Markus Rupp

Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6

BackgroundHypoxic pulmonary vasoconstriction (HPV) is an essential mechanism of the lung that matches blood perfusion to alveolar ventilation to optimize gas exchange. Recently we have demonstrated that acute but not sustained HPV is critically dependent on the classical transient receptor potential 6 (TRPC6) channel. However, the mechanism of TRPC6 activation during acute HPV remains elusive. We hypothesize that a diacylglycerol (DAG)-dependent activation of TRPC6 regulates acute HPV.MethodsWe investigated the effect of the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) on normoxic vascular tone in isolated perfused and ventilated mouse lungs from TRPC6-deficient and wild-type mice. Moreover, the effects of OAG, the DAG kinase inhibitor R59949 and the phospholipase C inhibitor U73122 on the strength of HPV were investigated compared to those on non-hypoxia-induced vasoconstriction elicited by the thromboxane mimeticum U46619.ResultsOAG increased normoxic vascular tone in lungs from wild-type mice, but not in lungs from TRPC6-deficient mice. Under conditions of repetitive hypoxic ventilation, OAG as well as R59949 dose-dependently attenuated the strength of acute HPV whereas U46619-induced vasoconstrictions were not reduced. Like OAG, R59949 mimicked HPV, since it induced a dose-dependent vasoconstriction during normoxic ventilation. In contrast, U73122, a blocker of DAG synthesis, inhibited acute HPV whereas U73343, the inactive form of U73122, had no effect on HPV.ConclusionThese findings support the conclusion that the TRPC6-dependency of acute HPV is induced via DAG.

Heme Oxygenase-2 and Large-Conductance Ca2+-activated K+ Channels: Lung Vascular Effects of Hypoxia

RATIONALE Hypoxic pulmonary vasoconstriction (HPV) is an important mechanism by which pulmonary gas exchange is optimized by the adaptation of blood flow to alveolar ventilation. In chronic hypoxia, in addition to HPV a vascular remodeling process leads to pulmonary hypertension. A complex of heme oxygenase-2 (HO-2) and the BK channel has been suggested as a universal oxygen sensor system. OBJECTIVES We investigated whether this complex serves as an oxygen sensor for the vascular effects of alveolar hypoxia in the lung. METHODS The investigations were performed in chronically hypoxic mice, in isolated perfused and ventilated lungs, and on the cellular level, including HO-2- and BK-channel deficient mice. MEASUREMENTS AND MAIN RESULTS Immunohistochemical analysis of mouse lungs identified HO-2 mainly in pulmonary arteries, the bronchial epithelium, and alveolar epithelial cells. BK channel alpha-subunit (BKalpha) immunoreactivity was found primarily in the bronchial and vascular smooth muscle layer. Immunofluorescence staining and coimmunoprecipitation suggested only a weak complexation of HO-2 and BKalpha in pulmonary arterial smooth muscle cells. The strength of acute and sustained HPV, determined in isolated perfused and ventilated lungs, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice. Exposure of mice to 3 weeks of chronic hypoxia resulted in a slight down-regulation of HO-2 and no alteration in BKalpha expression. The degree of pulmonary hypertension that developed, quantified on the basis of right ventricular pressure, right-heart hypertrophy, and the degree of muscularization of precapillary pulmonary arteries, was not different among wild-type, HO-2-deficient, and BKalpha-deficient mice. CONCLUSIONS It is demonstrated that neither deletion of HO-2 nor BK channels affect acute, sustained, and chronic vascular responses to alveolar hypoxia in the lung.

Better is the foe of good: Outcome of operatively treated ankle fractures in the elderly

BACKGROUND Ankle fractures are the second most common fractures of the lower extremities. Nonetheless, no standardized treatment protocol for unstable ankle fractures of the elderly exists today. Choices to treat ankle fractures are debated controversially, including (1) conservative treatment, (2) open reduction and internal fixation (ORIF), and (3) primary hind-foot arthrodesis. This retrospective study aimed to examine the healing result in patients treated by ORIF after unstable ankle fractures. METHODS The study was designed as a retrospective comparative series. The American Orthopaedic Foot and Ankle Society (AOFAS) score was followed to assess the postsurgical outcome. Data was obtained from 66 patients younger than 65 (median age, 42 years; range, 18-63) and 28 patients aged 65 or older (median age, 71 years; range, 65-81). The mean follow-up period for the younger-than-65 group was 48 months; for patients older than 65, it was 49 months. RESULTS An AOFAS score of 86.4 in the older and 92.4 in the younger group was determined, p-value<0.05. Elderly patients suffered from significantly more open-ankle fractures and comorbidities than the younger group did, p-value<0.05 each. The duration of hospital stay and the time needed to reach sufficient self-mobilization were both significantly different between the two groups, p-value<0.05. CONCLUSION ORIF treatment of ankle fractures resulted in good functional assessment after a mean follow-up of 49 months in the elderly. Pre-fracture health condition positively affected the healing results in younger patients. This study confirms the basic AO Foundation principles for good postsurgical results. LEVEL OF EVIDENCE Level III, retrospective comparative series.

