Modelling fungal hypha tip growth via viscous sheet approximation.

In this paper we present a new model for single-celled, non-branching hypha tip growth. The growth mechanism of hypha cells consists of transport of cell wall building material to the cell wall and subsequent incorporation of this material in the wall as it arrives. To model the transport of cell wall building material to the cell wall we follow Bartnicki-Garcia and Gierz in assuming that the cell wall building material is transported in straight lines by an isotropic point source. To model the dynamics of the cell wall, including its growth by new material, we use the approach of Campàs and Mahadevan, which assumes that the cell wall is a thin viscous sheet sustained by a pressure difference. Furthermore, we include a novel equation which models the hardening of the cell wall as it ages. We validate the new model by comparing it to experimental data.

Virus-encoded G-protein-coupled receptors: constitutively active (dys)regulators of cell function and their potential as drug target.

G-protein-coupled receptors encoded by herpesviruses such as EBV, HCMV and KSHV are very interesting illustrations of the (patho)physiological importance of constitutive GPCR activity. These viral proteins are expressed on the cell surface of infected cells and often constitutively activate a variety of G-proteins. For some virus-encoded GPCRs, the constitutive activity has been shown to occur in vivo, i.e., in infected cells. In this paper, we will review the occurrence of virus-encoded GPCRs and describe their known signaling properties. Moreover, we will also review the efforts, directed towards the discovery of small molecule antagonist, that so far have been mainly focused on the HCMV-encoded GPCR US28. This virus-encoded receptor might be involved in cardiovascular diseases and cancer and seems an interesting target for drug intervention.

Auditory rehabilitation of older people from the general population--the Leiden 85-plus study.

BACKGROUND: Very few older people with severe hearing loss use hearing aids to reduce the negative consequences of reduced hearing in daily functioning. AIM: Assessment of a screening test and a standardised auditory rehabilitation programme for older people from the general population with untreated severe hearing loss. DESIGN OF STUDY: Intervention study and qualitative exploration. SETTING: Leiden 85-Plus Study, a prospective population-based study of 85-year-old inhabitants of Leiden, the Netherlands. METHOD: Hearing loss was measured by pure-tone audiometry in 454 subjects aged 85 years. Subjects with hearing loss above 35 dB at 1, 2, and 4 kHz who did not use hearing aids were invited to participate in a standardised programme for auditory rehabilitation. In-depth interviews were held with participants to explore arguments for participating in this programme. RESULTS: Of the 367 participants with severe hearing loss (prevalence = 81%), 66% (241/367) did not use a hearing aid. Three out of four of these participants (n = 185) declined participation in the auditory rehabilitation programme. The most common reason given for not participating was the subjects' feeling that their current hearing loss did not warrant the use of a hearing aid. Subjects who participated in the programme were found to suffer from more severe hearing loss and experienced more hearing disability. Those who did not participate in the programme felt they could cope with their disabilities and considered a hearing aid unnecessary. CONCLUSION: Untreated hearing loss is prevalent among older people from the general population. The majority of older people decline auditory rehabilitation. For these people the use of a hearing aid is not perceived as necessary in order to function on a daily basis. Older people who have expected benefits from a hearing aid have already obtained them, marginalising the benefits of a rehabilitation (and screening) programme.

[Diagnostic image (108). A boy with malaise and pain above one eye. Meningoencephalitis as a result of sinusitis of the sphenoid sinus]. / Diagnose in beeld (108). Een jongen met malaise en pijn boven één oog. Meningoencefalitis op basis van sinusitis sphenoidalis.

A 16-year-old boy developed a meningo-encephalitis as a result of sinusitis of the sphenoid sinus.

A set-point model with oscillatory behavior predicts the time course of 8-OH-DPAT-induced hypothermia.

