Left recurrent laryngeal nerve palsy associated with silicosis.

Left recurrent laryngeal nerve palsy usually results from invasion or compression of the nerve caused by diseases localized within the aortopulmonary window. This study reports the case of a 76-yr-old male with vocal cord paralysis due to lymph node involvement by silicosis. This rare entity was identified by video-mediastinoscopy, which revealed a granulomatous and fibrosed recurrent lymph node encasing the nerve. The nerve was dissected and released from scar tissues. Progressive clinical improvement was observed followed by total and durable recovery of the voice after 15 weeks follow-up.

Correlation between subjective evaluation of symptoms and objective findings in early recurrent head and neck squamous cell carcinoma.

IMPORTANCE: This study addresses the value of patients' reported symptoms as markers of tumor recurrence after definitive therapy for head and neck squamous cell carcinoma. OBJECTIVE: To evaluate the correlation between patients' symptoms and objective findings in the diagnosis of local and/or regional recurrences of head and neck squamous cell carcinomas in the first 2 years of follow-up. DESIGN: Retrospective single-institution study of a prospectively collected database. SETTING: Regional hospital. PARTICIPANTS: We reviewed the clinical records of patients treated for oral cavity, oropharyngeal, laryngeal, and hypopharyngeal carcinomas between January 1, 2008, and December 31, 2009, with a minimum follow-up of 2 years. MAIN OUTCOMES AND MEASURES: Correlation between symptoms and oncologic status (recurrence vs remission) in the posttreatment period. RESULTS: Of the 101 patients included, 30 had recurrences. Pain, odynophagia, and dysphonia were independently correlated with recurrence (odds ratios, 16.07, 11.20, and 5.90, respectively; P < .001). New-onset symptoms had the best correlation with recurrences. Correlation was better between 6 to 12 and 18 to 21 months after therapy and in patients initially treated unimodally (P < .05). Primary stage and tumor site had no effect. CONCLUSIONS AND RELEVANCE: The correlation between symptoms and oncologic status is low during substantial periods within the first 2 years of follow-up. New-onset symptoms, especially pain, odynophagia, or dysphonia, better correlate with tumor recurrence, especially in patients treated unimodally.

Canakinumab vs triamcinolone acetonide for treatment of acute flares and prevention of recurrent flares in "difficult to treat" gouty arthritis

Monosodium urate crystal deposition seen in gout stimulates IL-1 beta OR IL-1_; release. Canakinumab, a long-acting, fully human anti- IL-1 beta OR IL-1_; monoclonal antibody, effectively neutralizes IL-1 beta OR IL-1_;. Methods: This was an 8-week, dose-ranging, multi-center, blinded, doubledummy, active-controlled trial. Patients (aged 18-80 years) with an acute gout flare, refractory to or contraindicated to NSAlDs and/or colchicine, were randomized to one dose of canakinumab 10, 25, 50, 90, 150 mg s.c. or triamcinolone acetonide (TA) 40 mg i.m. Primary variable was assessed as pain intensity at 72 h post-dose (0-100 mm VAS). Secondary variables included pain intensity 24 and 48 h post-dose, time to 50% reduction in pain intensity, time to recurrence of gout flares up to 8 weeks post-dose, and rescue medication use. Results: 191/200 enrolled patients (canakinumab, n_143; TA, n_57) completed the study. Canakinumab showed significant dose-dependent pain reduction at 72 h. Canakinumab 150 mg showed superior pain relief versus TA starting from 24 h: estimated mean difference in pain intensity on VAS was -11.5 (24 h), -18.2 (48 h), and -19.2 (72 h) (all p_0.05). Canakinumab 150 mg provided a rapid onset of pain relief: median time to 50% reduction in pain was reached at 1 day with canakinumab 150 mg versus 2 days with TA (p_0.0006). At Week 8, recurrent flares occurred in 1 patient (3.7%) on canakinumab 150 mg versus 25 (44.6%) patients on TA (relative risk reduction, 94%; p_0.006). During 7 days post-dose, 6 patients (22.2%) on canakinumab 150 mg, and 31 patients (55.4%) on TA, took rescue medication. Time to first rescue medication was significantly longer with canakinumab 150 mg versus TA (hazard ratio, 0.36; p_0.02). Serious adverse events (canakinumab _lsqb_n_4_rsqb_ and TA _lsqb_n_1_rsqb_) were considered not treatment-related by investigators and no patient discontinued due to adverse events. Conclusions: Canakinumab 150 mg was well-tolerated, provided rapid and sustained pain relief in patients with acute gout flares, and significantly reduced the recurrent flare risk by 94% at 8-weeks post-dose compared with triamcinolone acetonide.

Canakinumab (ACZ885) vs triamcinolone acetonide for treatment of acute flares and prevention of recurrent flares in gouty arthritis patients refractory to or contraindicated to nsaids and/or colchicine.

