Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases.

BACKGROUND: Lemierre syndrome is characterized by head/neck vein thrombosis and septic embolism usually complicating an acute oropharyngeal bacterial infection in adolescents and young adults. We described the course of Lemierre syndrome in the contemporary era. METHODS: In our individual-level analysis of 712 patients (2000-2017), we included cases described as Lemierre syndrome if these criteria were met: (i) primary site of bacterial infection in the head/neck; (ii) objectively confirmed local thrombotic complications or septic embolism. The study outcomes were new or recurrent venous thromboembolism or peripheral septic lesions, major bleeding, all-cause death and clinical sequelae. RESULTS: The median age was 21 (Q1-Q3: 17-33) years, and 295 (41%) were female. At diagnosis, acute thrombosis of head/neck veins was detected in 597 (84%) patients, septic embolism in 582 (82%) and both in 468 (80%). After diagnosis and during in-hospital follow-up, new venous thromboembolism occurred in 34 (5.2%, 95% CI 3.8-7.2%) patients, new peripheral septic lesions became evident in 76 (11.7%; 9.4-14.3%). The rate of either was lower in patients who received anticoagulation (OR: 0.59; 0.36-0.94), higher in those with initial intracranial involvement (OR: 2.35; 1.45-3.80). Major bleeding occurred in 19 patients (2.9%; 1.9-4.5%), and 26 died (4.0%; 2.7-5.8%). Clinical sequelae were reported in 65 (10.4%, 8.2-13.0%) individuals, often consisting of cranial nerve palsy (n = 24) and orthopaedic limitations (n = 19). CONCLUSIONS: Patients with Lemierre syndrome were characterized by a substantial risk of new thromboembolic complications and death. This risk was higher in the presence of initial intracranial involvement. One-tenth of survivors suffered major clinical sequelae.

Cytostatic and cytotoxic effects of fostriecin on human promyelocytic HL-60 and lymphocytic MOLT-4 leukemic cells.

Exposure of exponentially growing human promyelocytic of lymphocytic leukemic cells to the putative DNA topoisomerase II inhibitor fostriecin (FST), at a concentration of 1 microM, results in the suppression of their rate of progression through the S and G2 phases of the cell cycle. At concentrations between 5 microM and 0.5 mM, FST triggers endonucleolytic DNA degradation in human promyelocytic leukemia cells, resulting in apoptotic cell death; this effect is not selective for any particular phase of the cell cycle. Little or no apoptotic cell death is observed in lymphocytic leukemic cells at any FST concentration. Because FST, unlike other inhibitors of topoisomerase II, such as teniposide (TN) or amsacrine (m-AMSA), does not stabilize cleavable DNA-topoisomerase complexes, the observed differences between the effects of FST versus TN or m-AMSA on the cell cycle may provide clues regarding the role of such complexes in the kinetic effects of these inhibitors. The present results, therefore, are compared with our earlier data on the effects of TN and m-AMSA on the same cells. The only observed difference is the loss of cell cycle phase-specific triggering of DNA degradation by FST in human promyelocytic leukemia cells, compared to the S phase-specific effects of TN and m-AMSA. Therefore, stabilization of the DNA-topoisomerase cleavable complexes may be essential in the selectivity of cell kill during S phase. However, it appears that the presence of stabilized complexes is not essential to the suppression of cell progression through S or G2 or the induction of apoptotis or necrosis, in general, by topoisomerase II inhibitors.

Type of inducing signal regulates transactivation by p53.

