Clinical efficacy of a dry extract of five herbal drugs in acute viral rhinosinusitis.

OBJECTIVE: A herbal drug combination (Dry Extract BNO 1016) has been assessed for efficacy and tolerability in patients with acute viral rhinosinusitis. METHODOLOGY: In this randomised, controlled trial patients with symptom duration of up to 3 days, mild to moderate facial pain and a Major Symptom Score (MSS) between 8 and 12 were treated for 15 days with BNO 1016 or placebo (coated tablets administered orally). Primary efficacy endpoint was mean MSS at end of treatment. Secondary outcome measures included treatment response and changes in paranasal sinuses assessed by ultrasonography. RESULTS: Treatment resulted in clinically relevant, significant differences in mean MSS for BNO 1016 versus placebo. BNO 1016 provided symptom relief two days earlier than placebo. The number needed to treat for healing is 8. BNO 1016 was superior regarding responder rates at Day 10 and Day 14 and percentage of patients without signs of acute viral rhinosinusitis assessed by ultrasonography at end of treatment. BNO 1016 was well tolerated; no serious adverse events were reported. CONCLUSION: The herbal dry extract BNO 1016 is efficacious and well tolerated in patients with acute viral rhinosinusitis. TRIAL REGISTRATION: ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT01146860; EudraCT: 2009-016682-28).

[Adenocarcinoma in the tear sack after endonasal dacryocystorhinostomy]. / Adenokarzinom des Tränensackes nach endonasaler Dakryozystorhinostomie.

Primary adenocarcinoma of the nasolacrimal drainage system is a highly uncommon diagnosis, which is presumably derived from malignantly transformed glandular cells that are interspersed amongst the epithelium of the nasolacrimal duct. The patients usually present with unspecific orbital or sinus-nasal symptoms. An appropriate therapeutic regime consists of a preferably early, radical resection and local postoperative radiation therapy. This brief contribution deals with an especially uncommon case of a carcinoma of the nasolacrimal drainage system. On his first presentation, the 62-year old patient complained about right sided epiphora which had been present over the last few weeks. Eight years prior to presentation, he had been treated for a nasolacrimal duct stenosis by endoscopic dacryocystorhinostomy on this side. Diagnostic imaging revealed a soft tissue mass in the right nasolacrimal duct which was removed by a combined extra-endonasal approach. The final histopathological evaluation was adenocarcinoma. Following postoperative radiotherapy, the patient has been free of disease for 42 months. The occurrence of adenocarcinoma of the nasolacrimal drainage system in the setting of previous surgery may provide a new insight into the clinical spectrum of the natural history of this disease.

Estimation of relative blood volume in head and neck squamous cell carcinomas.

PURPOSE: MR based first-pass method can be utilized to obtain hemodynamic information in the head and neck region. The purpose of this study was to estimate the regional relative blood volume (rBV) in head and neck tumors, which is useful for tumor staging and tumor biopsy. METHODS: Eighteen patients with head and neck tumors (17 squamous cell carcinomas, 1 hemangiopericytoma) were studied on a 1.5-T system. Conventional T1-weighted MR images and T2-weighted images and sequential T2*-weighted images were obtained. During repetitive image sequence acquisition, a bolus (0.2 mmol/kg) of gadopentetate dimeglumine was mechanically injected. Image processing of the dynamic raw data was performed on a pixel-by-pixel basis. RESULTS: Regional relative blood volume maps of the head and neck were successfully reconstructed in all (18/18) patients. The regional relative blood volume values within the tumor area of squamous cell carcinoma were 7.0 +/- 2.8, normalized on muscle, whereas the rBV of a single hemangiopericytoma was 11.6. The difference of rBV values of tumor and muscle was highly significant at statistical evaluation (p < 0.001). CONCLUSIONS: Relative blood volume imaging of head and neck tumors is valid using MR-based first-pass method. This method provides hemodynamic information which is not available from conventional MR imaging and is promising for further characterization of head and neck tumors

Nasopharyngeal epignathus causing nasal airway blocking in a 4-year old child.

Congenital oral teratoma or epignathus is a very rare lesion, especially in older children. We report on a 4-year old female infant presenting with nasal blocking, little watery discharge and recurrent otitis. First adenoids were suspected. An endoscopic examination of the nose and nasopharynx demonstrated an irregular mass in the nasopharynx, covered partly by mucosa. A MRI-scan (T1-weighted) showed fat-intensity. Histological examination revealed a teratomatous malformation. Although rare, teratoma should be included in the differential diagnosis of a nasopharyngeal mass in the paediatric age group.