Agonists for the 5-hydroxytryptamine (HT)(1A) receptor induce a hypothermic response that is believed to occur by lowering of the body's set-point temperature. We have developed a physiological model that can be used to predict the complex time course of the hypothermic response after administration of 5-HT(1A) agonists to rats. In the model, 5-HT(1A) agonists exert their effect by changing heat loss through a control mechanism with a thermostat signal that is proportional to the difference between measured and set-point temperature. Agonists exert their effect in a direct concentration-dependent manner, with saturation occurring at higher concentrations. On the basis of simulations, it is shown that, depending on the concentration and the intrinsic efficacy of a 5-HT(1A) agonist, the model shows oscillatory behavior. The model was successfully applied to characterize the complex hypothermic response profiles after administration of the reference 5-HT(1A) agonists R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) and S-8-OH-DPAT. This analysis revealed that the observed difference in effect vs. time profile for these two reference agonists could be explained by a difference in in vivo intrinsic efficacy.

New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity.

A series of 3,7-disubstituted-2(3',4'-dihydroxyphenyl) flavones has been studied as potential cardioprotective agents in doxorubicin antitumor therapy. The influence of substituents on the 3 and 7 position of the flavone nucleus on antioxidant activity cytotoxicity and cardioprotective properties was explored to improve the activity of our lead compound 7-monohydroxyethylrutoside. In the protection against Fe(2+)/vitamin C-induced microsomal lipid peroxidation (LPO assay), IC(50) values ranged from 0.2 to 37 microM. In general, the 3-substituted flavones were the most potent compounds in this assay. The cytotoxicity of the new compounds was tested (up to 250 microM) in hepatocytes. LDH leakage ranged from 2.6-29.2%, whereas the GSH concentrations decreased to 87.3-41.3%. Only four compounds out of this series protected the isolated mouse left atrium against doxorubicin-induced toxicity. Because of the positive inotropic effect of 8d (N-(3-(3',4'-dihydroxyflavon-7-yl)oxypropyl)-N,N,N-trimethylammonium chloride) and 10c (3-hydroxyethoxy-7,3',4'-trihydroxyflavone) on the atrium, compounds 9i (3',4'-dihydroxy-3-glucosylflavone) and 10d (N-(3-(7,3',4'-trihydroxyflavon-3-yl)oxypropyl)-N,N,N-trimethylammonium chloride) were selected to be evaluated as cardioprotective agents in vivo.

Tinnitus suppression by intravenous lidocaine in relation to its plasma concentration.

In a double-blind controlled trial in nine patients with tinnitus we measured the lidocaine plasma concentrations during and after intravenous administration of lidocaine or placebo and scored the level of tinnitus on a visual analog scale. No patient showed any effect during the placebo infusion. Administration of lidocaine resulted in total suppression or suppression to a non-annoying level of tinnitus in five patients, slight suppression but still annoying tinnitus in two patients, and worsening tinnitus in one patient. No effect of lidocaine was observed in one patient. Most relief was obtained at plasma concentrations between 1.5 and 2.5 micrograms/ml. In this concentration range a significant (p < 0.05) effect of lidocaine on tinnitus was observed. However, notable side effects were observed at plasma concentrations greater than 2.0 micrograms/ml. The effect persisted until plasma levels of about 0.5 microgram/ml were reached. A large variability in the effects existed because of variations in lidocaine kinetics and because of the presumed psychologic components of tinnitus.

A method for quantitative measurement of mitochondrial creatine kinase in human skeletal muscle.

Defects in the mitochondrial energy generating system in patients with a mitochondrial myopathy are known to be localized in various enzyme complexes involved in energy production. Such a defect may exist at the level of mitochondrial creatine kinase (Mi-CK). On that account we have developed a method for measurement of the enzyme activity in human skeletal muscle biopsy material (greater than 10 mg). Interfering creatine kinase isoenzymes are removed by anion exchange and affinity chromatography. The activity of Mi-CK in reference skeletal muscle homogenates amounts to 240 +/- 88 mU/mg protein (30 +/- 8.0 mU/mg wet weight).

The effect of iontophoresis of lignocaine in the treatment of tinnitus.

