[Genetics of recurrent airway obstruction (RAO)]. / Genetik der rezidivierenden Atemwegsobstruktion (RAO).

Recurrent airway obstruction (RAO) is a multifactorial and polygenic disease. Affected horses are typically 7 years of age or older and show exercise intolerance, increased breathing effort, coughing, airway neutrophilia, mucus accumulation and hyperreactivity as well as cholinergic bronchospasm. The environmental factors responsible are predominantly allergens and irritants in haydust, but the immunological mechanisms underlying RAO are still unclear. Several studies have demonstrated a familiar predisposition for RAO and it is now proven that the disease has a genetic basis. In offspring, the risk of developing RAO is 3-fold increased when one parent is affected and increases to almost 5-fold when both parents have RAO. Segregation analysis in two high-prevalence families demonstrated a high heritability and a complex inheritance with several major genes. A whole genomescan showed chromosome-wide significant linkage of seven chromosomal regions with RAO. Of the microsatellites, which were located near atopy candidate genes, those in a region of chromosome 13 harboring the IL4R gene were strongly associated with the RAO phenotype in the offspring of one RAO-affected stallion. Furthermore, IgE-levels are influenced by hereditary factors in the horse, and we have evidence that RAO-affected offspring of the same stallion have increased levels of specific IgE against moldspore allergens. The identification of genetic markers and ultimately of the responsible genes will not only allow for an improved prophylaxis, i.e. early identification of susceptible individuals and avoidance of high-risk matings, but also improve our ability to find new therapeutic targets and to optimize existing treatments.

Sustainability in humanitarian surgery during medical short-term trips (MSTs): feasibility of inguinal hernia repair in rural Nigeria over 6 years and 13 missions.

PURPOSE: Surgical teaching missions are known to contribute significantly in reducing the local burden of disease. However, the value of short-term medical service trips (MSTs) remains under debate. Humanitarian surgery is highly dependent on funding, and consequently, data evaluation is needed to secure funding for future projects. The aim of this trial is to evaluate the results of 6-year MSTs to rural Nigeria with a specific emphasis on hernia repairs. METHODS: Retrospective series of consecutive operations performed between 2011 and 2016 in rural Nigeria during 13 MSTs. Operations were categorized into type and number of procedures and origin of the surgeon. In terms of inguinal hernia repairs additional data was evaluated such as frequency of local anaesthesia (LA) and the type of hernia. The total amount of disability-adjusted life years (DALYs) averted during each mission are presented and discussed with regard to sustainability of these missions. RESULTS: From 2011 to 2016, a total of 1674 patients were operated. Of these, 1302 patients were operated for 1481 hernias of which 36.7% accounting as inguinoscrotal hernias. The percentage of operations performed by Nigerian staff increased from 31 to 55%. Overall, eighteen percent of the operations was solely performed by Nigerians. Totally, we averted 8092.83 DALY's accounting for 5.46 DALY's per hernia. CONCLUSION: The presented missions contribute significantly to an improvement in local healthcare and decrease the burden of disease. We were able to show the sustainable character of these surgical missions. As a next step, we will analyse the cost-effectiveness of MSTs.

Submassive pulmonary embolism and muscular calf vein thrombosis after complicated hip fracture.

The clinical relevance of distal deep vein thrombosis is discussed controversly. A 26-year-old man presented with dyspnea on exertion and pleuritic pain since the day before. Five weeks ago, he sustained multiple fractures at an accident--among others a complicated hip fracture needing screw fixation. He stopped the antithrombotic prophylaxis three days before admission. Our examinations showed calf muscle vein thrombosis and submassive bilateral pulmonary embolism. Due to our own clinical experiences, we support an anticoagulation treatment with compression therapy for isolated calf muscle vein thrombosis in patients with coexisting risk factors for venous thromboembolism.

[Acute vascular occlusion of the upper extremity after blunt trauma]. / Akuter Gefässverschluss der oberen Extremität nach stumpfem Trauma.