In vivo cancer gene therapy by adenovirus-mediated transfer of a bifunctional yeast cytosine deaminase/uracil phosphoribosyltransferase fusion gene.

Direct transfer of prodrug activation systems into tumors was demonstrated to be an attractive method for the selective in vivo elimination of tumor cells. However, most current suicide gene therapy strategies are still handicapped by a poor efficiency of in vivo gene transfer and a limited bystander cell killing effect. In this study, we describe a novel and highly potent suicide gene derived from the Saccharomyces cerevisiae cytosine deaminase (FCY1) and uracil phosphoribosyltransferase genes (FUR1). This suicide gene, designated FCU1, encodes a bifunctional chimeric protein that combines the enzymatic activities of FCY1 and FUR1 and efficiently catalyzes the direct conversion of 5-FC, a nontoxic antifungal agent, into the toxic metabolites 5-fluorouracil and 5-fluorouridine-5'monophosphate, thus bypassing the natural resistance of certain human tumor cells to 5-fluorouracil. Unexpectedly, although the uracil phosphoribosyltransferase activity of FCU1 was equivalent to that encoded by FUR1, its cytosine deaminase activity was 100-fold higher than the one encoded by FCY1. As a consequence, tumor cells transduced with an adenovirus expressing FCU1 (Ad-FCU1) were sensitive to concentrations of 5-FC 1000-fold lower than the ones used for cells transduced with a vector expressing FCY1 (Ad-FCY1). Furthermore, bystander cell killing was also more effective in cells transduced with Ad-FCU1 than in cultures infected with Ad-FCY1 or Ad-FUR1, alone or in combination. Finally, intratumoral injections of Ad-FCU1 into allo- or xenogeneic tumors implanted s.c. into mice, with concomitant systemic administration of 5-FC, led to substantial delays in tumor growth. These unique properties make of the FCU1/5-FC prodrug activation system a novel and powerful candidate for cancer gene therapy strategies.

[Rhinitis, sore throate and otalgia... Benign common cold or dangerous infection?]. / Schnupfen, Hals- und Ohrenweh.... Harmlose Erkältung oder bedrohlicher Infekt?

One of mankind's most common illnesses is rhinitis, which almost regularly leads to involvement of the paranasal sinuses. Acute sinusitis is a consequence of a viral infection which, by damaging the mucosa, opens the door to bacterial superinfection. The aim of treatment is to cure the acute inflammation, re-establish normal drainage and ventilation, and prevent the development of "rhinosinugenic" complications. Acute otitis media is also preceded by viral damage to the mucosa. In children, acute otitis media is favored by the short, straight Eustachian tube, and often by adenoids. The therapeutic aim of antibiotic treatment and decongestive nose drops is to re-establish the draining function of the tube. Children who suffer from otitis media several times a year, need adenoidectomy. Acute tonsillitis, or quinsy, should be distinguished in particular from infectious mononucleosis. It is imperative to recognize a peritonsillar abscess, which requires more aggressive treatment.

[Rapidly progressing course of cutaneous angiosarcoma in the area of the head-neck]. / Rapid progredient verlaufendes kutanes Angiosarkom im Kopf-Hals-Bereich.

INTRODUCTION: Angiosarcomas are rare, aggressive tumors of vascular origin, most commonly affecting older males. An optimum treatment strategy has not yet been defined. CASE REPORT: We report on a 68-year-old male patient who initially presented with a small, bruise-like macule of the cheek. He was treated with different antibiotics and steroids for a few weeks. Due to failure of any clinical improvement, a biopsy was taken revealing an undifferentiated malignant tumor. Subsequently, the patient was referred to our department, where the lesion was excised. Histology showed an extensive, well-differentiated angiosarcoma. According to oncological protocols, the patient underwent 5 cycles of chemotherapy with etoposid, ifosphamid and adriamycine. Despite therapy, tumor size remained unchanged. After therapy was discontinued, tumor growth rapidly proceeded with semicircular infiltration of the right face and neck. A few weeks later the patient died. DISCUSSION: About 50 percent of cutaneous angiosarcomas are found in the head and neck region of the elderly. No clear etiology has been implicated with respect to the origin of this tumor. Traumatic bruises, infections, and allergic reaction may be confused clinically with angiosarcoma. Differential diagnosis also comprises other vascular neoplastic diseases, i.e. lymphangioma, hemangiopericytoma and Kaposi's sarcoma. If complete excision is possible, radical surgery is the treatment of choice. The effectiveness of chemotherapy is unclear. The role of radiation therapy is also under discussion due to the technical problems of administering radiotherapy to the extensive volume at risk. As the late diagnosis adversely affects the prognosis, the importance of early biopsy in suspicious lesions is mandatory.

