Introduction of SGRT in clinical practice.

To describe the rationale and process how SGRT was implemented in our department from the original decision to daily clinical practice.

Neuronal circadian clock protein oscillations are similar in behaviourally rhythmic forager honeybees and in arrhythmic nurses.

Internal clocks driving rhythms of about a day (circadian) are ubiquitous in animals, allowing them to anticipate environmental changes. Genetic or environmental disturbances to circadian clocks or the rhythms they produce are commonly associated with illness, compromised performance or reduced survival. Nevertheless, some animals including Arctic mammals, open sea fish and social insects such as honeybees are active around-the-clock with no apparent ill effects. The mechanisms allowing this remarkable natural plasticity are unknown. We generated and validated a new and specific antibody against the clock protein PERIOD of the honeybee Apis mellifera (amPER) and used it to characterize the circadian network in the honeybee brain. We found many similarities to Drosophila melanogaster and other insects, suggesting common anatomical organization principles in the insect clock that have not been appreciated before. Time course analyses revealed strong daily oscillations in amPER levels in foragers, which show circadian rhythms, and also in nurses that do not, although the latter have attenuated oscillations in brain mRNA clock gene levels. The oscillations in nurses show that activity can be uncoupled from the circadian network and support the hypothesis that a ticking circadian clock is essential even in around-the-clock active animals in a constant physical environment.

Optimal suturing techniques for superior results: hints from a plastic surgeon and a dermatologic surgeon.

Suturing the skin together has been a part of medicine for hundreds of years. Over the centuries, the materials used and techniques utilized have evolved. Presently, there are more than 100 materials that are used for suturing and the needles to place these materials are even more varied. Methods of placing sutures in the skin also vary and run the gamut from simple, running sutures to intricate mattress sutures. Each material and method has its place. This review will present a brief overview of the materials and methods used for suturing.

Rejuvenation of the lip with injectables.

As the range of soft tissue augmentation products proliferates, most will be used (with varying degrees of success) to shape and augment the lip. The range of outcomes for this indication depends on the skill of the injector, the anatomy of the patient and the intrinsic properties of the product. Permutations of these interacting factors are infinite and it is the range of combinations that is responsible for the complexity (and fascination) of lip rejuvenation with injectable products. Based on personal experience, the perfect lip is the one that "wows" the patient and makes them happy with the procedure. Individualizing the injection is of paramount importance and should take priority over a formulaic approach that defines each lip injection as identical. This review will discuss some of the factors that should be considered prior to injecting a lip with soft tissue augmentation products.

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Establishing radiological percutaneous gastrostomy with balloon-retained tubes as an alternative to endoscopic and surgical gastrostomy in patients with tumours of the head and neck or oesophagus.

The purpose of this study was to report our experience introducing radiological percutaneous gastrostomy (RPG) catheters at a hospital where hitherto only endoscopic and surgical methods have been used. The feasibility, success, time requirements, and complications of RPG were prospectively evaluated during a 12-month period. 26 consecutive patients (median age 63 years, range 41-91 years) underwent gastropexy with T-fasteners followed by insertion of a 12-18 F balloon tube through a peel-away introducer and were followed-up clinically and radiologically. Success and complications occurring within 30 days were assessed. RPG was technically successful in all cases. Median procedure time was 34 min (range 20-90 min), median fluoroscopy time 6.9 min (range 2.3-30 min). 13 surgical gastrostomies were avoided. One minor complication (peristomal leakage) occurred in a patient with gastric reflux and atony. Another patient destroyed the balloon of his tube by injecting food into the balloon port, which led to tube dislocation and peritonitis. In conclusion, radiological gastrostomy can be quickly learned by radiologists and is readily accepted by clinicians. It is an alternative to surgical gastrostomy when percutaneous endoscopic gastrostomy is not feasible, but can also be used as the primary method instead of the endoscopic method.

Evidence for a putative senescence gene locus within the chromosomal region 10p14-p15.