Intimal ruptures after blunt trauma without joint dislocation are rare. We report the case of a 62 year old male patient presenting with paraesthesia in the fingers I to III and a cool left hand after a blunt trauma of the upper arm. Non-invasive examination documented the thrombotic occlusion of the axillary artery. Due to a circular rupture of the intima surgical revascularization was performed with a vein graft.

Percutaneous embolization of renal arteriovenous fistula.

Acquired renal arteriovenous fistula is a rare complication following a nephrectomy and its diagnosis may be made many years after the intervention. The closure of the fistula is advisable in most cases, since it represents a risk for heart failure and rupture of the vessel. There are an increasing number of publications describing different techniques of occlusion. The case of a 70-year-old woman with abdominal discomfort due to a large renal arteriovenous fistula, 45 years after nephrectomy, is presented and current literature is reviewed. Percutaneous embolization was performed by placing an occluding balloon through the draining vein followed by the release of nine coils through arterial access. One day after successful occlusion of the fistula, clinical symptoms disappeared.

[First experience with a critical incident reporting system in surgery]. / Critical incident reporting system. Erste Erfahrungen in der Chirurgie.

Systems that record critical incidents were initially developed for aeronautics and are being increasingly applied in medicine. The objective is to detect problems inherent to systems and system errors before they lead to complications or do harm to patients. We report our preliminary experience with a critical incident reporting system (CIRS). Since February 1 2001, all employees of our surgical department have been able to report incidents, anonymously or candidly, to a central board using a standardized documentation form. The results are presented at monthly internal quality meetings, where two to three crucial incidences are thoroughly discussed. New information is communicated and put into practice as quickly as possible. A total of 424 incidents were reported from February 1, 2001 to December 31, 2003. Reversible damages, some of which resulted in prolonged hospitalization, were consequential to 22% of the cases. Thirteen percent were classified as "near miss" (almost incidents), whereas 65% had no consequences for patients. As expected, doctors and nurses were most frequently involved, as 36% of the reported incidents occurred in connection with the prescription and administration of medication. In particular, the near miss category revealed system errors which in 85% of cases had immediate consequences for therapeutic procedures. Based on our initial experiences, working with CIRS may be evaluated as positive. The open discussion of incidents and errors also revealed minor but often significant system errors, which resulted in alteration of our internal proceedings and thus improved the quality and safety of treatment.

[The role of video-thoracoscopy in thoracic surgery]. / Video-thorakoskopische Eingriffe--was hat sich durchgesetzt.

The widespread acceptance of minimal invasive techniques has revolutionized the practice of surgery including, thoracic surgery. Within a short period of time, video-assisted thoracic surgery (VATS) has become an acceptable approach to a wide range of thoracic procedures. The use of VATS as a diagnostic modality is now well established. For therapeutic procedures, VATS has also been generally accepted as the treatment for spontaneous pneumothorax, thoracic sympathectomy, treatment of loculated effusions and resection of simple mediastinal cysts and benign tumors. Its role in major procedures, e.g. anatomic lung resections and thymectomy, however, remain poorly defined at present although some of the existing intermediate results are encouraging. The technique continues to evolve, with further miniaturization to reduce access-induced trauma. No matter how attractive the new techniques may appear, carefully conducted clinical trials should precede the general acceptance and widespread use.

Synthesis and structure-activity relationships of benzo[b]thienylallylamine antimycotics.

Benzo[b]thiophene analogues of the allylamine antimycotic terbinafine (2) bearing the side chain at various positions and optionally substituted by halogen have been prepared and their antifungal activity studied. Derivatives bearing the side chain at positions 3, 4, or 7 are bioequivalents of 2. Compounds containing the allylamine side chain at position 7, with a further substituent at position 3, showed significantly enhanced activity against Candida albicans, an effect which appears to be specifically linked only to this particular substitution pattern. 3-Chloro-7-benzo[b]thienyl derivative 7m was found to be the most potent allylamine antimycotic identified so far. In general, substituted benzo[b]thiophenes can be used not only as potential equivalents of naphthalene in bioactive compounds but also as a tool to selectively modify biological activities.