New insights into the pyrimidine salvage pathway of Saccharomyces cerevisiae: requirement of six genes for cytidine metabolism.

Cytidine metabolism in the yeast Saccharomyces cerevisiae was analyzed by genetic and biochemical approaches. Disruption of a unique ORF (Genbank accession No. U 20865) bearing homology with eucaryotic or bacterial cytidine deaminases abolished cytidine deaminase activity and resulted in 5-fluorocytidine resistance. The gene encoding cytidine deaminase will be referred to as CDD1 (Genbank accession number AF080089). The ability to isolate mutants resistant to 5-fluorocytidine which mapped to five other loci demonstrated the existence of a complex cytidine metabolic network. Deciphering this network revealed several original features:(1) cytidine entry is mediated by the purine-cytosine transporter (Fcy2p),(2) cytidine is cleaved into cytosine by the uridine nucleosidase (Urh1p),(3) cytidine is phosphorylated into CMP by the uridine kinase (Urk1p),(4) a block in cytosine deaminase (Fcy1p), but not in cytidine deaminase (Cdd1p), constitutes a limiting step in cytidine utilisation as a UMP precursor.

Changes in head and neck tumor hypoxic fraction during split-course radiochemotherapy.

This study explored patterns of oxygen distribution in human tumors during primary radiochemotherapy. Patients with positive nodes from head and neck squamous cell carcinoma (n = 15) were investigated before therapy, before and after a 2-week respite, and at the end of the treatment. Intratumoral tissue oxygen tension (pO2) was measured with sterile polarographic needle electrodes and a computerized histography system. The 2 lowest pO2 classes, ie, 0 and 5 mm Hg, were designated the hypoxic fraction, and the mean and median pO2 were evaluated for each tumor. In the beginning, a marked variability in tissue pO2 was found. The initial size of the hypoxic fraction ranged from 0% to 61% of measured values. At the end of treatment, 4 tumors showed an increase in mean pO2, and 7 tumors a lower mean pO2 in comparison to the initial values. However, an impressive finding was that the hypoxic fraction of 9 tumors became smaller during the pause, 1 tumor showed no change, and 1 showed an increase in hypoxic fraction. The results show that there is a widely distributed tissue oxygenation with marked hypoxic zones in human neck nodes. During radiochemotherapy, tissue oxygenation changed, with great intertumor variability. A tendency toward a decrease of the hypoxic fraction after the respite could be seen. This change in tumor oxygenation during therapy needs further evaluation.

Embryonal rhabdomyosarcoma of the nose in an elderly patient, case report and review of the literature.

Embryonal rhabdomyosarcoma of the head and neck is very rare in adults. We report on an embryonal rhabdomyosarcoma of the nose, occuring in a 74-year-old female patient presenting with nasal congestion as the only clinical symptom. Suspected to be an amelanotic melanoma, further biopsies and histological examinations provided the correct diagnosis. She first underwent a course of chemotherapy which led to a partial shrinkage of the tumor mass which was followed by a complete resection of the residual tumor mass. Biologic behaviour of this tumor must be fully appreciated as treatment is interdisciplinary. Rhabdomyosarcoma should be considered in the differential diagnosis of tumors of the nose and paranasal sinuses not only in children, but also in adults.

[Intra-parotid neurofibroma of the facial nerve]. / Intraparotideales Neurofibrom des Nervus facialis.

BACKGROUND: Solitary intraparotid facial neurofibromas are extremely rare. These tumours arise from Schwann cells, in most cases as a manifestation of neurofibromatosis. In an intraparotid localisation, they can mimic other parotideal tumours. Due to their slow growth, they may be clinically inapparent for a long time. CASE REPORT: We present the case of a patient with a right intraparotid neurofibroma originating from the facial nerve. He noted a slight facial weakness for the last three years and dullness over the preauricular area. On operation, all facial nerve branches were incorporated in the tumour mass. A total resection via monitoring technique of facial nerve function was performed. Postoperatively, the patient suffered from an incomplete facial palsy. CONCLUSION: This case highlights particularly the importance of a concise diagnostic work-up of every facial palsy. Precise histological diagnosis is particularly essential because of the different biological behaviour of neurofibromas in contrast to neurinomas. With preoperative facial palsy the chance of facial nerve preservation decreases. Clinical and operative experience with parotid gland neurofibromas shows that recovery of facial nerve defects is mostly incomplete.

