Spätergebnisse der chirurgischen Behandlung chronischer Verschlußprozesse der supraaortalen Äste

Zusammenfassung Als Spätergebnisse 1–16 Jahre nach Desobliteration einer Carotisstenose im Stadium I bleiben 97,8% der Patienten asymptomatisch, nach Korrektur eines Stadium II sind 79,3% völlig beschwerdefrei und 13,0% deutlich gebessert. Nach operativer Behandlung des frischen Schlaganfalls finden sich als Spätergebnis 20% geheilt und 70% gebessert. Im Defektstadium nach durchgemachtem Schlaganfall werden keine weiteren neurologischen Ausfälle beobachtet. Nach Eingriffen an den anderen Aortenbogenästen zeigen sich in 92,5% überzeugende Langzeitergebnisse.

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Late results of reconstructive surgery for supraaortic occlusions

Summary Internal carotid endarterectomy is an effective and longlasting means of preventing cerebrovascular accidents. After 1–16 years it was entirely successful in 97.8% of asymptomatic patients; 79.3% of patients with transient ischemic attacks experienced no further symptoms, 13% were improved. In patients with acute stroke 20% were cured, 70% improved, and 10% unchanged. The follow-up of patients with completed stroke yielded no further neurological deficit. The late results 1–14 years after reconstruction of the other supraaortic vessels were good in 92,5% of cases.

Herrn Prof. Dr. Dr. h.c. W. Doerr aus gegebenem Anlaß zugeeignet     

Selective photothermolysis of lipid-rich tissues: a free electron laser study

BACKGROUND AND OBJECTIVES: In theory, infrared vibrational bands could be used for selective photothermolysis of lipid-rich tissues such as fat, sebaceous glands, or atherosclerotic plaques. STUDY DESIGN/MATERIALS AND METHODS: Absorption spectra of human fat were measured, identifying promising bands near 1,210 and 1,720 nm. Photothermal excitation of porcine fat and dermis were measured with a 3.5-5 microm thermal camera during exposure to the free electron laser (FEL) at Jefferson National Laboratory. Thermal damage to full-thickness samples exposed at approximately 1,210 nm through a cold contact window, was assessed by nitrobluetetrazolium chloride staining in situ and by light microscopy. RESULTS: Photothermal excitation of fat was twice that of dermis, at lipid absorption bands (1,210, 1,720 nm). At 1,210 nm, a subcutaneous fat layer several mm thick was damaged by FEL exposure, without apparent injury to overlying skin. CONCLUSION: Selective photothermal targeting of fatty tissues is feasible using infrared lipid absorption bands. Potential clinical applications are suggested by this FEL study.     

Inhibition of heat shock protein 90 (HSP90) as a therapeutic strategy for the treatment of myeloma and other cancers

Heat shock protein 90 (HSP90) is a molecular chaperone that is induced in response to cellular stress and stabilizes client proteins involved in cell cycle control and proliferative/anti-apoptotic signalling. HSP90 is overexpressed in a range of cancers, and may contribute to tumour cell survival by stabilizing aberrant signalling proteins and by interfering with apoptosis. Tanespimycin, an HSP90 inhibitor, reduces tumour cell survival in vitro. In multiple myeloma (MM), HSP90 inhibition affects multiple client proteins that contribute to tumour cell survival, including the IGF1 receptor and the IL-6 receptor, and elements of the PI3/Akt, STAT3, and MAPK signalling pathways. HSP90 inhibition also abrogates the protective effect of bone marrow stromal cells and inhibits angiogenesis and osteoclastogenesis. Tanespimycin acts synergistically with the proteasome inhibitor bortezomib in MM cells and tumour explants, possibly reducing their ability to resist bortezomib-induced stress to the endoplasmic reticulum. The combination of tanespimycin and bortezomib has demonstrated significant and durable responses with acceptable toxicity in a phase I/II study in patients with relapsed and relapsed/refractory MM. HSP90 inhibition is a promising strategy in MM especially in combination with bortezomib; additional studies will further evaluate optimal dosings of candidate drugs and schedules, as well as confirm efficacy in comparative phase III trials.     

Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63

Waanders E, Venselaar H, te Morsche RHM, de Koning DB, Kamath PS, Torres VE, Somlo S, Drenth JPH. Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation‐sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, Poly Phen , and p Mut and sift . We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non‐sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.     

A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma

The purpose of this study was to assess the safety and identify the recommended doses of enzastaurin and bortezomib in combination for future Phase II studies in patients with relapsed or refractory multiple myeloma. Three dose levels (DLs) of oral enzastaurin and intravenous bortezomib were used according to a conventional "3 + 3" design. A loading dose of enzastaurin (250 mg twice/day [BID]) on Day 1 was followed by enzastaurin 125 mg BID for 1 week, after which bortezomib was added (Cycle 1, 28 days, 1.0 mg/m(2) : Days 8, 11, 15, and 18; seven subsequent 21-day cycles, 1.3 mg/m(2) : Days 1, 4, 8, and 11). Twenty-three patients received treatment; all patients received prior systemic therapy. Most patients received ≥3 regimens; 17 patients were bortezomib-refractory. A median of four treatment cycles (range 1-24) was completed. No dose-limiting toxicities were observed; thus, DL 3 was the recommended Phase II dose. The most common drug-related Grade 3/4 toxicities were thrombocytopenia (n = 6) and anemia (n = 2). No patients died on therapy. One patient (DL 1) achieved a very good partial response; three patients (DLs 2 and 3), a partial response; nine patients, stable disease; and four patients, progressive disease. The recommended Phase II doses in patients with relapsed or refractory multiple myeloma are as follows: enzastaurin loading dose of 375 mg three times/day on Day 1 followed by 250 mg BID, with bortezomib 1.3 mg/m(2) on Days 1, 4, 8, and 11 of a 21-day cycle. The combination was well-tolerated and demonstrated some antimyeloma activity.     

Airway pressure release ventilation during ex vivo lung perfusion attenuates injury

Objective

Critical organ shortages have resulted in ex vivo lung perfusion gaining clinical acceptance for lung evaluation and rehabilitation to expand the use of donation after circulatory death organs for lung transplantation. We hypothesized that an innovative use of airway pressure release ventilation during ex vivo lung perfusion improves lung function after transplantation.