Squamous cell carcinoma and Zenker diverticulum.

Squamous cell carcinoma in a Zenker diverticulum is a very rare condition. We report a case of a patient with a Zenker carcinoma, who was primarily functionally inoperable and therefore received neoadjuvant radiochemotherapy before cardiac bypass surgery. After a complicated course with cardiogenic shock and myocardial infarction, a re-evaluation of functional risk analysis and the tumor situation revealed operability. Subsequently, partial hypopharyngectomy and partial cervical esophageal resection with lymphadenectomy was performed. Reconstruction of the gastrointestinal continuity was made by interposition of a free small bowel graft and microvascular anastomosis. The postoperative course showed a small anastomotic leakage of the hypopharyngeal-small bowel anastomosis, which was successfully treated conservatively.

Estradiol increases proteinuria and angiotensin II type 1 receptor in kidneys of rats receiving L-NAME and angiotensin II.

Prospective, placebo-controlled clinical trials suggest that estrogen may have adverse effects on the vascular system in women. The goal of this study was to determine if 17beta-estradiol (E2) would have adverse effects on the renovasculature in a rat model of renal injury characterized by low nitric oxide (NO) and high angiotensin II (AngII). We studied female Wistar rats that were sham-operated (sham), ovariectomized (OVX), or ovariectomized and replaced with E2 (OVX/E2). All rats were maintained on a high salt diet and renovascular injury was caused by treating rats with an inhibitor of NO synthase, N(omega)-nitro-L-arginine-methyl-ester (L-NAME), for 14 days, plus AngII on days 11 through 14. L-NAME/AngII treatment, as compared to placebo, caused proteinuria, glomerular injury, and fibrinoid necrosis of renal arterioles in sham-operated rats. Ovariectomy reduced L-NAME/AngII-induced renal damage, whereas E2 treatment increased L-NAME/AngII-induced damage in OVX rats. In rats treated with L-NAME/AngII, levels of AngII type 1 receptor (AT(1)R) protein were higher in the renal cortex of sham and OVX/E2 rats than in OVX rats. AT(1)R protein correlated with renal injury. E2 treatment also increased expression of AT(1)R mRNA. Thus, under conditions of low NO and high AngII, E2 exacerbated renal injury. E2-mediated increases in renal cortical AT(1)R expression may represent a novel mechanism for the adverse renovascular effects of estrogen.

Structural brain changes in tinnitus.

Tinnitus is a common but poorly understood disorder characterized by ringing or buzzing in the ear. Central mechanisms must play a crucial role in generating this auditory phantom sensation as it persists in most cases after severing the auditory nerve. One hypothesis states that tinnitus is caused by a reorganization of tonotopic maps in the auditory cortex, which leads to an overrepresentation of tinnitus frequencies. Moreover, the participation of the limbic system in generating tinnitus has been postulated. Here we aimed at identifying brain areas that display structural change in tinnitus. We compared tinnitus sufferers with healthy controls by using high-resolution magnetic resonance imaging and voxel-based morphometry. Within the auditory pathways, we found gray-matter increases only at the thalamic level. Outside the auditory system, gray-matter decrease was found in the subcallosal region including the nucleus accumbens. Our results suggest that reciprocal involvement of both sensory and emotional areas are essential in the generation of tinnitus.

Stability of immobilized D-hydantoinase from Vigna angularis and repeated cycles of highly enantioenriched production of N-carbamoyl-D-phenylglycines.

D-hydantoinase from Vigna angularis was immobilized by covalent linkage to aminopropyl glass beads. Thermal stability, resistance to storage at different pH values and temperatures of this biocatalyst were studied. This enzyme preparation was used as a catalyst to prepare enantioenriched N-carbamoyl-D-phenylglycine, N-carbamyl-D-p-fluorophenylglycine and N-carbamoyl-D-p-trifluoromethylphenylglycine, using a stirred batch reactor. Reactions were conducted during eight repeated reaction cycles, without loss of enzymatic activity or variation of the enantiomeric excess of the respective product (>98%).

Ethinylestradiol/cyproterone acetate in polycystic ovary syndrome: lipid and carbohydrate changes.