Synthesis and structure-activity relationships of the novel homopropargylamine antimycotics.

Analogues of the antimycotic allylamine terbinafine were prepared in which the naphthalene and the tert-butyl-acetylene moieties were preserved, but the spacer between these two groups was varied, and the antifungal activity of the new compounds was evaluated. All modifications of the original spacer such as reduction of the double bond, switching the position of the nitrogen atom, shortening, and elongation resulted in decreased potencies with one exception: Compounds with the CH2NMeCH2CH2 group between the 1-naphthalene and the optionally substituted tert-butyl-acetylene function demonstrated high antifungal activity in vitro. The new homopropargylamine derivatives are more potent than terbinafine against Aspergillus fumigatus. The results support the hypothesis that two lipophilic domains linked by a spacer of appropriate length and a polar center at a defined position in the spacer are the general requirements for high activity of allylamine antimycotics.

Synthesis and structure-activity relationships of side-chain-substituted analogs of the allylamine antimycotic terbinafine lacking the central amino function.

Terbinafine is a therapeutically used inhibitor of fungal squalene epoxidase that has prompted extensive derivatization programs for structure-activity relationship studies. In the present study, derivatives of terbinafine were synthesized that lack the central tertiary amino group but have polar substitutents at the tert-butyl residue of the side chain. Evaluation of the antifungal potential revealed that representatives of this novel structural type can also exhibit broad antifungal activity, indicating that the central amino function of allylamine antimycotics is not essential for inhibition of fungal growth. Potency appears to correlate with the polarity of the introduced functional groups, while broad antifungal activity seems to be restricted to compounds with basic substituents. The dimethylamino-substituted "carba-analog" of terbinafine (8k) showed the best antimycotic profile within the whole series.

Novel antiproliferative agents derived from lavendustin A.

The active partial structure of the potent tyrosine kinase inhibitor lavendustin A was derivatized in the search for novel agents against cellular proliferation. The antiproliferative potential of the new derivatives was determined using the human keratinocyte cell line HaCaT as the primary test system. Whereas the lavendustin A partial structure is ineffective in inhibiting cell proliferation, esterification of its carboxylic acid function leads to measurable antiproliferative activity. Additional O-methylation of the 2,5-dihydroxyphenyl moiety yields activity in the micromolar range. Further substantial increases in activity are achieved by replacing the nitrogen with oxygen and carbon within the 2,5-dimethoxyphenyl series (but not within the 2,5-dihydroxyphenyl analogs) leading to 5-[2-(2,5-dimethoxyphenyl) ethyl]-2-hydroxybenzoic acid methyl ester (13) as the most potent analog identified to date. These increases in antiproliferative activity are paralleled, however, by the disappearance of activity against the epidermal growth factor receptor-associated tyrosine kinase, suggesting another mechanism of action.

Synthesis and structure-activity relationships of phenyl-substituted benzylamine antimycotics: a novel benzylbenzylamine antifungal agent for systemic treatment.

Derivatives of the benzylamine antimycotics with an extra phenyl ring incorporated in the side chain have been prepared and their antifungal activity evaluated. The potency is strongly dependent on the distance between the two phenyl groups and the type of spacer. Linking the aryl rings with a quaternary carbon atom resulted in the identification of highly active compounds 7f and 12a, having a novel 4-benzylbenzylamine side chain. Compound 7f and its 7-benzo[b]thienyl analogue 12a show significantly enhanced efficacy, in particular against Candida albicans, and are among the most potent allyl/benzylamine antimycotics identified so far. Extended investigations with the benzylbenzylamine derivative 7f revealed that, in addition to the enhanced antimycotic profile, the compound is the first representative of the benzylamine antimycotics suitable for systemic treatment.

