiol reduction and alkylation, indicating that HbA polymerization is due to disulfide bonds. By using mass spectrometry, we identify Cys5 of the αA subunit of HbA as specifically responsible for forming disulfide bonds between adjacent HbA tetramers. Polymerization of HbA does not affect oxygen affinity, cooperativity and sensitivity to the allosteric cofactor ATP, indicating that HbA is still fully functional. Polymers also form in T. scripta blood after exposure to anoxia but not normoxia, indicating that they are of physiologically relevance. Taken together, these results show that HbA polymers may form during oxidative stress and that Cys5αA of HbA is a key element of the antioxidant capacity of turtle red blood cells.
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"Atypical" Pleomorphic Lipomatous Tumor: A Clinicopathologic, Immunohistochemical and Molecular Study of 21 Cases, Emphasizing its Relationship to Atypical Spindle Cell Lipomatous Tumor and Suggesting a Morphologic Spectrum (Atypical Spindle Cell/Pleomorphic Lipomatous Tumor).
The classification of the until recently poorly explored group of atypical adipocytic neoplasms with spindle cell features, for which recently the term atypical spindle cell lipomatous tumor (ASLT) has been proposed, remains challenging. Recent studies have proposed ASLT as a unique entity with (in at least a significant subset of cases) a specific genetic background, namely deletions/losses of 13q14, including RB1 and its flanking genes RCBTB2, DLEU1, and ITM2B. Similar genetic aberrations have been reported in pleomorphic liposarcomas (PLSs). This prompted us to investigate a series of 21 low-grade adipocytic neoplasms with a pleomorphic lipoma-like appearance, but with atypical morphologic features (including atypical spindle cells, pleomorphic [multinucleated] cells, pleomorphic lipoblasts and poor circumscription), for which we propose the term "atypical" pleomorphic lipomatous tumor (APLT). Five cases of PLS were also included in this study. We used multiplex ligation-dependent probe amplification to evaluate genetic changes of 13q14. In addition, array-based comparative genomic hybridization was performed on 4 APLTs and all PLSs. Multiplex ligation-dependent probe amplification showed consistent loss of RB1 and its flanking gene RCBTB2 in all cases of APLT. This genetic alteration was also present in all PLSs, suggesting genetic overlap, in addition to morphologic overlap, with APLTs. However, array-based comparative genomic hybridization demonstrated more complex genetic alterations with more losses and gains in PLSs compared with APLTs. APLTs arose in the subcutis (67%) more frequently than in the deep (subfascial) soft tissues (33%). With a median follow-up of 42 months, recurrences were documented in 2 of 12 APLTs for which a long follow-up was available. Herein, we also demonstrate that APLTs share obvious overlapping morphologic, immunohistochemical, genetic and clinical characteristics with the recently defined ASLT, suggesting that they are related lesions that form a spectrum (atypical spindle cell/pleomorphic lipomatous tumor). Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Diagnostic Efficiency in Digital Pathology: A Comparison of Optical Versus Digital Assessment in 510 Surgical Pathology Cases.
Prior work has shown that digital images and microscopic slides can be interpreted with comparable diagnostic accuracy. Although accuracy has been well-validated, the interpretative time for digital images has scarcely been studied and concerns about efficiency remain a major barrier to adoption. We investigated the efficiency of digital pathology when compared with glass slide interpretation in the diagnosis of surgical pathology biopsy and resection specimens. Slides were pulled from 510 surgical pathology cases from 5 organ systems (gastrointestinal, gynecologic, liver, bladder, and brain). Original diagnoses were independently confirmed by 2 validating pathologists. Diagnostic slides were scanned using the Philips IntelliSite Pathology Solution. Each case was assessed independently on digital and optical by 3 reading pathologists, with a >=6 week washout period between modalities. Reading pathologists recorded assessment times for each modality; digital times included time to load the case. Diagnostic accuracy was determined based on whether a rendered diagnosis differed significantly from the original diagnosis. Statistical analysis was performed to assess for differences in interpretative times across modalities. All 3 reading pathologists showed comparable diagnostic accuracy across optical and digital modalities (mean major discordance rates with original diagnosis: 4.8% vs. 4.4%, respectively). Mean assessment times ranged from 1.2 to 9.1 seconds slower on digital versus optical. The slowest reader showed a significant learning effect during the course of the study so that digital assessment times decreased over time and were comparable with optical times by the end of the series. Organ site and specimen type did not significantly influence differences in interpretative times. In summary, digital image reading times compare favorably relative to glass slides across a variety of organ systems and specimen types. Mean increase in assessment time is 4 seconds/case. This time can be minimized with experience and may be further balanced by the improved ease of electronic chart access allowed by digital slide viewing, as well as quantitative assessments which can be expedited on digital images. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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Melanotic Translocation Renal Cell Carcinoma With a Novel ARID1B-TFE3 Gene Fusion.
A 36-year-old male was found to have a 7.0 cm left upper pole renal mass on renal ultrasound. Following nephrectomy, the mass was grossly ill-demarcated, friable and red-brown, invading renal parenchyma, hilar fat and the renal vein. Microscopically, the tumor had a nested and papillary architecture. The cells demonstrated abundant clear and eosinophilic cytoplasm and focal intracytoplasmic melanin pigment. Nucleoli were prominent. By immunohistochemistry, the tumor was positive for TFE3; HMB-45 stained approximately 5% of tumor cells corresponding to the histologic melanin pigment, which was confirmed with Fontana-Masson stain with bleach. Immunostains for PAX8, CD10, MiTF, and CAIX were negative; keratins Cam 5.2 and AE1/AE3 were focally positive. Targeted next-generation sequencing revealed an ARID1B-TFE3 gene fusion. Melanotic Xp11 renal cell carcinoma is a rare, pigment containing translocation variant demonstrating overlapping features with melanoma and is usually associated with an SFPQ-TFE3 gene fusion. The patient is alive and without evidence of disease 7 years after his diagnosis. The combination of high grade histopathology, the presence of melanin, absent PAX8, keratin positivity, and relatively indolent clinical behavior with a unique translocation may warrant recognition as a distinct renal cell carcinoma translocation subtype. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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