The tumor suppressor gene p53 is expressed in the contrasting cell fates apoptosis and proliferation. We examined whether the transactivation of the p53 target genes, waf1 and mdm2, is dependent on the cause of p53 induction in human peripheral blood mononuclear cells (PBMC). Both apoptosis triggered by the purine analog 2-chlorodeoxyadenosine (CdA) and growth stimulation by the mitogen phytohemagglutinin (PHA) induced a comparable level and time course of p53 mRNA expression. Both stimuli led also to an increase of p53 protein levels. The cytotoxic agent, but not the mitogen, led to transactivation of waf1 and mdm2 within 18 h. Transactivation was followed by apoptosis of 89% of the PBMC within 48 h. The c-myc oncogene and poly(ADP-ribose)polymerase (PARP), which also have a dual function in proliferation and apoptosis, showed an early induction by both CdA and PHA. These results add further evidence that growth stimulation and DNA damage-induced apoptosis share early gene activation pathways in normal cells. However, since p53 does selectively translate into transactivation of target genes depending on the cause of induction, this function of p53 seems to be regulated by additional factors, which are closely related to the ultimate fate of the cell.

Biomechanical properties of sterilized human auditory ossicles.

Bone allograft material is treated with sterilization methods to prevent the transmission of diseases from the donor to the recipient. The effect of some of these treatments on the integrity of the bone is unknown. This study was performed to evaluate the effect of several sterilization methods on the mechanical behaviour of human middle ear bones. Due to the size and composition of the bones (approximately 1.5 mm diameter by 4 mm long), mechanical testing options were limited to the traditional platens compression test. Experiments were first performed with synthetic bone to evaluate the precision of this test applied to small specimens. Following this, fresh frozen human ossicles were thawed and sterilized with (i) 1 N NaOH (n = 12); (ii) 0.9% LpH, a phenolic solution (n = 12); or (iii) steam at 134 degrees C (n = 18). A group of 26 control specimens did not receive any sterilization treatment. Material and structural properties were determined from axial compression testing. Results from the synthetic bone showed that the test was reproducible, with standard deviations less than 20% of the means. Significant differences occurred in stiffness and ultimate force values between NaOH-treated and autoclaved bones when compared to normals (p<0.05), but not for LpH-treated bones. LpH is not approved for medical use, so NaOH is the most appropriate of the treatments studied for the sterilization of ossicle allografts.

Otoacoustic emissions: an approach for monitoring aminoglycoside-induced ototoxicity.

Ototoxic drugs, such as aminoglycosides, affect outer hair cell integrity in the inner ear. Transiently evoked otoacoustic emission (TEOAE) characteristics are related to outer hair cell function and can be expected to reflect the influence of ototoxic agents. Transiently evoked otoacoustic emissions were measured during amikacin sulfate therapy in nine patients. The duration of treatment for individual patients ranged from 9 to 33 days. A reversible decrease of overall TEOAE level, occurring after a treatment period longer than 16 days, was found in the majority of patients. The monitoring of TEOAEs is proposed as a method for early identification and, as a result, prevention of aminoglycoside-induced ototoxicity.

Value of fine-needle aspiration cytology of parotid gland masses.

OBJECTIVE: To evaluate the usefulness and accuracy of fine-needle aspiration cytology (FNAC) in the diagnosis of parotid gland masses. STUDY DESIGN: Retrospective chart review of patients undergoing FNAC. METHODS: Between January 1990 and December 1998, 410 parotid glands were resected at the Department of Otorhinolaryngology-Head and Neck Surgery at the University of Berne, Inselpital (Berne, Switzerland). Included in the study were 228 cases with preoperative FNAC. In a retrospective study the results of FNAC were analyzed and compared with the corresponding histopathological diagnosis. RESULTS: Histological evaluation revealed 65 malignant tumors and 163 benign lesions (150 neoplasms and 13 nonneoplastic lesions). The cytological findings were nondiagnostic in 13 (5.7%), true-negative in 146 (64%), true-positive in 39 (17%), false-negative in 22 (9.8%) and false-positive in 8 (4.5%) cases in detecting malignant tumors. Nineteen of 39 (49%) malignant tumors (true-positive) and 123 of 146 (84%) benign lesions (true-negative) were classified accurately. The accuracy, sensitivity, and specificity were 86%, 64%, and 95% respectively. CONCLUSIONS: Fine-needle aspiration cytology is a valuable adjunct to preoperative assessment of parotid masses. Preoperative recognition of malignant tumors may help prepare both the surgeon and patient for an appropriate surgical procedure.