Synthesis and structure-activity relationships of naphthalene-substituted derivatives of the allylamine antimycotic terbinafine.

Derivatives of the allylamine antimycotic terbinafine (1) with varied substitution at the naphthalene ring system have been prepared, and their antifungal activity has been evaluated. In general, the potency is strongly dependent on the bulkiness of the substituent. Only hydrogen or in some cases fluorine are tolerated as substituents at positions 2-4 and 6-8 of the naphthalene moiety, whereas 5-substituents may be larger in size (F, Cl, Br, Me). Derivatives with fluorine at positions 3, 5, and 7 or chlorine at position 5 showed enhanced activity against yeasts relative to 1. This increase in sensitivity could be intensified by simultaneous introduction of two fluoro substituents at positions 5 and 7. Compound 7q demonstrated 8- to 16-fold improved potency against Aspergillus fumigatus, Candida albicans, and Candida parapsilosis.

Long-term outlook after atrial correction of transposition of great arteries.

Late results were reviewed in 220 survivors after atrial correction of transposition of the great arteries who were operated between 1964 and 1985. Senning's procedure and its various modifications have been used; all patients who survived 30 days after correction were included in this analysis. Average follow-up for the whole group was 10.3 years; 113 patients were observed for 10 years, 26 patients for 15 years, and 8 patients for 20 years. The actuarial survival rate for the whole group was 89% at 10 years, 87% at 15 years, 82% at 20 years. It was higher in simple than in complex transposition (92% versus 84% at 10 years). Sudden deaths (8 patients) and late heart failure (6 patients) were the principal causes of death, predominantly in the complex transposition group (10/13 deaths). Late survival was more common in the latter part of the study, with 95% of patients operated on after 1978 surviving 9 years as opposed to 84% of patients operated on earlier. Late reoperation was necessary in 18 patients (8%), with 12 reoperations occurring within 2 years after correction. Cumulative reoperation rate reached 11.7% after 10 years. Reoperations were more common in complex than in simple transposition (14% versus 6%, p less than 0.05). Late arrhythmias can occur after atrial correction, and the cumulative incidence of pacemaker implantations was 8% at 10 years. Most of the survivors are functionally free of symptoms (83% of the simple and 75% of the complex transposition group). Significant tricuspid valve incompetence was encountered in only three patients, with two valve reconstructions being possible. In summary, long-term outlook for survivors of atrial correction for transposition of the great arteries remains encouraging, although complex transposition does seem to engender more late problems. Atrial correction is still warranted in simple transposition, but close cardiological surveillance is necessary.

Stimulation of MCF-7 breast cancer cell proliferation by estrone sulfate and dehydroepiandrosterone sulfate: inhibition by novel non-steroidal steroid sulfatase inhibitors.

Steroid sulfatase (STS) regulates the formation of active steroids from systemic precursors, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS). In breast tissues, this pathway is a source for local production of estrogens, which support the growth of endocrine-dependent tumours. Therefore, inhibitors of STS could have therapeutic potential. In this study, we report on substituted chromenone sulfamates as a novel class of non-steroidal irreversible inhibitors of STS. The compounds are substantially more potent (6- to 80-fold) than previously described types of non-steroidal inhibitors when tested against purified STS. In MCF-7 breast cancer cells, they inhibit STS activity with IC(50) below 100 pM. Importantly, the compounds also potently block estrone sulfate-stimulated growth of MCF-7 cells, again with IC(50) below 100 pM. For one compound, we also observed a lack of any estrogenic effect at high concentrations (1 microM). We also demonstrate for the first time that STS inhibitors can block the DHEAS-stimulated growth of MCF-7 cells. Interestingly, this cannot be achieved with specific inhibitors of the aromatase, suggesting that stimulation of MCF-7 cell growth by DHEAS follows an aromatase-independent pathway. This gives further justification to consider steroid sulfatase inhibitors as potential drugs in the therapy of breast cancer.

Hairy roots of Datura candida×D. aurea: effect of culture medium composition on growth and alkaloid biosynthesis.