OBJECTIVE: Ethinylestradiol (EE) combined with the antiandrogenic progestin cyproterone acetate (CPA) is a possible treatment in polycystic ovary syndrome (PCOS). We investigated the impact of EE/CPA on lipid and carbohydrate metabolism in women with PCOS,who were otherwise healthy. METHOD: The 31 women were separated into two groups paired by body mass index (BMI): Group A (control, n = 15) were cycled with 10 mg medroxyprogesterone acetate (MPA) x 10 days (Provera, Pharmacia & Upjohn) every month for 3 months; Group B (n = 16) were treated with 35 microg EE/2 mg CPA (Diane 35, Schering) for 3 months. Metabolic and hormonal conditions were similar in both groups. RESULTS: Group A showed no change in any hormone or metabolic parameter. Group B showed a significant decrease in free androgen index (-81%) and increase in sex hormone binding globulin (+ 639%), a decrease in low density lipoprotein cholesterol (-14%) and total cholesterol/high density lipoprotein (HDL) cholesterol index (-19%), and increases in HDL cholesterol (+ 23%) and triglycerides (+ 82%) (p < 0.001). Fasting insulin increased in 18%, the glucose/insulin index worsened in 8%, and the plasma glucose disappearance worsened in 12%, with no statistical significance (p= 0.092, p=0.308 and p= 0.237, respectively). CONCLUSION: Treatment of PCOS with EE/CPA induces important favorable changes regarding hormone parameters associated with hyperandrogenism, significant favorable changes in lipid profile except for triglyceride increase, and no significant change in carbohydrate metabolism (measured by fasting insulin, glucose/insulin index and plasma glucose disappearance). MPA cycling does not change any of these parameters.

[Impalement injury of the neck]. / Pfählungsverletzung des Halses.

In comparison to the United States or South Africa, penetrating injuries of the neck are rare in Europe. Most of these traumas are due to sharp perforation mechanisms. We report on a 43-year-old man who was admitted to the emergency room because of an impressive transcervical penetrating neck trauma inflicted by a chisel. He survived the trauma since the chisel missed all important structures of the neck. The diagnostic strategy to evaluate the dimension of the trauma was primarily based on endoscopic and surgical exploration.

Role of substance P in the peripheral vestibular and auditory system.

The central role of substance P (SP) has attracted growing interest in the past two decades. One of the important physiological functions of SP and other tachykinins is that of a neurotransmitter in primary afferent neurons. Recent immunocytochemical, biochemical and electrophysiological investigations on various neurotransmitters support the hypothesis that SP has a similar function in the vestibular and auditory systems of all mammals including humans. The purpose of this review is to give an overview of the distribution and concomitant physiological functions of this peptide in these sensory systems.

Novel methods to estimate the enantiomeric ratio and the kinetic parameters of enantiospecific enzymatic reactions.

1The Enantiomeric Ratio (E) of the enzyme, acting as specific catalysts in resolution of enantiomers, is an important parameter in the quantitative description of these chiral resolution processes. In the present work, two novel methods hereby called Method I and II, for estimating E and the kinetic parameters Km and Vm of enantiomers were developed. These methods are based upon initial rate (v) measurements using different concentrations of enantiomeric mixtures (C) with several molar fractions of the substrate (x). Both methods were tested using simulated "experimental data" and actual experimental data. Method I is easier to use than Method II but requires that one of the enantiomers is available in pure form. Method II, besides not requiring the enantiomers in pure form shown better results, as indicated by the magnitude of the standard errors of estimates. The theoretical predictions were experimentally confirmed by using the oxidation of 2-butanol and 2-pentanol catalyzed by Thermoanaerobium brockii alcohol dehydrogenase as reaction models. The parameters E, Km and Vm were estimated by Methods I and II with precision and were not significantly different from those obtained experimentally by direct estimation of E from the kinetic parameters of each enantiomer available in pure form.

[Familial and isolated primary hyperparathyroidism. Case report]. / Hiperparatiroidismo primario, aislado y de carácter familiar. Caso clínico.

Familial hyperparathyroidism can be a part of a type 1 or 2 multiple endocrine neoplasia syndrome, can be associated to mandibular fibromas or can appear as an isolated disease. We report a family with 11 members affected by a primary hyperparathyroidism, all with a history of kidney stones and without evidences of other endocrine tumors. Not knowing the familial history of the disease, only one adenoma was resected in four cases and in all, the disease recidivated. Two were operated again, performing a total parathyroidectomy and heterologous autotransplantation of parathyroid tissue in the forearm. The presentation form of primary hyperparathyroidism in this family, is similar to other reported cases. It is more aggressive, is diagnosed at a lower age has a higher incidence of recurrence and multiglandular involvement than the sporadic disease.

Resolution of DL-hydantoins by D-hydantoinase from Vigna angularis: production of highly enantioenriched N-carbamoyl-D-phenylglycine at 100% conversion.