High-risk human papillomavirus (HPV) types 16 and 18 are involved in the multistep process of cervical cancer. Transfection of normal keratinocytes with high-risk HPV-DNA generally gives rise to immortal cultures. This may be explained by the loss of senescence genes as a consequence of HPV-induced genetic instability. On the basis of the dominance of cellular senescence over immortality, fusion of normal keratinocytes with HPV-immortalized cells results in complementation of these putative gene defects. In a previous study, we showed that underrepresentation of chromosome 10 is a characteristic phenomenon during the early phase of immortalization. Here we show that introduction of a normal copy of chromosome 10 into HPV16-immortalized cells (HPKII) by Microcell-mediated chromosome transfer resulted in senescence of a significant number of hybrids. By using several derivatives of chromosome 10 for further fusion experiments, the chromosomal region responsible for senescence could be assigned to 10p14-p15. The potential significance of loss of gene function in this region is underlined by the high frequency (38.7%) of loss of heterozygosity in cervical cancers including early stage tumors.

Identification of regions of Ail required for the invasion and serum resistance phenotypes.

Yersinia enterocolitica is an enteric pathogen that has served as a model system for the study of microbial pathogenesis. Numerous virulence gene have been identified both on the virulence plasmid and on the chromosome. One of the chromosomal genes that is highly correlated with virulence is ail, a gene identified along with inv in a screen for Y. enterocolitica genes that could confer an invasive phenotype to Escherichia coli. Ail also promotes serum resistance in both E. coli and Y. enterocolitica. Several virulence factors homologous to Ail have been identified in other pathogens, yet very little is known about what constitutes the functional domain(s) of these proteins. Proteins in this family are predicted to consist of eight transmembrane beta-sheets and four cell surface-exposed loops. We constructed and characterized a number of insertion, deletion and point mutations in the regions of ail predicted to encode the cell surface loops. The results from the analysis of these mutants indicate that cell surface loops one and four do not directly promote invasion or serum resistance, whereas mutations in loop three appear to modulate both phenotypes. Analysis of mutations in loop 2 suggests that this surface-exposed loop contains sequences required for serum resistance and invasion. In addition, a peptide derived from the sequence of loop 2 was able specifically to inhibit Ail-mediated invasion in a dose-dependent manner. These results suggest that Ail directly promotes invasion and that loop 2 contains an active site, perhaps a receptor-binding domain. Analyses of the mutations also suggest that the serum resistance and invasion phenotypes may be separable, because there are numerous mutations that affect one phenotype but not the other.

Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma.

BACKGROUND: Epidemiologic evidence points to a connection between viral infection by the human papillomavirus (HPV) and a subgroup of squamous cell carcinoma of the oropharynx. To assess the impact of HPV infection on the response of these tumors toward radiotherapy, the authors retrospectively determined the presence of the virus and the integrity of the viral E2 gene in tumors of patients who have undergone curative irradiation. METHODS: Paraffin embedded biopsies from 99 patients were analyzed for HPV infection and E2 gene integrity by multiplex PCR. The experimental findings were correlated with clinical characteristics, known risk factors, and treatment outcome. RESULTS: Fourteen of 99 tumors were HPV positive (11 HPV16, 1 HPV33, 1 HPV35, and 1 HPV45). Human papillomavirus positivity was closely linked to female gender (odds ratio [OR], 5.75; P = 0.004), age older than 56 years (OR, 7.42; P = 0.012), nonsmokers (OR, 21.33; P = 0.00001), and alcohol abstainers (OR, 5.35; P = 0.012). There was an inverse association with p53 nuclear immunoreactivity (OR, 0.06; P = 0.008). The Kaplan-Meier survival estimates showed a better local control (P = 0.050, log-rank) and a better overall survival (P = 0.046, log-rank) for patients with HPV positive tumors. In the multivariate analysis, HPV positivity remained to be associated with a lower risk of local failure (risk ratio [RR], 0.31; P = 0.048). Four of 11 HPV16 positive tumors had a disrupted E2 gene. Only tumors with a disrupted E2 gene manifested local treatment failure. CONCLUSIONS: Human papillomavirus positivity designates a specific subgroup of oropharyngeal squamous cell carcinomas of the oropharynx that arise preferentially among individuals with no consumption of tobacco and alcohol and that have a favorable outcome attributable to an increased sensitivity toward radiotherapy.

Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer.