Radiologic and mechanical properties of inactivated ossicle homografts.

OBJECTIVE: This study examined the effects of old and new inactivation (sterilization) techniques on the radiologic and mechanical properties of ossicle homografts. MATERIALS AND METHODS: Ninety normal incuses and malleuses received either treatment with 1) 5% formaldehyde/cialit, 2) 1N NaOH, 3) 0.9% LpH, or 4) autoclaving at 134'C, or no treatment. All ossicles were assessed radiologically by high-resolution computed tomography. After imaging, all ossicles underwent mechanical testing by destructive axial compression in a mechanical testing machine measuring force and displacement. RESULTS: Ossicles treated with cialit, NaOH, or autoclaving showed a significant decrease of ultimate force and stiffness compared with controls. LpH treatment caused no such changes in these structural properties. Material properties of yield strength, ultimate strength, and elastic modulus were also altered by cialit, NaOH, and autoclaving, but were much more difficult to assess because of uncertainty in parameter estimates. There was a significant increase in radiologic density in autoclaved ossicles, a reduction in cialit- and LpH-treated ossicles, and no change in NaOH-treated ossicles. CONCLUSIONS: All tested inactivation procedures changed the biomechanical and/or radiologic properties of ossicle homografts. However, the new procedures used to inactivate infectious agents produced changes similar to the older treatments with formaldehyde/cialit. Human allografts are able to withstand harsh but safe sterilization procedures. The NaOH treatment seems to be the most suitable method for the future. The biologic (osteogenic) potentials of ossicle homografts treated with these new preservation/inactivation methods are still unknown. Further investigations are necessary to re-evaluate the clinical use of ossicle homografts in middle ear reconstructive surgery.

Spontaneous apoptosis and the expression of p53 and Bcl-2 family proteins in locally advanced head and neck cancer.

BACKGROUND: Apoptotic cell death plays a key role in the pathogenesis, aggressiveness, and therapy responsiveness of cancer. The suicidal machinery of apoptosis is genetically controlled. Proteins of the Bcl-2 family as well as p53 are important regulators of apoptosis. OBJECTIVE: To assess the rate of spontaneous apoptosis and the expression of p53 and Bcl-2 family proteins in locally advanced squamous cell carcinomas of the head and neck. DESIGN: Twenty-six patients with locally advanced squamous cell carcinoma of the head and neck were included in the study. The expression of p53, Bcl-2, Mcl-1, Bax, and Bak was assessed by immunohistochemical analysis. The terminal deoxytransferase-mediated deoxyuridine nick end-labeling assay was used to quantify apoptosis by flow cytometry. RESULTS: Tumor cells containing immunostaining for the antiapoptotic proteins Bcl-2 and Mcl-1 were present in 4 (15%) and 24 (92%) of the cases evaluated, respectively, whereas immunopositivity for the proapoptotic proteins Bax and Bak was found in 9 (35%) and 24 (92%) of the samples. Immunoreactivity to p53 was detected in 20 (77%) of the samples. There was a positive correlation between the expression of Bcl-2 and Bax and between Mcl-1 and Bak. A low fraction of apoptotic cells (<2.5%) in the pretreatment tumor samples was significantly correlated with increased 2-year survival in these patients. CONCLUSIONS: Our results establish the frequent expression of the Bcl-2 family proteins Bcl-2, Mcl-1, Bax, and Bak in locally advanced head and neck cancer. In addition, this study suggests that the apoptotic fraction in pretreatment tumor samples might be of prognostic importance for the outcome in these patients.

Extramedullary solitary plasmacytoma of the head and neck. A clinicopathological study.