Lignocaine is the only drug available that suppresses tinnitus when given intravenously, but the mechanism and the site of its action are not well understood. Iontophoresis, a method by which chemical agents may be transported by electrical current from the ear canal throughout the tympanic membrane into the middle ear, could be expected to have a suppressive effect on tinnitus because the drug is brought so close to the cochlea. In the present study none of the 46 patients reported the suppression of tinnitus to a non-annoying level. Neither lignocaine nor any of its metabolites was found in blood sampled during the period of this treatment.

Large pituitary adenomas with extension into the nasopharynx. Report of three cases with a review of the literature.

Three cases of pituitary adenoma with extension into the nasopharynx and nasal cavity are reported. The occurrence of this rare tumor underscores the need to consider a pituitary tumor whenever a patient presents with rhinologic complaints and destruction of the sellar floor. Epistaxis, although exceptional, may be the first manifestation of a pituitary tumor. Immunohistochemical analysis combined with staining for the pituitary hormones proved to be essential for reaching a definite diagnosis. Magnetic resonance imaging seems to be the modality of choice for differentiation between tumorous and nontumorous sinus obstruction.

Vestibular investigations in acoustic neuroma.

Forty-eight patients with surgically proven acoustic neuroma were examined preoperatively with a comprehensive battery of vestibular tests. In 87% of the patients, reduced caloric responses were measured on the side of the lesion. In 60% of the patients a non-responsive labyrinth was found. Spontaneous nystagmus was observed in 29% of the patients. A significant correlation with the size of the tumour was found in the occurrence of abnormal saccades in the calibration test, pathological smooth pursuit movements and the occurrence of gaze nystagmus, respectively. There was no correlation between the magnitude of the caloric response reduction and the mean hearing loss, which suggests that the hearing loss and the vestibular function loss do not occur synchronously. This study shows that in most cases of acoustic neuroma, the peripheral part of the vestibular system is severely disturbed. Abnormalities in the central and peripheral part of the vestibular system are more easily recognized with increasing tumour size. We conclude that a complete battery of vestibular tests is essential in combination with audiometric, neurologic and radiologic analysis for the early clinical diagnosis of acoustic neuroma.

Glottic and supraglottic carcinoma: a retrospective comparison of radiotherapy alone with sandwich therapy in 366 patients.

From 1971 through 1982, 442 patients with laryngeal carcinoma were seen at the Leiden University Hospital. They were treated either with radiotherapy alone, sandwich therapy (pre- and postoperative radiotherapy) or by surgery followed by postoperative irradiation. Three hundred and sixty-six patients with glottic or supraglottic tumours could be analysed with respect to two different treatments, complications of treatment and some prognostic factors. Two endpoints of analysis were used: disease-free interval and survival to cancer death. In patients with glottic or supraglottic carcinoma, the survival of patients with advanced disease, treated with radiotherapy only, was worse as compared to the survival of the same category of patients who were treated with sandwich therapy (p less than 0.005). In patients with small glottic tumours, radiotherapy alone was mostly used. In small supraglottic tumours, the survival with both therapy policies was equal. Persistent hoarseness in patients with small glottic tumours, treated with radiotherapy only, is of predictive value for the development of a recurrence (p less than 0.001). There was no influence on prognosis of histological differentiation of the tumour. It appeared that interruption of radiotherapy for more than two days had an adverse effect on survival in patients with glottic carcinoma (p = 0.0001). Finally, the occurrence of second malignancies was analysed. It was found that 19% had a second malignancy. Almost 60% of them were lung cancers.

Dysphagia in inclusion body myositis.

Four elderly patients with inclusion body myositis and dysphagia are described. Dysphagia was the presenting symptom in three, preceding generalised weakness by 1.5 to 7 years. Myotomy of the cricopharyngeal muscle improved the symptoms and signs in 3 of the 4 patients. It is suggested that inclusion body myositis is not an infrequent cause of dysphagia in elderly people, and is amenable to treatment.

A helpful device in cricopharyngeal surgery.