Hypoxia has long been recognized as detrimental to the successful treatment of malignant tumors with ionizing radiation. Because hypoxia-inducible factor (HIF)-1alpha plays an essential role in oxygen homeostasis in vitro, we explored the predictive potential of this factor in a cohort of 98 patients with squamous cell cancer of the oropharynx, who were treated by curative radiation therapy. Ninety-four % of the primary tumors showed overexpression of HIF-1alpha, relative to the surrounding tissue, as determined by immunohistochemistry. The degree of HIF-1alpha immunoreactivity correlated inversely with both the rate of complete remission of the primary tumor (odds ratio, 0.33; P = 0.03) and lymph node metastases (odds ratio, 0.34; P = 0.02) as well as with local failure-free survival (risk ratio, 2.15; P = 0.006), disease-free survival (risk ratio, 2.01; P = 0.008), and overall survival (risk ratio, 2.17; P = 0.002). The multivariate analysis revealed the predictive power of HIF-1alpha to be independent of other covariables. We conclude that HIF-1alpha is overexpressed in the vast majority of patients with squamous cell cancer of the oropharynx and that the degree of expression has predictive and prognostic significance in individuals undergoing curative radiation therapy.

Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation.

The activation of cytoplasmic signal transduction pathways by a number of growth factors and their tyrosine-kinase receptors, including hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-met, exerts an inhibitory influence on apoptosis induced by ionizing radiation in vitro. The clinical relevance of the aforementioned ligand-receptor pair, of Bcl-xL, which is targeted by HGF/SF/c-met signaling, and of Bcl-2, was assessed by evaluating their predictive and prognostic impact in a cohort of 97 patients with radically irradiated squamous cell cancers of the oropharynx. Immunohistochemical expression of c-met and Bcl-xL was correlated with decreased rates of complete remission of the primary tumor in both the univariate (c-met: P = 0.01; Bcl-xL: P = 0.001) and multivariate analyses. Expression of c-met was, moreover, a significant and independent predictor of impaired local failure-free survival (P = 0.003), disease-free survival (P = 0.003) and overall survival (p = 0.001). Bcl-2 expression was, on the other hand, associated with a favorable outcome, in terms of both local failure-free survival (P = 0.01) and overall survival (P = 0.001). In accordance with in vitro data, c-met and Bcl-xL appear to be involved in the resistance of oropharyngeal cancers to ionizing radiation, and may therefore represent attractive targets for radiosensitization.

Intratumoral microvessel density predicts local treatment failure of radically irradiated squamous cell cancer of the oropharynx.

PURPOSE: To determine the predictive value of intratumoral microvessel density (IMD), and of the expression of p53, vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) for the radiocurability of patients with squamous cell cancer of the oropharynx. MATERIALS AND METHODS: 139 patients with squamous cell cancer of the oropharynx were radically irradiated (median dose, 74 Gy) between 1991 and 1997. Biopsies from 100 patients were processed for immunohistochemistry. IMD was determined in hot spot areas of tissue stained with anti-CD31 at a magnification of x200. Staining for p53 was considered positive if more than 10% of the cell nuclei overexpressed the protein. Immunostaining of VEGF and TSP-1 was assessed semiquantitatively. RESULTS: Increasing IMD (range, 54-282) was strongly correlated with incomplete remission of both the primary tumors (p = 0.01) and lymph node metastases (p = 0.02). Moreover, multivariate Cox regression analysis revealed local failure-free survival to decline with increasing IMD (IMD continuous: risk ratio = 1.01 per increase of 1 microvessel, p = 0. 0001; IMD categorical: 130: risk ratio = 13.01). Neither the expression of p53, nor that of VEGF or TSP-1 was associated with the treatment outcome or IMD, but VEGF and TSP-1 expression were positively correlated (p = 0.02). CONCLUSION: IMD represents a powerful and independent predictive factor for local treatment failure in radically irradiated patients with squamous cell cancer of the oropharynx.

Aprotinin decreases exposure to allogeneic blood during primary unilateral total hip replacement.

