Fiber-based source of 500 kW mid-infrared solitons.

Fiber-based sources delivering high-energy few-cycle pulses at high repetition rates are currently being developed in the near-infrared spectral range, thanks to the wide availability of telecommunication-grade optical fibers and components. Similar sources in the middle-wave infrared (mid-IR) spectral domain, however, are scarce, although such sources are of high interest for applications such as high-precision frequency metrology and molecular spectroscopy or as a seed source to reach further into the mid-IR via coherent nonlinear processes. Here we report on the design of a fiber-based source of 50-nJ energy 90 fs duration pulses up to 2950 nm, corresponding to 500 kW peak power. To obtain this level of peak power we exploit multi-solitonic fission and soliton self-frequency shift in large mode area fibers excited by picosecond pulses emitted at 2 µm from a megahertz repetition rate fiber laser. We leverage mature silica-based fiber technology up to 2.4 µm and restrict the use of fluoride fiber to the very last frequency-shifting stage. The level of instantaneous power and ultra-short duration achieved in this Letter pave the way to all-fiber format generation of an ultra-broadband coherent continuum in the mid-IR with profound implications for applications such as high-resolution molecular spectroscopy and imaging.

Long-Term Efficacy and Safety of Cyclosporine in a Cohort of Steroid-Refractory Acute Severe Ulcerative Colitis Patients from the ENEIDA Registry (1989-2013): A Nationwide Multicenter Study.

OBJECTIVES: To determine the efficacy and safety of cyclosporine (CyA) in a large national registry-based population of patients with steroid-refractory (SR) acute severe ulcerative colitis (ASUC) and to establish predictors of efficacy and adverse events. METHODS: Multicenter study of SR-ASUC treated with CyA, based on data from the ENEIDA registry. SR-ASUC patients treated with infliximab (IFX) or sequential rescue therapy (CyA-IFX or IFX-CyA) were used as comparators. RESULTS: Of 740 SR-ASUC patients, 377 received CyA, 131 IFX and 63 sequential rescue therapy. The cumulative colectomy rate was higher in the CyA (24.1%) and sequential therapy (32.7%) than in the IFX group (14.5%; P=0.01) at 3 months and 5 years. There were no differences in early and late colectomy between CyA and IFX in patients treated after 2005. 62% of patients receiving CyA remained colectomy-free in the long term (median 71 months). There were no differences in mortality between CyA (2.4%), IFX (1.5%) and sequential therapy (0%; P=0.771). The proportion of patients with serious adverse events (SAEs) was lower in CyA (15.4%) than in IFX treated patients (26.5%) or sequential therapy (33.4%; P<0.001). This difference in favor of CyA was maintained when only patients treated after 2005 were analyzed. CONCLUSIONS: Treatment with CyA showed a lower rate of SAE and a similar efficacy to that of IFX thereby supporting the use of either CyA or IFX in SR-ASUC. In addition, the risk-benefit of sequential CyA-IFX for CyA non-responders is acceptable.

Transdermal therapeutic systems for memantine delivery. Comparison of passive and iontophoretic transport.

Memantine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist used in the treatment of moderate to severe dementia including the symptoms of Alzheimer's disease (AD). It is administered orally but compliance, swallowing problems and the routine use of multiple medications in elderly AD patients means that an alternative route of administration would be of interest. The aim of the present study was to develop memantine hydrochloride occlusive transdermal therapeutic systems (TTS) for passive and iontophoretic delivery across the skin. Polyvinyl pyrrolidone (PVP) and a mixture with polyvinyl alcohol (PVA) were employed as polymeric matrices. The study involved the TTS characterization in addition to quantification of the memantine transport across porcine skin in vitro. The evaluation of the TTS physical properties suggested that systems were made more mechanically resistant by including PVA (6%) or high concentrations of PVP (24%). Moreover, a linear correlation was observed between the concentration of PVP and the bioadhesion of the systems. Drug delivery experiments showed that the highest transdermal flux provided by a passive TTS (PVP 24% w/w limonene) was 8.89±0.81µgcm-2h-1 whereas the highest iontophoretic transport was 46.4±3.6µgcm-2h-1. These innovative TTS would enable two dosage regimens that could lead to therapeutic plasma concentrations.

Development of antimigraine transdermal delivery systems of pizotifen malate.

The aim of this study was to develop and evaluate a transdermal delivery system of pizotifen malate. Pizotifen is frequently used in the preventive treatment of migraine, but is also indicated in eating disorders. In the course of the project, the effects of chemical enhancers such as ethanol, 1,8-cineole, limonene, azone and different fatty acids (decanoic, decenoic, dodecanoic, linoleic and oleic acids) were determined, first using a pizotifen solution. Steady state flux, diffusion and partition parameters were estimated by fitting the Scheuplein equation to the data obtained. Among the chemical enhancers studied, decenoic acid showed the highest enhancement activity, which seemed to be due to the length of its alkyl chain and unsaturation at the 9th carbon. The influence of iontophoresis and the involvement of electrotransport in said process was determined. The absorption profile obtained with iontophoresis was similar to that obtained with fatty acids and terpenes, though skin deposition of the drug was lower with the former. Transdermal delivery systems (TDS) of pizotifen were manufactured by including chemical enhancers, decenoic acid or oleic acid, and were subsequently characterized. When the results obtained with solutions were compared with those obtained with the TDS, a positive enhancement effect was observed with the latter with respect to the partitioning and diffusion of the drug across the skin. Our findings endorse the suitability of our TDS for delivering therapeutic amounts of pizotifen malate.

