Intratympanic gentamicin for intractable Meniere's disease

OBJECTIVE: The study aimed to analyze the results of the intratympanic injection of gentamicin as a treatment option for patients with unilateral Meniere's disease who were refractory to medical treatment. STUDY DESIGN: Prospective study in the setting of a tertiary care medical center. METHODS: Seventy-one patients with unilateral Meniere's disease according to 1995 American Academy of Otolaryngology-Head and Neck Surgery 1995 guidelines who had been unresponsive to medical therapy for at least 1 year were studied. Intratympanic injections of a prepared concentration of 27 mg/mL gentamicin were performed at weekly intervals until the development of symptoms and signs indicative of vestibular hypofunction in the treated ear. As the main outcome measure, the 1995 American Academy of Otolaryngology-Head and Neck Surgery criteria for reporting treatment outcome in Meniere's disease were used. The results of treatment were expressed in terms of control of vertigo, disability status (functional level and degree of overall impairment evaluated by the Dizziness Handicap Inventory and the University of California Los Angeles Dizziness Questionnaire), hearing level, and quantitative measurement of vestibular function. RESULTS: Vertigo was controlled in 83.1% of the 71 patients. Recurrence of vertigo spells after initially complete control was noted in 17 patients. In 13 of these patients, this was cured by another course of intratympanic injections of gentamicin. Functional level and measures of self-reported handicap were significantly and promptly lowered after treatment in the patients who attained control of vertigo. Hearing level as pure-tone average was unchanged 2 years after treatment, but hearing loss as a result of gentamicin injections occurred in 23 patients at the end of treatment and in 9 and 11 patients at 3 months and 2 years after the treatment, respectively. Vestibular function was kept normal or reduced in 49.3% of the patients, whereas in the rest of the patients vestibular areflexia was observed. Control of vertigo did not depend on the amount of vestibular damage. CONCLUSIONS: Ending weekly intratympanic injections when clinical signs of vestibular deafferentation appear can control vertigo in the majority of patients, and it is a useful alternative, together with other surgical options, for the treatment of patients with Meniere's disease who do not respond to medical treatment.     

Merkel cell carcinoma: report of seven cases

Merkel cell carcinoma (MCC) is an infrequent, highly malignant, primary skin tumor derived from neuroendocrine cells. Most MCCs occur in elderly individuals, on sun-exposed areas of the body, with the head and neck being the most common sites. We present 7 patients (2 male and 5 female, age 45-80 years) suffering from MCC and treated between 1993 and 2000. All tumors were located on the head and neck and varied from 0.9 to 2.3 cm in size. Five of the patients had stage II disease, 1 patient had stage Ia disease and 1 patient had stage III disease. Six of the patients had positive regional lymph nodes. All patients had local excision of the tumor. Six of them also had lymph node dissection and in 5 of them a superficial parotidectomy was performed. Five patients received adjuvant radiotherapy and 3 of them also received chemotherapy. Local and cervical lymph node recurrence was observed in only 1 patient. Metastases occurred in 5 patients. One patient died within 10 days for other reasons. The patient with the stage III tumor had a survival of 7 months. The other 5 patients had survivals varying from 15 to 54 months. MCC is a skin tumor with very poor prognosis and high recurrence and metastatic rates. Its treatment is still under discussion. Radical excision of the tumor is the main method of treatment. Selective lymph node dissection is suggested. Superficial parotidectomy seems necessary, especially if the tumor is on the auricle. Adjuvant radio- and chemotherapy may extend survival in case of small-size tumors.     

Are the 2-isomers of the drug rimantadine active anti-influenza A agents?

There is a lack of information in the medical chemistry literature concerning the anti-influenza A activity of the drug rimantadine's 2-isomer (2-rimantadine). We now present results showing that, although 2-adamantanamine (2-amantadine) 3 is only moderately active, some 2-rimantadine analogues are effective anti-influenza A virus agents in vitro. The 2-rimantadine analogues and their spirocyclobutane and spirocyclopentane congeners were synthesized through interesting routes. The 2-rimantadine analogues were 2-4 times more potent than rimantadine 2 against influenza virus A H2N2 strain; their spirocyclobutane congeners proved equally active to rimantadine 2. Two compounds exhibited a similar activity and one of the compounds was was fourfold more potent than rimantadine 2 against H3N2 strain.     