In vivo mutational analysis of highly conserved amino acid residues of the small subunit Cpa1p of the carbamylphosphate synthetase of Saccharomyces cerevisiae.

The role of selected amino acid residues located in the putative catalytic domain and of two conserved histidine residues within the small subunit of the carbamylphosphate synthetase (CPS) specific to the arginine biosynthesis pathway of the yeast Saccharomyces cerevisiae was studied using site-directed mutagenesis to change all residues to aspartic acid. Carbamylphosphate synthesis catalysed by modified CPS was tested in vivo. The C264D, H307D and H349D mutants were unable to grow on minimal medium, indicating the importance of these three residues for efficient CPS activity, whereas, four other mutated residues located in the catalytic site (including a proline residue) do not affect the growth rate. These results in comparison to those obtained with the CPS of Escherichia coli, implicate residues Cys 264 and His 349 in the glutaminase catalytic activity, and His 307 in the binding of glutamine to the active site. Using these three defective mutants, we investigated the in vivo utilization of ammonia by CPS. C264D and H307D mutants are able to use ammonia as a substrate when provided in sufficiently high concentrations (up to 200 mM). The H349D mutant, however, did not grow even at ammonium sulfate concentrations above 400 mM, suggesting that this substitution is critical to NH3-dependent CPS activity although the ammonia binding site is presumably located within the large subunit of the enzyme.

Characterization of the Saccharomyces cerevisiae FCY1 gene encoding cytosine deaminase and its homologue FCA1 of Candida albicans.

By functional complementation of a fcy1 null mutant of Saccharomyces cerevisiae, we have cloned and characterized the FCY1 gene, encoding cytosine deaminase in Saccharomyces cerevisiae, and its homologue FCA1, encoding cytosine deaminase in Candida albicans. Disruption of FCY1 resulted in high resistance to 5-fluorocytosine (10(-2) M) and in total loss of cytosine deaminase activity. By contrast the transformation by FCY1 or FCA1 of the haploid FCY1-disrupted host strain restored sensitivity to 5-fluorocytosine and allowed growth on cytosine, as a source of pyrimidine, or ammonium. FCA1 as opposed to FCY1 contains an intron. FCA1 and FCY1 encode respectively 150- and 158- residue proteins of 60% identity. Both Fcy1p and Fca1p share common motifs with cytidine and CMP deaminases, but homology with cytosine deaminase of E. coli could not be detected.

Susceptibility of isolated rat facial nerve to anaerobic stress.

Ischemic lesions are presumed to be part of many facial nerve pathologies, such as Bell's palsy. The response of facial nerve to hypoxia has not been evaluated previously in an in vitro model. In the present study, the effects of transient anaerobic stress on functional parameters and their recovery were assessed. Extratemporal rat facial nerves were desheathed and incubated in an experimental chamber using solutions containing either low (5 mM) or high (25 mM) D-glucose. In some of the experiments, 40 microM phenytoin or lidocaine was added to observe the effects of membrane stabilizing drugs. Peak height of compound nerve action potential (CNAP), extracellular direct current (DC) potential and latency were measured simultaneously during and after a 40-min period of hypoxia, induced by bubbling the solutions with N2 or application of 3 mM cyanide. This resulted in a rapid decrease of CNAP and a depolarization of the DC potential with a fast and complete post hypoxic recovery. Elevated glucose concentrations led to a slower decline in CNAP and a smaller rise of membrane potential depolarization. This was accompanied by a slower change of latency. However, post-anaerobic recovery was always diminished in the high glucose solutions. In experiments with phenytoin or lidocaine longer impulse conduction during hypoxia was observed. These findings indicate that the availability of energy-rich components underlies the complex array of physiological derangements seen in ischemia. Membrane-stabilizing drugs show an effect on signal conduction during hypoxia and need further exploration.

Urokinase-type plasminogen activator and its inhibitor plasminogen activator inhibitor-1.

Tumor associated proteolysis is an essential mechanism in invasion and metastasis of cancer. The influence of the serine protease urokinase-like plasminogen activator (u-PA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) on the clinical prognosis of squamous carcinoma of the head and neck region (HNSCC) was evaluated. U-PA and PAI-1 levels were measured in tumor biopsies of 41 HNSCC patients and 6 biopsies of healthy oral mucosa using ELISA technique. Patients were followed for an average of 24 months. U-PA concentration in tumor tissue was four times higher than in healthy mucosa (4.96 ng/mg protein versus 1.32 ng/mg). PAI-1 levels were 22 times higher (69.55 ng/mg versus 3.18 ng/mg). Univariate Cox regression analysis revealed significant correlation (p=0.022) of PAI-1 with recurrence of the disease and no significance for u-PA. PAI-1 might become a new functional risk factor reflecting clinical prognosis.