Transdermal absorption of memantin--effect of chemical enhancers, iontophoresis, and role of enhancer lipophilicity.

The transdermal administration of memantine may have advantages with respect to oral therapy when treating advanced stages of Alzheimer's disease. With the ultimate objective of administrating memantine through a transdermal patch, the absorption of the drug across skin was evaluated by means of in vitro permeation studies. The effect of several chemical enhancers was studied in order to enhance percutaneous absorption of the memantine. The iontophoretic transdermal transport of memantine hydrochloride using a current density of 0.5 mA/cm(2) was also investigated. Results demonstrated that pre-treatment of the skin with R-(+)-limonene, laurocapram, decenoic acid, or oleic acid produced a statistically significant increment in the transdermal flux of memantine hydrochloride with respect to the control. Iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In this study, the relationship between enhancement activity and lipophilicity was also studied. Satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficients of drugs. This relationship is a very useful tool that could allow to reduce time and to optimize the selection of appropriate enhancers for transdermal formulations.

HPLC-UV analytical method for determination of pizotifen after in vitro transdermal diffusion studies.

Pizotifen malate is an antihistamine and serotonin inhibitor used in the preventive treatment of migraine and eating disorders. A simple, rapid, accurate and precise high-performance liquid chromatography (HPLC) method involving ultraviolet detection was validated for the quantitative analysis of pizotifen malate in samples from in vitro transdermal diffusion studies. The method was validated for specificity, linearity, accuracy, precision, limit of detection, limit of quantification and robustness. Drug stability in the solution was also determined under different conditions. Separation was carried out using a 250 × 4.0 mm Kromasil(®) C(18) column at room temperature. The detector response, fitted at 254 nm, was found to be linear in a concentration range between 0.24 and 24.0 µg/mL. The limit of detection was 0.02 µg/mL and the limit of quantification was 0.07 µg/mL. Finally, in vitro transdermal diffusion of pizotifen malate was characterized using the validated HPLC method.

Effect of iontophoresis on in vitro transdermal absorption of almotriptan.

The aim of the present work was to characterize the in vitro transdermal absorption of almotriptan through pig ear skin. The passive diffusion of almotriptan malate and its iontophoretic transport were investigated using current densities of 0.25 and 0.50mA/cm(2). In vitro iontophoresis experiments were conducted on diffusion cells with an agar bridge without background electrolytes in the donor compartment. Although both current densities applied produced a statistically significant increment with respect to passive permeation of almotriptan (p<0.01), that of 0.50mA/cm(2) proved to be the best experimental condition for increasing the transport of almotriptan across the skin. Under these experimental conditions, the transdermal flux of the drug increased 411-fold with respect to passive diffusion, reaching 264±24µg/cm(2)h (mean±SD). Based on these results, and taking into account the pharmacokinetics of almotriptan, therapeutic drug plasma levels for the management of migraine could be achieved via transdermal iontophoresis using a reasonably sized (around 7.2cm(2)) patch.

Advantages of diagnostic nuclear medicine part 1: musculoskeletal disorders.

Radionuclide scans with improved imaging techniques such as single-photon-emission tomography and three-phase scanning have become safe, well-established, and highly effective diagnostic tools in sports medicine. The greatest strengths of the techniques include providing early physiologic information about injury sites and evaluating large areas or the whole body in a single examination. As described and illustrated here, bone scans are particularly useful for diagnosing such musculoskeletal injuries as stress fractures, avulsion fractures, periostitis, myositis ossificans, and rhabdomyolysis.

Advantages of diagnostic nuclear medicine part 2: cardiac and other nonmusculoskeletal disorders.

Advances in nuclear medicine have improved the detection and localization of very small abnormalities. Radionuclide imaging of myocardial perfusion is very useful for detecting coronary artery disease in patients who have an ambiguous presentation, such as those with chest pain syndrome and a nondiagnostic exercise test. Scintigraphy is also useful for diagnosing pulmonary thromboembolism, hyperthyroidism, testicular torsion, and fevers of unknown origin. In addition, improvements in positron-emission tomography and imaging with isotope-labeled monoclonal antibodies now permit detection and staging of prostate and brain malignancies and diagnosis of infections such as osteomyelitis.

Imaging quiz posterior ankle pain in a recreational athlete.

A 21-year-old male recreational soccer player presented with right posterolateral ankle pain of 4 weeks' duration that was provoked by prolonged weight-bearing and significant plantar flexion. Running, jumping, and kicking the ball exacerbated the pain. On physical examination, tenderness was noted anterolateral to the Achilles tendon and posterior to the talus. Resisted plantar flexion accentuated the pain. Anteroposterior, lateral, and mortise view radiographs revealed no bony lesions. A technetium 99m methylene diphosphonate bone scan (figure 1) was then obtained.

Insidious illness in active seniors: decoding atypical presentations.

Older athletes and active seniors may have serious medical problems without commonly recognized signs and symptoms. The cases of an older tennis player, a golfer, and a deep-sea sport fisherman illustrate unusual presentations of coronary artery disease, bacterial pneumonia, and peptic ulcer disease in senior patients. Alertness for the effects of coexisting illnesses, chronic use of medicines, reduced physiologic and immunologic reserves, altered pain perception, and symptom denial can facilitate prompt treatment of active senior patients.

A Soldier's Neck and Shoulder Pain.

A 38-year-old male soldier presented to an acute care clinic complaining of 24 hours of persistent, bilateral shoulder and neck pain after a 12-mile road march. He denied any history of prior trauma to either area. On physical examination, there was diffuse tenderness in both supraclavicular areas as well as over the posterior neck.