BACKGROUND: Aprotinin, a hemostatic agent, regulates fibrinolysis, modulates the intrinsic coagulation pathway, stabilizes platelet function, and exhibits anti-inflammatory properties through inhibition of serine proteases, such as trypsin, plasmin, and kallikrein. Aprotinin has been used successfully for many years in cardiac operations, and there have been preliminary investigations of its use in hip replacement operations. The objectives of this multicenter, randomized, placebo-controlled, double-blind trial were to evaluate the efficacy and safety of aprotinin as a blood-sparing agent in patients undergoing an elective primary unilateral total hip replacement and to examine its effect on the prevalence of deep-vein thrombosis in this population. METHODS: Seventy-three patients received a placebo; seventy-six patients, a low dose of aprotinin (a load of 500,000 kallikrein inhibitor units [KIU]); seventy-five, a medium dose of aprotinin (a load of 1,000,000 KIU, with infusion of 250,000 KIU per hour); and seventy-seven patients, a high dose of aprotinin (a load of 2,000,000 KIU, with infusion of 500,000 KIU per hour). The end points for the determination of efficacy were transfusion requirements and blood loss. Patients received standard prophylaxis against deep-vein thrombosis and underwent compression ultrasonography with color Doppler imaging of the proximal and distal venous systems of both legs to evaluate for the presence of deep-vein thrombosis. RESULTS: Aprotinin reduced the percentages of patients who required any form of blood transfusion (47 percent of the patients managed with a placebo needed a transfusion compared with 28 percent of those managed with low-dose aprotinin [p = 0.02],27 percent of those managed with high-dose aprotinin [p = 0.008], and 40 percent of those managed with medium-dose aprotinin [p = 0.5]). Only 6 percent (twelve) of the 212 patients treated with aprotinin required allogeneic blood compared with 15 percent (ten) of the sixty-eight patients treated with the placebo (p = 0.03). Aprotinin decreased the estimated intraoperative blood loss (p = 0.02 for the low-dose group, p = 0.04 for the medium-dose group, and p = 0.1 for the high-dose group), the measured postoperative drainage volume (p = 0.4 for the low-dose group, p = 0.006 for the medium-dose group, and p = 0.000 for the high-dose group), and the mean reduction in the hemoglobin level on the second postoperative day (thirty-four grams per liter for the placebo group, twenty-eight grams per liter for the low-dose group [p = 0.000], twenty-six grams per liter for the medium-dose group [p = 0.000], and twenty-three grams per liter for the high-dose group [p = 0.0001). The rate of deep-vein thrombosis was similar for all groups. CONCLUSIONS: We concluded that aprotinin is safe and effective for use as a hemostatic agent in primary unilateral total hip replacements. In patients who are at high risk of receiving allogeneic blood, use of aprotinin may be of particular clinical and economic benefit.

[Skin and mucous membrane reactions during and after radiotherapy]. / Haut- und Schleimhautreaktionen während und nach Radiotherapie.

The temporary acute reactions during radiotherapy are a burden for the patient. These reactions are due to a depletion of stem cells and depend on the single dose, the total dose and the irradiated volume. The WHO describes the acute changes in a graded scale from 0 to IV. A knowledge of the course of these events helps the otolaryngologist to inform patients competently, calm their fears and give support during treatment. Efficacious measures to alleviate symptoms are presented.

Carcinoma of the oropharynx: local failure as the decisive parameter for distant metastases and survival.

OBJECTIVE: How important and predictive are clinical parameters and locoregional failure after radical radiotherapy of oropharyngeal carcinomas for the probability of the occurrence of distant metastases? PATIENTS AND METHODS: From 1 August 1990 to 1 October 1998, 139 patients with carcinomas of the oropharynx were treated in a prospective study by radical radiotherapy and evaluated in regard to the clinical parameters reflex-otalgia, predominant structure of tumor growth, T-category, presence of involved lymph nodes, and smoking and drinking habits. Twenty-nine patients received a concomitant chemotherapy. Twenty-five out of 139 patients had a planned neck dissection after completion of radiotherapy. Ten patients received a salvage operation. RESULTS: The median follow up time was 24 months (range, 4 to 74). Two- and 5-year overall survival rates according to Kaplan Meier were 56.1 and 49.6%. The tumors were controlled in 77/139 patients (55%). The therapy failed in 62/139 patients (45%). Both groups, 62 patients with locoregional therapy failure and 77 patients with locoregionally control led tumors, were comparable in regard to performance status (Karnofsky index), age, gender, TNM-categories, histological differentiation, drinking habits, pretherapeutic diagnostics, total dose (Gy), and number of simultaneous chemotherapy cycles. Locoregional tumor control was significantly determined by the parameters reflex-otalgia (p < 0.0078), predominant growth pattern (p < 0.012), T-category (p < 0.03), and smoking (p < 0.0285). The median survival time of patients with locoregional failure is 17 months. At this moment 81% of locoregionally controlled patients are still alive. In 14/62 patients (23%) with locoregional failure, distant metastases were detectable against 4/77 (5%) of locally controlled patients, p < 0.0026. Probability of local control and distant metastases, predominantly pulmonary, reached a plateau after 24 months. CONCLUSIONS: Locoregional tumor control, determined by several clinical parameters, is an important parameter for the probability of the development of distant metastases. Failure of local therapy is caused by the biologic aggressiveness of the tumor.

