Chitinase 3–like–1 and its receptors in Hermansky-Pudlak syndrome–associated lung disease

Hermansky-Pudlak syndrome (HPS) comprises a group of inherited disorders caused by mutations that alter the function of lysosome-related organelles. Pulmonary fibrosis is the major cause of morbidity and mortality in patients with subtypes HPS-1 and HPS-4, which both result from defects in biogenesis of lysosome-related organelle complex 3 (BLOC-3). The prototypic chitinase-like protein chitinase 3–like–1 (CHI3L1) plays a protective role in the lung by ameliorating cell death and stimulating fibroproliferative repair. Here, we demonstrated that circulating CHI3L1 levels are higher in HPS patients with pulmonary fibrosis compared with those who remain fibrosis free, and that these levels associate with disease severity. Using murine HPS models, we also determined that these animals have a defect in the ability of CHI3L1 to inhibit epithelial apoptosis but exhibit exaggerated CHI3L1-driven fibroproliferation, which together promote HPS fibrosis. These divergent responses resulted from differences in the trafficking and effector functions of two CHI3L1 receptors. Specifically, the enhanced sensitivity to apoptosis was due to abnormal localization of IL-13Rα2 as a consequence of dysfunctional BLOC-3–dependent membrane trafficking. In contrast, the fibrosis was due to interactions between CHI3L1 and the receptor CRTH2, which trafficked normally in BLOC-3 mutant HPS. These data demonstrate that CHI3L1-dependent pathways exacerbate pulmonary fibrosis and suggest CHI3L1 as a potential biomarker for pulmonary fibrosis progression and severity in HPS.     

Diagnosis of a variant of Mayer–Rokitansky–Kuster–Hauser syndrome: useful MRI findings

Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome consists of vaginal aplasia associated with other müllerian duct abnormalities. Its penetrance varies, as does the involvement of other organ systems. Type I MRKU syndrome is characterized by an isolated absence of the proximal two thirds of the vagina, whereas type II is marked by other malformations which include vertebral, cardiac, urologic (upper tract), and otologic anomalies. In both types, the extent of vaginal aplasia varies, ranging from virtually absent to a length much more inferior than the normal one (2–5 cm). MRKU syndrome usually remains undetected until the patient presents with primary amenorrhea despite normal female sexual development. It is important to underline the fact that this syndrome is the second most common cause of primary amenorrhea. Although this condition has psychologically devastating consequences, its anatomical defects can be surgically treated. In fact, following diagnosis, surgery allows patients to have normal sexual function while reproduction may be possible if assisted techniques are performed.     

Tension–type headache in 40–year-olds: a Danish population–based sample of 4000

The aim of this study was to evaluate the one–year prevalence of tension–type headache in the general population. Three thousand men and one thousand women aged 40 years from the Danish population were included. They received a mailed questionnaire and the response rate was 87%. The selfreported one–year prevalence of tension– type headache was 84.7%. The one–year prevalence of infrequent episodic, frequent episodic and chronic tension–type headache was 48.2%, 33.8% and 2.3%, respectively. No tension–type headache and infrequent episodic tension–type headache was significantly more frequent in men than women (p<0.0005 and p=0.004), while frequent and chronic tension–type headache was significantly more frequent in women than men (p<0.0005 and p<0.0005). No tension– type headache and infrequent tension–type headache was significantly more frequent among those without than with self–reported migraine (no headache, men, p<0.0005 and women, p=0.002 and infrequent, men, p<0.0005 and women, p<0.0005), while episodic frequent and chronic tension–type headache was significantly more frequent among those with than those without self–reported migraine, with the exception of chronic tension–type in women (frequent episodic, men, p<0.0005 and women, p<0.0005 and chronic, men, p<0.0005 and women, p=0.08). Women are more prone to tensiontype headache than men and they have it more frequently than men. Self–reported migraine increases the risk for frequent episodic and chronic tension–type headache.     