Rheuma der unteren Extremität: Wann gelenkerhaltend operieren?

Neben Aussagen oder Fragen zu geeigneten Therapieformen einer rheumatischen Erkrankung müssen sich Ärzte auch mit der zeitlichen Dimension auseinandersetzen. Häufig ist hier bei den betroffenen Patienten Angst über mögliche verpasste Chancen oder den richtigen Zeitpunkt herauszuhören. Der Begriff des therapeutischen Fensters stammt ursprünglich aus der Strahlentherapie. In der Rheumatologie wird heute meist neudeutsch von „window of opportunity“ gesprochen, wenn der Zeitraum zwischen den ersten Symptomen und dem Beginn der Differenzierungs- und Manifestationsphase gemeint ist.

Intestinal Perforation by a Toothpick as Reason for Necrotizing Fasciitis

Necrotizing fasciitis is an uncommon but often fatal disease. Given the various causes of necrotizing fasciitis, we report a case of sigmoid colon perforation caused by a toothpick subsequently resulting in fulminant necrotizing fasciitis of the retroperitoneum and right thigh successfully treated by hemipelvectomy and Hartmann´s procedure.

Total Elbow Arthroplasty Following Septic Arthritis with Staphylococcusaureus: A Case Report and Review of the Literature

Septic arthritis of the elbow seems to be a contraindication for total elbow arthroplasty (TEA). We here describe a 65-year-old male, American Society of Anesthesiologists (ASA) class 3-patient, with a severely destructed right elbow due to septic arthritis with Staphylococcus aureus. His treatment consisted of multiple irrigation and debridement procedures including resection of the distal humerus, soft tissue coverage by local rotational flap and the use of a gentamicin-vancomycin loaded PMMA spacer, i.v. and oral antibiotics. After eradication of infection, a constraint cemented TEA could then successfully be performed eight months after the initial surgery and twenty-five weeks after the last debridement procedure. Twenty-one months after the TEA, the patient remained infect free and shows excellent functional results: Disabilities of the Arm, Shoulder and Hand (DASH) score: 38.3, Broberg and Morrey score: 91/100, Mayo elbow score: 95/100. To the best of our knowledge this is the first case in the literature that demonstrates TEA after septic elbow arthritis with S. aureus. Although TEA is known as a typical surgical procedure with a low volume in numbers and higher complication rates, such as elevated infection rates compared to other types of arthroplasty, septic arthritis with S. aureus can successfully be performed after eradication of the infection and targeted antibiotic therapy.

Bilateral scapulothoracic osteochondromas in a patient with hereditary multiple exostosis: a case report and review of the literature

Hereditary multiple exostosis (HME) is an autosomal dominant disorder characterized by two or more benign growing, cartilage capped tumors of long bones called osteochondromas. If abnormal growth and clinical symptoms of osteochondromas newly appear in adults, malignant transformation of the usually benign growing tumors should be suspected and diagnostic testing should be initiated. Against the background of hypothesized higher malignant transformation of osteochondromas into chondrosarcoma in individuals with shoulder exostoses, we report a case of bilateral scapulothoracic osteochondromas in a patient suffering from HME. A 60-year-old female with HME complained of chest pain while being hospitalized for bilateral femoral fractures. A computed tomography scan of the chest was performed to rule out pulmonary embolism. However, bilateral osteochondromas in the scapulothoracic spaces were detected. Due to absence of radiographic evidences for malignant transformation in the patient, invasive diagnostic procedures such as biopsy and histological examination were recommended in order to exclude malignant transformation of both osteochondromas. Physicians should be aware that patients with HME who present with shoulder pain should be examined for osteochondromas in the scapulothoracic space. Due to possible sarcomatous transformation, regular follow-ups are necessary for adolescents and adults.