[Tissue oxygen partial pressure in human head-neck carcinomas during primary radio-chemotherapy]. / Der Sauerstoffpartialdruck im Gewebe menschlicher Kopf-Hals-Karzinome während primärer Radio-Chemotherapie.

BACKGROUND: Experimental data have shown that hypoxic areas in tumors can increase their malignant potential and reduce their sensitivity to chemotherapy and radiation treatment. Until now, the only incomplete data on the oxygenation of human tumors during therapy have been available. METHODS: The distribution of partial pressure of oxygen in malignant head and neck processes was measured in four patients with lymph-node metastases by means of invasive computerized histography (system manufactured by Eppendorf). All patients received primary radiation treatment and chemotherapy with a two-week respite after 30 Gy and the first cycle of chemotherapy. The total dose consisted of 70 Gy in the tumor and two cycles of chemotherapy. Oxygen measurements were taken before the onset of treatment, before and after the respite, and after completion of treatment. RESULTS: In three of the four patients, we measured prominent hypoxic areas in the cancers with PO2 values less than 5 mmHg. The average value was between 12 and 46 mmHg. We were impressed by the observation that oxygenation appeared to improve in every cancer during the respite. Only the patient who showed good initial oxygenation without any measurable hypoxic fraction suffered a complete recurrence six weeks after the completion of therapy. CONCLUSIONS: Prominent areas of hypoxic tissue are present in human head and neck cancers. Radiation treatment and chemotherapy can alter the oxygenation. Further studies are required to investigate the significance of the oxygenation of human head and neck cancers and the changes occurring in it during different types of therapy in order to assess its clinical impact.

Determination of a specific region of the purine-cytosine permease involved in the recognition of its substrates.

Three u.v.-induced mutants of the purine-cytosine permease gene of Saccharomyces cerevisiae, with altered apparent Michaelis constant of transport (Kmapp), were cloned and sequenced. One of the mutants had extensive nucleotide replacement, whereas the other two had a single mutation. To evaluate the contribution of the different amino acid replacements to the phenotype of the complex mutant, simpler mutants were created by site-directed mutagenesis. All the amino acid replacements found in the segment from amino acids 371 to 377 inclusive, contribute to the determination of the phenotype. According to the model postulated this segment lies on the cell surface. In particular, amino acids at position 374 and 377 modulate the affinity of the permease towards its substrates. In the wild-type, when asparagine is present at both of these positions, the lowest Kmapp values are found.

Differences in sensitivity to hyperglycemic hypoxia of isolated rat sensory and motor nerve fibers.

We explore whether the prevalence of sensory deficits in diabetic neuropathy can be explained by diffuse endoneurial hypoxia. Isolated ventral and dorsal rat spinal roots incubated in 2.5 or 25 mM extracellular glucose were transiently exposed to hypoxia (30 min) in a solution of low buffering power. Compound nerve action potentials and extracellular direct current potentials were continuously recorded before, during, and after hypoxia. In both ventral and dorsal roots incubated in 2.5 mM glucose, sensitivity to hypoxia and posthypoxic recovery were similar. In contrast, hypoxia in 25 mM glucose preferentially induced electrophysiological damage in dorsal roots as indicated by a lack of posthypoxic recovery. This observation was not made in the presence of 25 mM bicarbonate, which suggests involvement of nerve acidosis. In conclusion, the different sensitivity of sensory and motor fibers to hyperglycemic hypoxia supports the hypothesis that hypoxia has an important role in the pathogenesis of diabetic neuropathy.

[Spastic movement disorders: non-medicamentous therapies based on neurophysiologic principles]. / Spastische Bewegungsstörungen: nichtmedikamentöse Therapien auf neurophysiologischer Grundlage.

Lesions of the upper motor neurons cause a spastic syndrome and a central paresis. The consequence of these "plus" and "minus" symptoms on locomotor function is a spastic movement disorder. Strategies of physical therapy for the spastic movement disorders are discussed in relation to research findings in neurophysiology and muscle physiology. The main therapeutic technics are physiotherapy, functional electrical stimulation (FES) and biofeedback training (BFB). Various methodological problems which arise in carrying out and evaluating therapeutic studies are described. Valid prognostic criteria are essential in order to achieve an optimal use of the different therapeutic procedures. This review underlines the need for further research, since some important questions remain open.