Extramucosal myotomy of the pharyngoesophageal sphincter muscle, ie, the cricopharyngeal muscle, is a widely used therapy for dysphagia due to neurologic diseases. The cricopharyngeal muscle is dissected free via a lateral cervical incision. To cut the muscle fibers it is necessary to expose and to stretch them. A device is developed to make this possible. A light source is brought within a cuffed tube. The tube is inserted in the esophagus with the cuff in the cricopharyngeal sphincter. Inflating the cuff with air causes stretching of the muscle fibers, whereas the light source inside makes all muscle fibers visible. They can be cut carefully, leaving the mucosa intact.

The effect of nicotinamide on tinnitus: a double-blind controlled study.

The vasodilatory drug nicotinic acid is still widely used in the treatment of tinnitus. Although neither the success rate of this drug nor the pharmacokinetic mechanism underlying the supposed suppressive effect on tinnitus is known, it is clear from the literature that the vasodilative effect is not responsible for its effect on tinnitus. In a double blind controlled trial performed in 48 patients, the value of the related drug nicotinamide was assessed and compared with the effect of a placebo. The results obtained with nicotinamide were not better than those observed for the placebo.

The distribution of motoneurons supplying hind limb muscles in the clawed toad, Xenopus laevis.

The distribution of motoneurons in the lumbar spinal cord (spinal segments 8-10) of the clawed toad, Xenopus laevis, was studied with the horseradish peroxidase technique. In a total of 13 different hind limb muscles this tracer was applied in a slow-release gel. Motoneurons innervating a particular hind limb muscle were clustered in longitudinally arranged motor pools. Motor pools of different muscles did show considerable overlap both in the rostrocaudal and transverse plane. But, the various motor pools clearly show a somatotopic organization of motoneurons even in such a condensed lumbar spinal cord as in Xenopus laevis. Motoneurons innervating more distally positioned muscles are generally found in more caudal segments, while proximal muscles (with the exception of the m. adductor magnus) are supplied by motoneurons more or less throughout the lumbar enlargement. Flexor muscles usually are innervated by motoneurons situated ventrolaterally in the ventral horn, extensor muscles by dorsomedially found motoneurons. This pattern is particularly apparent for proximal (thigh) muscles, less so for more distal (shank and foot) muscles. The present data are in keeping with those obtained with the retrograde cell degeneration technique in ranid frogs and are consistent with observations in other tetrapods, although a more clear separation of motor pools is evident in "higher" vertebrates such as birds and mammals.

The loudness of tinnitus.

Although tinnitus causes considerable suffering to many patients, its loudness is small in most cases. Traditionally the loudness is measured with a binaural loudness balance procedure. It is stated that when there is recruitment in the ear to which the test tone is presented, the intensity of the test tone is smaller than its loudness. Therefore in the case of recruitment in the ear to which the test tone is presented, the loudness of tinnitus will be underestimated. In this study the loudness in a group with recruitment in the ear to which the test tone was presented was compared with the loudness in a group with a normal ear to which the test tone was presented. The present results show that although recruitment does have a certain effect, it is very small.

Dose finding of tocainide in the treatment of tinnitus.

A dose finding study was performed for the use of oral tocainide in the treatment of tinnitus. In a single-blind study, increasing doses of tocainide hydrochloride ranging from 0 to 1800 mg and back to 0 mg were administered to 19 patients. Each dose was given for 4 days and the effects as well as the serum concentrations were recorded on the 4th day. In 8 patients the symptoms regressed to a non-troublesome level. In most instances this effect was seen at doses of 900 and 1800 mg, respectively. Side effects were frequent. The most important side effect, which was an absolute indication for termination of the study, was an exanthema that developed in 7 of the patients (37%). Taking into account all side effects observed, it was concluded that no justification exists for doses over 900 mg daily for the treatment of tinnitus. However, in comparison with lidocaine, which can only be given intravenously, the therapeutic score of tocainide is low and in fact tocainide is no satisfactory alternative to lidocaine.