Monoclonal extramedullary plasmacytoma (EMP) is a rare, low-grade lymphoma found predominantly in the head and neck region. Only since the introduction of immunophenotyping techniques 2 decades ago has it been possible to differentiate EMP from benign polyclonal plasma cell proliferation. The purpose of this study was to trace the evolutionary profile of the disease under consideration of monoclonality assessment. The records of 24 patients with morphologically diagnosed EMP treated in a single institution underwent clinical and pathological review. Only 14 patients had true monoclonal plasmacytoma. No EMP-related deaths occurred. Two patients had local recurrence, and 2 patients developed multiple myeloma. Review of the literature confirms the low-grade malignancy of EMP. Diagnostic procedures must exclude benign polyclonal plasmacytoma, multiple myeloma, and solitary bone plasmacytoma. The slow natural progression of the disease and the rarity of secondary multiple myeloma favor nonmutilating local surgery whenever possible to avoid the long-term sequelae of radiotherapy.

Monitoring the effects of noise exposure using transiently evoked otoacoustic emissions.

One possible alternative to conventional pure-tone testing for screening and monitoring cochlear changes is the measurement of otoacoustic emissions. The aims of this study were to determine the feasibility of using transiently evoked otoacoustic emission (TEOAE) measurements as an objective field procedure and to compare the sensitivity of the measurements indirectly to pure-tone thresholds. The test groups were 117 male recruits and 30 male career cadets in compulsory military service in Switzerland. Transiently evoked otoacoustic emissions were measured before and at the end of a 17-week training period that included exposure to noise from firearms. Results revealed significant changes in response amplitudes in the frequency range from 2 to 4 kHz, whereas changes in the frequency range from 0.5 to 2 kHz were not significant for either group. The changes in relative amplitude did not exceed 15% when spectra containing the lower frequencies were considered. However, they were always greater than 83% within the higher-frequency range. All mean changes were in the direction expected from cochlear damage. Comparison of TEOAE results with pure-tone thresholds measured for a similar sample of subjects indicated that TEOAE testing may be more sensitive than pure-tone audiometry in detecting early cochlear damage from noise. The testing of TEOAEs is feasible as a screening procedure. It offers objective and repeatable information and is substantially less time consuming than pure-tone audiometry.

[Dysphagia]. / Dysphagie.

The otolaryngologist has a central role in the detailed examination for dysphagia with its vast differential diagnosis. The carefully elicited medical history and a deliberately focused physical examination are the most important tools to disclose the basis of the dysphagia. Nonspecific blind treatment of dysphagia is obsolete.

[Münchhausen syndrome in otorhinolaryngology]. / Das Münchhausen-Syndrom in der Hals-Nasen-Ohren-Heilkunde.

The case of a 22-year-old nurse with Münchausen syndrome is described. Faked symptoms included sudden hearing loss and fever. In addition to the definition and classification, clues for diagnosis of faked disease are given. Early diagnosis avoids unnecessary diagnostic and therapeutic procedures. The prognosis of Münchhausen's syndrome depends on the ability to establish an effective doctor-patient relationship, even though the nature of disease renders any treatment difficult.

[Epiglottitis--a pediatric disease?]. / Die Epiglottitis--eine Erkrankung im Kindesalter?

Epiglottitis, commonly described as a paediatric disease, also occurs in adults. Early diagnosis and immediate treatment are crucial because of the rapid and possibly lethal course of upper airway obstruction due to swelling. Initial treatment consists in securing the upper airway and in antibiotic treatment. Streptococci and, especially in children, Haemophilus influenzae b are the most common bacteria. Our study focused on clinical and epidemiological changes since children started to be vaccinated against Haemophilus influenzae b in Switzerland (1992). We reviewed patient histories of 31 adults and 88 children who were hospitalised with epiglottitis at the University Hospital of Berne between 1989 and 1999. Our findings show that the incidence of epiglottitis in children, a clinically, epidemiologically and bacteriologically homogeneous disease, has dramatically decreased. Epiglottitis in adults presents as a more heterogeneous disease without change since the beginning of the vaccination programme. Due to the variety of germs it is impossible to recommend vaccination for adults against Haemophilus influenzae b.