Purpose: Current treatments for arthritis flares in gout (gouty arthritis) are not effective in all patients and may be contraindicated in many due to underlying comorbidities. Urate crystals activate the NALP 3 inflammasome which stimulate production of IL-1β, driving inflammatory processes. Targeted IL-1β blockade may be an alternative treatment for gouty arthritis. Canakinumab (ACZ885) is a fully human monoclonal anti- IL-1β antibody with a long half-life (28 days). Method: This was an 8-weeks, dose-ranging, multicenter, blinded, double-dummy, active-controlled trial of patients ≥18 to ≤80 y with an acute gouty arthritis flare, refractory to or contraindicated to NSAIDs and/or colchicine. Patients were randomized to 1 subcutanous (sc) dose of canakinumab (10, 25, 50, 90, or 150 mg) or 1 intra muscular (im) dose of triamcinolone acetonide (TA) [40 mg]. The primary variable was assessed 72 h post-dose, measured on a 0-100 mm VAS pain scale. Secondary variables included pain intensity 24 and 48 h post dose, time to 50% reduction in pain intensity, and time to recurrence of gout flares up to 8 weeks post dose. Results: 200 patients were enrolled (canakinumab n=143, TA n=57) and 191 completed the study. A statistically significant dose response was observed at 72 h. The 150 mg dose reached superior pain relief compared to TA starting from 24h: estimated mean difference in pain intensity on 0-100 mm VAS was -11.5 at 24 h, -18.2 at 48 h, and -19.2 at 72 h (all p<0.05). Canakinumab 150 mg provided a rapid onset of pain relief: median time to 50% reduction in pain was reached at 1 day with canakinumab 150 mg vs 2 days for the TA group (p=0.0006). The probability of recurrent gout flares was 3.7% with canakinumab 150 mg vs. 45.4% with TA 8 weeks post treatment, a relative risk reduction of 94% (p=0.006). Serious AEs occurred in 2 patients receiving canakinumab (appendicitis and carotid artery stenosis) and 1 receiving TA (cerebrovascular disorder). Investigator's reported these events as not study drug related. There were no discontinuations due to AEs. Conclusion: Canakinumab 150 mg provided faster onset and superior pain relief compared to TA for acute flares in gouty arthritis patients refractory to or contraindicated to standard treatments. The 150 mg dose of canakinumab prevented recurrence of gout flares with a relative risk reduction compared to TA of 94% at 8 weeks post-dose, and was well tolerated.

Secular changes of spinal canal dimensions in Western Switzerland: a narrowing epidemic?

STUDY DESIGN: Computed tomography-based anatomical study. OBJECTIVE: To study the secular changes in lumbar spinal canal dimensions. SUMMARY OF BACKGROUND DATA: Development of symptomatic lumbar spinal stenosis, among other factors, is related to the dimensions of the bony canal. The canal reaches its adult size early on in life. Several factors, including protein intake, may influence its final dimensions. As with increases in human stature from improvements of socioeconomic conditions, we hypothesized that adult bony canal size has also grown larger in recent generations. METHODS: This study analyzes computed tomographic reconstructions from 184 subjects performed for either trauma (n = 81) or abdominal pathologies (n = 103) and born either between 1940 and 1949 (n = 88) or 1970 and 1979 (n = 96). The cross-sectional area of the bony canal was digitally measured at the level of the pedicle (i.e., at a level not influenced by degenerative changes) for each lumbar vertebra. Intra- and interobserver reliability was assessed. RESULTS: Intra- and interobserver measurement reliability were excellent (interclass correlation coefficient = 0.87) and good (interclass correlation coefficient = 0.61), respectively. Contrary to our hypothesis, the 1940-1949 generation patient group exhibited larger lumbar canals at all levels as compared with the 1970-1979 group. Statistically this difference was highly significant (P < 0.001) and particularly pronounced in the trauma subgroup. CONCLUSION: Given that human stature evolution has stabilized and adult height is established during the first 2 years of long bone growth, it is possible that antenatal factors are responsible for this surprising finding. Maternal smoking and age may be possible explanations. This finding may have significant implications. An increasing number of patients may emerge with lumbar spinal stenosis as degenerative changes develop, putting a strain on health resources. Further studies in different population groups and countries will be important to further confirm this trend. LEVEL OF EVIDENCE: 3.

Inferring epidemic contact structure from phylogenetic trees.

Contact structure is believed to have a large impact on epidemic spreading and consequently using networks to model such contact structure continues to gain interest in epidemiology. However, detailed knowledge of the exact contact structure underlying real epidemics is limited. Here we address the question whether the structure of the contact network leaves a detectable genetic fingerprint in the pathogen population. To this end we compare phylogenies generated by disease outbreaks in simulated populations with different types of contact networks. We find that the shape of these phylogenies strongly depends on contact structure. In particular, measures of tree imbalance allow us to quantify to what extent the contact structure underlying an epidemic deviates from a null model contact network and illustrate this in the case of random mixing. Using a phylogeny from the Swiss HIV epidemic, we show that this epidemic has a significantly more unbalanced tree than would be expected from random mixing.

Misconceptions about fructose-containing sugars and their role in the obesity epidemic.