Risk–benefit and cost–benefit ratio in headache treatment

The cost–benefit and the risk–benefit ratios are two of the most relevant items in ongoing health organisation procedures. The choice of a new or an old therapeutic treatment depends on a number of factors and the evaluation of the cost, in terms of economics, but also in terms of quality of life and type of facilities necessary for one treatment are crucial criteria. Therefore, we have to consider in evaluating treatment strategies not only the activity of a drug in reaching the main end–points, (i.e., pain free or headache relief) but also the safety and perception of safety by patients, and the cost effectiveness, including indirect costs compared with personal and social benefits. Because it is reasonable that a subgroup of migraine patients may have a clinically progressive disorder, studies should be necessary to assess strategies for migraine treatments.     

Valsartan–amlodipine–hydrochlorothiazide: the definitive fixed combination?

A significant proportion of patients with hypertension will need three or more antihypertensive agents to achieve blood pressure goals, particularly those at higher risk. On the other hand, fixed combinations provide an extra beneficial effect, as they improve medication adherence and, secondarily, the attainment of blood pressure goals during follow-up. Triple therapy is recommended in the treatment of hypertension in those patients not adequately controlled with two antihypertensive drugs. In this context, guidelines recommend the combination of a renin–angiotensin system inhibitor, a calcium channel blocker and a diuretic. The triple fixed combination of valsartan–amlodipine–hydrochlorothiazide has been shown to be an effective and safe therapy for treating hypertension and seems a logical approach for those patients uncontrolled with two antihypertensive agents as well as in those patients already treated with three drugs to improve treatment compliance. In this article, available evidence about the efficacy and tolerability of the triple fixed combined therapy valsartan–amlodipine–hydrochlorothiazide for the treatment of hypertension is updated.     

Koronare Stents / Von der Idee zum High–Tech–Implantat

ZusammenfassungHintergrund:  Der koronare Stent ist Mitte der 80er Jahre in die Kardiologie eingeführt worden, da die alleinige Ballonangioplastie mit einer hohen Inzidenz periinterventioneller akuter Gefäßverschlüsse und einer hohen Restenoserate einherging.Entwicklung der Stenttechnologie:   Als Implantat entwickelt, das den elastischen Rückstellkräften der Gefäßwand entgegenwirken sollte, konnte sich die Technik aufgrund subakuter Stentthrombosen zunächst nur langsam durchsetzen. Erst durch die Entwicklung einer intensivierten thrombozytenaggregationshemmenden Medikation und der Hochdruckimplantation (> 16 atm) konnte der Stent seine überlegenen Ergebnisse gegenüber der Angioplastie zeigen. Obwohl durch die Stentimplantation die Akut– und auch die Langzeitergebnisse signifikant verbessert werden konnten, blieb die Restenosierung weiterhin das führende Problem der interventionellen Kardiologie. Verschiedene Designs und unterschiedliche Materialien sind verwendet worden, ohne jedoch zu einer durchgreifenden Lösung des Problems zu führen. Erst die Einführung medikamentenfreisetzender, beschichteter Stents beseitigte diese Limitationen fast vollständig. Durch das Aufbringen proliferationsund entzündungshemmender Substanzen ist die Inzidenz einer Wiedereinengung und eines damit verbundenen Wiederholungseingriffs auf < 10% gesenkt worden. Aktuelle Entwicklungen befassen sich mit bioresorbierbaren Materialien, um die Implantation dauerhafter Fremdkörper zu vermeiden, die Implantation bei Kindern zu ermöglichen und die Kompatibilität mit nichtinvasiven bildgebenden Verfahren zu verbessern. Initial lediglich als einfaches Drahtgeflecht zur Abstützung verengter Gefäßsegmente gedacht, ist der Stent als kardiologisches Implantat in den letzten 20 Jahren multiplen Modifikationen unterzogen worden. Schlussfolgerung:  Durch die Entwicklung eines elaborierten Designs, verschiedener verwendeter metallischer und polymerer Werkstoffe in Verbindung mit biologisch aktiven Substanzen ist der Stent somit zum High– Tech–Implantat der Kardiologie avanciert.