[Campaign against radio-xerostomia]. / Kampf der Radio-Xerostomie.

The radiation induced xerostomia is a common and, up to now, irreversible side effect of the definitive or postoperative treatment of ENT cancers. A possible mechanism is the apoptosis of serous gland cells. The sequelae of xerostomia are increasing cavities, plaques and parodontosis, infections in the pharynx, taste alterations and weight loss. Therapeutic approaches include improved oral hygiene, dietetic adjustments, artificial saliva and most recently, medication. Pilocarpine, a parasympathomimeticum, results in a degranulation of the secretoric granula and consequently, lowers the radiosensitivity of the cells. Amifostine acts a scavenger of radicals and is concurrently tested in a phase III clinical trial to evaluate the selective protection of normal tissue during radiotherapy.

[Management of skin and mucous membrane reactions in patients treated with irradiation]. / Die Pflege von Haut- und Schleimhautreaktionen bei Patientlnnen, die bestrahlt werden.

Acute reactions during radiotherapy are due to a depletion of stem cells. Depending on single and total dose and the irradiated volume there is a different degree of changes of the skin and mucosa. To alleviate symptoms, several efficacious, prophylactic measures of care should be used.

[Predictive significance of reflex otalgia in local radical radiotherapy of oropharyngeal carcinomas]. / Prädiktive Bedeutung der Reflexotalgie in der lokal radikalen Radiotherapie von Oropharynxkarzinomen.

BACKGROUND: Patients with carcinomas of the upper aero-digestive tract often suffer from ear pain as a tumor associated syndrome. This prospective study examines the predictive and prognostic value of this symptom. PATIENTS AND METHODS: Ninety-six consecutive patients who completed a locally radiotherapy of a carcinoma of the oropharynx were prospectively evaluated and followed. Forty-nine out of 96 patients stated the symptom, either spontaneously or after questioning. The 2 groups showed no difference regarding TNM-classification, histology and total dose. Overall survival, local control and disease specific survival were calculated according to Kaplan-Meier and compared by the log-rank test. RESULTS: A clinically complete remission was obtained in significantly fewer patients with reflex-otalgia as compared to patients without reflex-otalgia, 61.2% versus 89.3%, p < 0.002. Local control of patients with reflex-otalgia was significantly less with 49%, mean follow-up 564 days, in comparison to local control in patients without reflex-otalgia, mean follow-up 613 days, p = 0.01. Disease specific survival was significantly worse for patients with reflex-otalgia, p < 0.012. The probability of local control of T1/T2 tumors with reflex-otalgia was similar to T3/T4 tumors without reflex-otalgia. Local control for all tumor categories combined is 74% for patients without reflex-otalgia versus 49% for patients with reflex-otalgia. CONCLUSION: In our patients, reflex-otalgia is a new and statistically significant parameter for the probability of local control and disease specific survival.

No predictive value of the micronucleus assay for patients with severe acute reaction of normal tissue after radiotherapy.

In approximately 5% of cancer patients undergoing radiotherapy, this treatment has to be interrupted because of an acute reaction of normal tissues. To test the possibility of predicting this type of reaction, the micronucleus assay was used to determine radiosensitivities of peripheral blood lymphocytes of 15 patients with severe acute reaction of normal tissue, 15 patients without this reaction and 15 healthy donors. Whole-blood cultures were irradiated with X-rays (4 Gy, 1.08 Gy/min) and treated with cytochalasin B. The micronuclei scores observed in irradiated cells were corrected for the scores in unirradiated cells. Intra-individual and interindividual variations in micronuclei scores were analysed in samples from healthy donors, and highly significant interindividual differences were found (P < 0.001). Scores of cells not irradiated in vitro were higher for cancer patients before radiotherapy than for healthy donors (P < 0.001), and those for cancer patients after radiotherapy were higher than for patients before radiotherapy (P < 0.001). Average micronuclei scores induced by in vitro irradiation were significantly higher in samples from cancer patients compared with those from healthy donors (P < 0.01). Moreover, all subgroups of cancer patients included individuals with very high levels of micronuclei after in vitro irradiation. There was, however, no relationship between the micronuclei scores and the occurrence of severe acute reactions in normal tissues.