[Assessment of outer hair cell function recovery by means of the DPOAE threshold]. / Die Erfassung von Regenerationsvorgängen äusserer Haarzellen mit Hilfe der DPOAE-Schwelle.

Distortion product otoacoustic emissions (DPOAE) originate from nonlinear mechanical sound processing in the inner ear, mainly due to normal outer hair cell function. Outer hair cell impairment can be detected by means of DPOAE. With a special primary tone level paradigm which optimises the primary tone level difference over a wide stimulus level range (L1 = 0.4 L2 + 39 dB, L2 = 20 to 65 dB SPL, f2 = 0.5 to 8 kHz, f2/f1 = 1.2), DPOAE can be measured at levels close to the psychophysical hearing threshold. From the DPOAE growth functions, which are constructed from measurements at different stimulus levels, a DPOAE threshold can be defined (Boege et al., 1998), which can be interpreted as a threshold of mechanical processing by the outer hair cells. In this study, DPOAE thresholds were examined in 9 patients with reversible cochlear hearing loss, i.e. sudden deafness or noise trauma. With increasing hearing loss, low primary tone level DPOAE in particular decreased, and thus the DPOAE threshold increased. The DPOAE threshold makes it possible to detect mechanical sensitivity losses in a frequency-specific manner. Thus, loss of mechanical amplification may be differentiated from a non-mechanical cause of hearing loss.

Changes in nuclear chromatin related to apoptosis or necrosis induced by the DNA topoisomerase II inhibitor fostriecin in MOLT-4 and HL-60 cells are revealed by altered DNA sensitivity to denaturation.

The antitumor drug fostriecin (phosphotrienin, FST) has been reported to exert its cytostatic and cytotoxic effects via inhibition of DNA topoisomerase II. The sensitivity of human lymphocytic leukemic MOLT-4 and promyelocytic HL-60 leukemic cells to a wide range of FST concentrations was studied by analyzing the cell cycle-specific effects and changes in nuclear chromatin induced by this inhibitor. The latter was evaluated by assaying the sensitivity of DNA in situ to acid-induced denaturation cytofluorimetrically, with the use of the metachromatic fluorochrome acridine orange (AO), which differentially stains double-stranded and denatured DNA. The cytostatic effects were observed soon after addition of FST (at concentrations of 1-30 microM for MOLT-4 cultures and 1-5 microM for HL-60 cultures) as a perturbation of cell progression through S and G2 phases of the cell cycle. Cell progression through the cycle was halted at greater than 30 microM FST in MOLT-4 cultures and at greater than 5 microM in HL-60 cultures; the effect was instantaneous and affected all phases of the cycle, so that no changes in the cell cycle distribution were apparent with increasing length of exposure to the drug. Instead, at these high FST concentrations, immediate cytotoxic effects became evident, manifesting either as cell apoptosis or necrosis. Apoptosis was observed only in the case of HL-60 cells, at FST concentrations of 5-100 microM, and was characterized by markedly increased sensitivity of DNA to denaturation combined with a decrease in overall DNA stainability, either with the DNA-specific dye DAPI or with AO, indicative of the activation of endogenous nucleases. Necrotic cell death was observed at FST concentrations of 1 mM and at greater than 30 microM for HL-60 and MOLT-4 cells, respectively: in both cases the overall DNA stainability, with either DAPI or AO, was unchanged compared to the control, but their DNA was very sensitive to denaturation. Interestingly, DNA in G2 and late S phase MOLT-4 cells, which were undergoing necrotic death, was much more sensitive to denaturation than was DNA in G1 cells of this lineage. The data indicate that chromatin changes induced by DNA topoisomerase II inhibitors in cells that undergo apoptotic or necrotic death can be conveniently monitored by the assay of DNA in situ sensitivity to denaturation.