A causal role of fructose intake in the aetiology of the global obesity epidemic has been proposed in recent years. This proposition, however, rests on controversial interpretations of two distinct lines of research. On one hand, in mechanistic intervention studies, detrimental metabolic effects have been observed after excessive isolated fructose intakes in animals and human subjects. On the other hand, food disappearance data indicate that fructose consumption from added sugars has increased over the past decades and paralleled the increase in obesity. Both lines of research are presently insufficient to demonstrate a causal role of fructose in metabolic diseases, however. Most mechanistic intervention studies were performed on subjects fed large amounts of pure fructose, while fructose is ordinarily ingested together with glucose. The use of food disappearance data does not accurately reflect food consumption, and hence cannot be used as evidence of a causal link between fructose intake and obesity. Based on a thorough review of the literature, we demonstrate that fructose, as commonly consumed in mixed carbohydrate sources, does not exert specific metabolic effects that can account for an increase in body weight. Consequently, public health recommendations and policies aiming at reducing fructose consumption only, without additional diet and lifestyle targets, would be disputable and impractical. Although the available evidence indicates that the consumption of sugar-sweetened beverages is associated with body-weight gain, and it may be that fructose is among the main constituents of these beverages, energy overconsumption is much more important to consider in terms of the obesity epidemic.

Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06).

BACKGROUND: Pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients. METHODS: Bevacizumab (10 mg/kg) and PLD (20 mg/m(2)) were infused on days 1 and 15 of a 4-week cycle for a maximum of six cycles. Thereafter, bevacizumab monotherapy was continued at the same dose until progression or toxicity. The primary objective was safety and tolerability, and the secondary objective was to evaluate efficacy of the combination. RESULTS: Thirty-nine of 43 patients were assessable for the primary end point. Eighteen of 39 patients (46%, 95% confidence interval 30% to 63%) had a grade 3 toxicity. Sixteen (41%) had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity. Secondary end point of overall response rate among 43 assessable patients was 21%. CONCLUSIONS: In this nonrandomized single-arm trial, the combination of bimonthly PLD and bevacizumab in locally recurrent and MBC patients demonstrated higher than anticipated toxicity while exhibiting only modest activity. Based on these results, we would not consider this combination for further investigation in this setting.

Stimulus statistics shape oscillations in nonlinear recurrent neural networks.

Rhythmic activity plays a central role in neural computations and brain functions ranging from homeostasis to attention, as well as in neurological and neuropsychiatric disorders. Despite this pervasiveness, little is known about the mechanisms whereby the frequency and power of oscillatory activity are modulated, and how they reflect the inputs received by neurons. Numerous studies have reported input-dependent fluctuations in peak frequency and power (as well as couplings across these features). However, it remains unresolved what mediates these spectral shifts among neural populations. Extending previous findings regarding stochastic nonlinear systems and experimental observations, we provide analytical insights regarding oscillatory responses of neural populations to stimulation from either endogenous or exogenous origins. Using a deceptively simple yet sparse and randomly connected network of neurons, we show how spiking inputs can reliably modulate the peak frequency and power expressed by synchronous neural populations without any changes in circuitry. Our results reveal that a generic, non-nonlinear and input-induced mechanism can robustly mediate these spectral fluctuations, and thus provide a framework in which inputs to the neurons bidirectionally regulate both the frequency and power expressed by synchronous populations. Theoretical and computational analysis of the ensuing spectral fluctuations was found to reflect the underlying dynamics of the input stimuli driving the neurons. Our results provide insights regarding a generic mechanism supporting spectral transitions observed across cortical networks and spanning multiple frequency bands.

Franceschetti hereditary recurrent corneal erosion.

PURPOSE: To describe new affected individuals of Franceschetti's original pedigree of hereditary recurrent erosion and to classify a unique entity called Franceschetti corneal dystrophy. DESIGN: Observational case series. METHODS: Slit-lamp examination of 10 affected individuals was conducted. Biomicroscopic examinations were supplemented by peripheral corneal biopsy in 1 affected patient with corneal haze. Tissue was processed for light and electron microscopy and immunohistochemistry was performed. DNA analysis was carried out in 12 affected and 3 nonaffected family members. RESULTS: All affected individuals suffered from severe ocular pain in the first decade of life, attributable to recurrent corneal erosions. Six adult patients developed bilateral diffuse subepithelial opacifications in the central and paracentral cornea. The remaining 4 affected individuals had clear corneas in the pain-free stage of the disorder. Histologic and immunohistochemical examination of the peripheral cornea in a single patient showed a subepithelial, avascular pannus. There was negative staining with Congo red. DNA analysis excluded mutations in the transforming growth factor beta-induced (TGFBI) gene and in the tumor-associated calcium signal transducer 2 (TACSTD2) gene. CONCLUSION: We have extended the pedigree of Franceschetti corneal dystrophy and elaborated its natural history on the basis of clinical examinations. A distinctive feature is the appearance of subepithelial opacities in adult life, accompanied by a decreased frequency of recurrent erosion attacks. Its clinical features appear to distinguish it from most other forms of dominantly inherited recurrent corneal erosion reported in the literature.