Rosacea – global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group

Background The absence of specific histological or serological markers, the gaps in understanding the aetiology and pathophysiology of rosacea, and the broad diversity in its clinical manifestations has made it difficult to reach international consensus on therapy guidelines. Objectives The main objective was to highlight the global diversity in current thinking about rosacea pathophysiology, classification and medical features, under particular consideration of the relevance of the findings to optimization of therapy. Methods The article presents findings, proposals and conclusions reached by the ROSacea International Expert group (ROSIE), comprising European and US rosacea experts. Results New findings on pathogenesis provide a rationale for the development of novel therapies. Thus, recent findings suggest a central role of the antimicrobial peptide cathelicidin and its activator kallikrein‐5 by eliciting an exacerbated response of the innate immune system. Cathelicidin/kallikrein‐5 also provide a rationale for the effect of tetracyclines and azelaic acid against rosacea. Clinically, the ROSIE group emphasized the need for a comprehensive therapy strategy – the triad of rosacea care – that integrates patient education including psychological and social aspects, skin care with dermo‐cosmetics as well as drug‐ and physical therapies. Classification of rosacea into stages or subgroups, with or without progression, remained controversial. However, the ROSIE group proposed that therapy decision making should be in accordance with a treatment algorithm based on the signs and symptoms of rosacea rather than on a prior classification. Conclusion The ROSIE group reviewed rosacea pathophysiology and medical features and the impact on patients and treatment options. The group suggested a rational, evidence‐based approach to treatment for the various symptoms of the condition. In daily practice this approach might be more easily handled than prior subtype classification, in particular since patients often may show clinical features of more than one subtype at the same time.     

Exercise capacity with transdermal nitroglycerin in patients with stable angina pectoris

Transdermally delivered nitroglycerin (TTS-NTG) through a rate-controlling membrane yields stable blood levels for 24 h. We studied the effect of TTS-NTG (25 mg per 10 cm2) on exercise induced angina in 10 patients with stable angina pectoris, all in NYHA class III, who were not under treatment with other cardiac drugs. In a pre-study exercise test, all patients had angina pectoris and more than one mm ST depression. The study was placebo controlled and double blind with a randomized cross-over. Exercise tests were carried out on a treadmill according to the Bruce-protocol, 12 to 16 h after administration of TTS-NTG or of an identical placebo. After a 48 h wash-out period, the procedure was repeated after application of a plaster with the alternative content. A significant improvement was seen on TTS nitroglycerin compared with placebo in the total duration of exercise (7.2 +/- 3.6 min (mean +/- SD) vs 6.2 +/- 3.8 min; P less than 0.002). In 7 patients, the time to onset of angina was extended by TTS nitroglycerin. Maximal ST depression (lead V4 and V6) was significantly lower on TTS nitroglycerin (1.85 +/- 1 mm) compared with placebo (2.2 +/- 1 mm; P less than 0.05). It is concluded that 12 to 16 h after administration, transdermally delivered nitroglycerin improves exercise capacity and reduces maximal ST depression in patients with stable angina.     

A versatile technique for aortic root replacement without pre-manufactured composite graft: a 12-year experience

BACKGROUND AND AIM OF THE STUDY: Replacement of the aortic root is the treatment of choice for aneurysmal dilatation. Many modifications of the Bentall technique have been described, as have valve-sparing procedures. The study aim was to determine the outcome of a versatile modification of composite replacement that has been adopted over the past 12 years. Separate graft and prosthetic valve components were used to allow freedom of valve choice and the use of an appropriately sized graft for the distal aortic anastomosis. METHODS: Between January 1990 and March 2002, 59 patients (45 males, 14 females; mean age 56 +/- 14 years) underwent aortic root replacement using this technique. Indications for surgery were elective in 35 patients and emergent (usually type A aortic dissection) in 24. The range of valve prostheses used, their size, and the size of aortic graft used in each case was assessed. Durations of ischemia and cardiopulmonary bypass were recorded, as was postoperative blood loss and subsequent patient progress, including valve-related events, perioperative mortality and actuarial survival. RESULTS: A wide range of aortic graft sizes was combined with both mechanical and tissue valves (from 1-7 mm larger in diameter). Median postoperative blood loss was 550 ml (IQR 400-800 ml). Perioperative mortality was 5.1%. There were no valve- or technique-related deaths, and the median actuarial survival was 13.17 years. During a 12-year follow up there were no proximal aortic reoperations. CONCLUSIONS: This technique had favorable perioperative mortality, produced a secure proximal suture line, and allowed the surgeon free choice of both valve type and size of aortic graft. This minimized tension at the distal suture line, and produced good hemostasis, especially in those patients with fragile dissected tissues.     

Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes: A case-control study

Because other coronaviruses enter the cells by binding to dipeptidyl-peptidase-4 (DPP-4), it has been speculated that DPP-4 inhibitors (DPP-4is) may exert an activity against severe acute respiratory syndrome coronavirus 2. In the absence of clinical trial results, we analysed epidemiological data to support or discard such a hypothesis. We retrieved information on exposure to DPP-4is among patients with type 2 diabetes (T2D) hospitalized for COVID-19 at an outbreak hospital in Italy. As a reference, we retrieved information on exposure to DPP-4is among matched patients with T2D in the same region. Of 403 hospitalized COVID-19 patients, 85 had T2D. The rate of exposure to DPP-4is was similar between T2D patients with COVID-19 (10.6%) and 14 857 matched patients in the region (8.8%), or 793 matched patients in the local outpatient clinic (15.4%), 8284 matched patients hospitalized for other reasons (8.5%), and when comparing 71 patients hospitalized for COVID-19 pneumonia (11.3%) with 351 matched patients with pneumonia of another aetiology (10.3%). T2D patients with COVID-19 who were on DPP-4is had a similar disease outcome as those who were not. In summary, we found no evidence that DPP-4is might affect hospitalization for COVID-19.     

Heparan sulfate proteoglycans regulate responses to oocyte paracrine signals in ovarian follicle morphogenesis

In the ovarian follicle, oocyte-secreted factors induce cumulus-specific genes and repress mural granulosa cell specific genes to establish these functionally distinct cell lineages. The mechanism establishing this precise morphogenic pattern of oocyte signaling within the follicle is unknown. The present study investigated a role for heparan sulphate proteoglycans (HSPG) as coreceptors mediating oocyte secreted factor signaling. In vitro maturation of cumulus oocyte complexes in the presence of exogenous heparin, which antagonizes HSPG signaling, prevented cumulus expansion and blocked the induction of cumulus-specific matrix genes, Has2 and Tnfaip6, whereas conversely, the mural granulosa-specific genes, Lhcgr and Cyp11a1, were strongly up-regulated. Heparin also blocked phosphorylation of SMAD2. Exogenous growth differentiation factor (GDF)-9 reversed these heparin effects; furthermore, GDF9 strongly bound to heparin sepharose. These observations indicate that heparin binds endogenous GDF9 and disrupts interaction with heparan sulphate proteoglycan coreceptor(s), important for GDF9 signaling. The expression of candidate HSPG coreceptors, Syndecan 1-4, Glypican 1-6, and Betaglycan, was examined. An ovulatory dose of human chorionic gonadotropin down-regulated Betaglycan in cumulus cells, and this regulation required GDF9 activity; conversely, Betaglycan was significantly increased in luteinizing mural granulosa cells. Human chorionic gonadotropin caused very strong induction of Syndecan 1 and Syndecan 4 in mural granulosa as well as cumulus cells. Glypican 1 was selectively induced in cumulus cells, and this expression appeared dependent on GDF9 action. These data suggest that HSPG play an essential role in GDF9 signaling and are involved in the patterning of oocyte signaling and cumulus cell function in the periovulatory follicle.     

Water and sustainable land use at the ancient tropical city of Tikal, Guatemala

The access to water and the engineered landscapes accommodating its collection and allocation are pivotal issues for assessing sustainability. Recent mapping, sediment coring, and formal excavation at Tikal, Guatemala, have markedly expanded our understanding of ancient Maya water and land use. Among the landscape and engineering feats identified are the largest ancient dam identified in the Maya area of Central America; the posited manner by which reservoir waters were released; construction of a cofferdam for dredging the largest reservoir at Tikal; the presence of ancient springs linked to the initial colonization of Tikal; the use of sand filtration to cleanse water entering reservoirs; a switching station that facilitated seasonal filling and release; and the deepest rock-cut canal segment in the Maya Lowlands. These engineering achievements were integrated into a system that sustained the urban complex through deep time, and they have implications for sustainable construction and use of water management systems in tropical forest settings worldwide.