A transformed root clone of Datura candida×D. aurea was established following infection with Agrobacterium rhizogenes strain A4. This clone was examined for its growth and hyoscyamine and scopolamine content under various culture conditions. Among the three basal culture media tested, half-strength Gamborg's B5 medium supplemented with 5% sucrose was the best for root growth (288 mg dry weight/flask) and full-strength B5 medium for hyoscyamine and scopolamine content (0.36 and 0.17% dry weight, respectively). Experiments with exogenous nitrate added to the medium revealed that the biomass increased (353 mg dry weight/flask) and the hyoscyamine content improved remarkably (0.54% dry weight), but that the scopolamine content was significantly reduced. The addition of various precursors at two different concentrations did not significantly modify root growth. Feeding (R,S)-phenyllactic acid stimulated the biosynthesis of both alkaloids, whereas the addition of ornithine specifically reduced the scopolamine content.

[Perianal mucinous adenocarcinoma. A further reason for histological study of anal fistula or anorectal abscess]. / Das perianale mucinöse Adenocarcinom. Ein weiterer Grund für die histologische Untersuchung bei Analfistel oder Anorectalabscess.

A 39-year-old man came to us for surgical treatment of a hidradenitis suppurativa. Upon excision of a perianal abscess, the diagnosis of a rare tumor, a perianal mucinous adenocarcinoma (pT4, pN 1, MO), was made. An abdominoperineal resection was performed, followed by a combination of adjuvant radiation and chemotherapy. A year after the operation, the patient is doing well without any signs of recurrence. This carcinoma probably arises in the anal glands. It often presents as a perirectal abscess and/or an anal fistula. Therefore, the diagnosis is often delayed. At presentation, the tumor is bigger than 5 cm in diameter in 80% of the cases, and the prognosis is poor. It metastasizes mostly to the superficial inguinal or to the retrorectal lymph nodes. There are only case reports and no comparative studies in the literature. In the last 10 years, the carcinoma has mostly been treated by neoadjuvant radiation and chemotherapy, followed by abdominoperineal resection. Since then, the median survival has increased to 3 years. This is the first case report of a combination of a perianal mucinous adenocarcinoma with a hidradenitis suppurativa.

Lower shedding of strongylid eggs by Warmblood horses with recurrent airway obstruction compared to unrelated healthy horses.

An association between equine recurrent airway obstruction (RAO) and increased resistance to intestinal parasites has been demonstrated in descendants of an RAO-affected stallion. It was hypothesised that members of another high-incidence RAO family (F) and unrelated RAO-affected Warmblood horses (UA) would shed fewer strongylid eggs than unrelated RAO-unaffected pasture mates (PM) under the same environmental conditions. Faecal worm egg counts were performed on faecal samples (63 F, 86 UA, 149 PM) and classified into three categories: 0, 1-100 and >100 eggs per gram. While results for F did not differ from PM, UA were 2.5-times less likely to shed strongylid eggs than PM. RAO-affected Warmblood horses may be more resistant to strongylid nematodes than unrelated unaffected pasture mates and a family history of RAO does not necessarily confer protection against helminth infections.

[Endoscopic pre-peritoneal prolene mesh-plasty for management of inguinal and femoral hernias]. / Die endoskopische präperitoneale Prolennetzplastik zur Versorgung von Inguinal- und Femoralhernien.

From October 1994 to March 1996 158 inguinal or femoral hernias were repaired in 124 patients through a total extraperitoneal approach. The repairs were done with polypropylene mesh. The patients were seen 6 to 8 weeks postop; until today 57 patients were seen 12 months postop. This method favours an early return to work. Patients with unilateral hernias returned to work after an average of 14 days, patients with bilateral hernias after an average of 19 days. Complications were rare and mostly minor. So far we have seen no recurrences and no mesh related complications. We consider the laparoscopic extraperitoneal mesh repair a safe procedure for inguinal and femoral hernias.