Modeling the time dependence of the association between human papillomavirus infection and cervical cancer precursor lesions

The authors studied the time-dependent association between human papillomavirus (HPV) infection and squamous intraepithelial lesions (SIL) among women enrolled in a cohort study in Brazil (1993-2002), using repeated Papanicolaou cytologic examination and HPV testing by polymerase chain reaction. Through simulation with conceivable alternative cohort designs, they investigated different regression modeling approaches using time-varying covariates, time-varying hazard ratio functions, and repeated events to assess the effect of delay in lesion detection. Associations between HPV and early SIL were of high magnitude. The age-adjusted hazard ratios for the association between HPV at enrollment and low-grade SIL decreased gradually with time until 72 months for both oncogenic types of HPV (hazard ratio = 3.96, 95% confidence interval (CI): 2.5, 6.4) and nononcogenic types (hazard ratio = 2.37, 95% CI: 1.3, 4.3). The hazard ratio for incident high-grade SIL remained constant, ranging from 7.15 (95% CI: 2.0, 25.1) at 12 months to 6.26 (95% CI: 2.7, 14.5) at 72 months for oncogenic types of HPV. With oncogenic HPV as the time-dependent predictor variable, the hazard ratios for incident SIL and high-grade SIL events were 14.2 (95% CI: 8.7, 23.1) and 32.7 (95% CI: 8.4, 127.3), respectively. Investigators may underestimate the prognostic value of HPV detection using designs that rely on HPV ascertainment at a single time point. The waning in hazard ratios should be considered in the implementation of HPV testing-based screening programs.     

An improved instrument mounting arm

Although some form of commercial instrument mounting arm is available, a paucity of information in the literature may cause problems in selecting the most appropriate model for an ENT department wishing to trial their invention for use in the clinic or operating theatre. The instrument mounting arm described here is based on existing designs used by hobbyists and model makers for many years but the main benefit of this innovation is its multi-purpose use in the operating theatre and cost effectiveness since it is made of aluminum alloy. It is compact, stable and easily adjustable and can incorporate an endoscope holder or an operating end piece to mount various ENT instruments that offers considerable advantages to the unassisted operator.     

Assessment of neurotoxicity following repeated cremophor / ethanol injections in rats

As the mixture cremophor/ethanol is known to have side-effects affecting the peripheral nervous system, we have assessed its behavioural and morphological neurotoxicity after repeated intraperitoneal injections in male Sprague Dawley rats. Clinical status of the animals was good throughout the experiment and no motor deficits were observed. Nevertheless, sensory testing demonstrated an hyperalgesia and an allodynia to mechanical stimuli, associated to peripheral axon degeneration.     

Large and diverse numbers of human diseases with HIKE mutations

HIKE is a highly conserved sequence motif identified as a candidate pleckstrin-homology (PH) domain binding site in Gbeta proteins, protein kinases, ankyrin and kinesin. HIKE motifs occur also in gelsolin, neurogranin, neuromodulin and in the PH domain of Bruton tyrosin kinase (BTK). Phosphatidylinositol-binding sequences more distantly related to HIKE are present in gelsolin, in the G protein-coupled receptor kinase 4 and in Trop-2. HIKE regions have been demonstrated to bind both proteins and lipids, and to regulate the interaction of Gbeta, neuromodulin and the BTK PH domain with downstream effectors and the cell membrane. Remarkably, mutations of the HIKE regions are common in diverse human genetic diseases. Several HIKE mutations in protein kinases lead to constitutive activation and cellular transformation, e.g. in MEN-2B, acute myeloid and mast cell leukemias, hereditary papillary renal carcinomas and multiple myeloma. Kinase-inactivating HIKE mutations cause Hirschsprung's disease, piebaldism, insulin resistance and developmental dysplasias. HIKE mutations in the PH domain of BTK lead to X-linked agammaglobulinemia, and different forms of amyloidosis are caused by mutations of HIKE-bearing molecules, for example gelsolin, Ret and Trop-2. Thus, quite diverse genetic diseases might share common molecular mechanisms. These include altered interactions of the mutated molecules with downstream effectors or the cell membrane, and defects in intracellular transport.