D-Hydantoinase from Vigna angularis hydrolyzed rac-5-monosubstituted-hydantoins with polar and aromatic side chains and dihydrothymine but rac-5,5-disubstituted-hydantoins were not substrates of this enzyme. 5-Phenylhydantoin was the best substrate. By using this substrate, Ncarbamoyl-D-phenylglycine was obtained in quantitative yield and over 98% ee.

Alpha and beta subunits of acetylcholine receptors in the human inner ear.

The localization and distribution of nicotinic acetylcholine receptors (n-ACh-r) was characterized by studying alpha and beta subunits in the adult human inner ear by FITC fluorescence technique. In the cochlea, distinct fluorescence staining occurred for beta subunits in outer hair cells (OHCs), but no alpha subunits were identified. Beta subunits differ quantitatively between the three rows of OHCs, decreasing along a base-to-apex gradient in the cochlea. Both alpha and beta subunits were identified on spiral ganglion cells, adjacent nerve fibres and in vestibular hair cells (HCs). It would appear that they form an active complex in n-ACh-r at these locations.

Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology.

There is evidence that primary aldosteronism (PA) may be common in patients with essential hypertension (EH) when determinations of serum aldosterone (SA), plasma renin activity (PRA), and the SA/PRA ratio are used as screening. An inherited form of primary hyperaldosteronism is the glucocorticoid-remediable aldosteronism (GRA) caused by an unequal crossing over between the CYP11B1 and CYP11B2 genes that results in a chimeric gene, which has aldosterone synthase activity regulated by ACTH. The aim of this study was to evaluate the prevalence of PA and the GRA in 305 EH patients and 205 normotensive controls. We measured SA (1-16 ng/dL) and PRA (1-2.5 ng/mL x h) and calculated the SA/PRA ratio in all patients. A SA/PRA ratio level greater than 25 was defined as being elevated. PA was diagnosed in the presence of high SA levels (>16 ng/dL), low PRA levels (<0.5 ng/mL x h), and very high SA/PRA ratio (>50). Probable PA was diagnosed when the SA/PRA ratio was more than 25 but the other criteria were not present. A Fludrocortisone test was done to confirm the diagnosis. GRA was differentiated from other forms of PA by: the aldosterone suppression test with dexamethasone, the high levels of 18-hydroxycortisol, and the genetic detection of the chimeric gene. In EH patients, 29 of 305 (9.5%) had PA, 13 of 29 met all the criteria for PA, and 16 of 29 were initially diagnosed as having a probable PA and confirmed by the fludrocortisone test. Plasma potassium was normal in all patients. The dexamethasone suppression test was positive for GRA in 10 of 29 and 18-hydroxycortisol levels were high in 2 of 29 patients who had also a chimeric gene. In normotensive subjects, 3 of 205 (1.46%) had PA, and 1 of 205 had a GRA. In summary, we found a high frequency of normokalemic PA in EH patients. A high proportion of PA suppressed SA with dexamethasone, but only a few had a chimeric gene or high levels of 18-hydroxycortisol. These results emphasize the need to further investigate EH patients.

Neurotrophin 3 potentiates glutamatergic responses of IHC afferents in the cochlea in vivo.

Neurotrophins have traditionally been regarded as slow-acting signals essential for neuronal survival and differentiation. Recent studies with neuronal slices, cultures and nerve ending preparations have shown that neurotrophins generate acute changes in nerve activity. Among the secondary sensory cells are the inner hair cells (IHC) and taste buds, cells which express the neurotrophic factors necessary for the survival of their innervating neurons. If in these cells neurotrophins acutely affect the nerve activity of their afferent neurons, as in the central nervous system (CNS), this may have important functional implications for the corresponding sensory transduction processes. The neurotrophin NT-3 has been reported to be expressed in IHCs. We chose an in vivo application system for the microiontophoretic supply of NT-3 in the subsynaptic region of the IHC. The effect of NT-3 on spontaneous and evoked afferent cochlear nerve activities in adult guinea pig inner ear was studied. We observed that NT-3 rapidly increases the spontaneous and glutamate-evoked firing rate of IHC afferents. Moreover, firing induced by both N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) were specifically enhanced during the presence of NT-3, a process which was selectively blocked by the tyrosine kinase receptor inhibitor K252a. Because we localized NT-3 mRNA not only in IHCs but also in the spiral ganglion, we propose that similar to other sensory systems, afferent and autocrine neurotrophin activities may be responsible for survival of cochlear neurons. In addition, NT-3 in IHCs may operate as a signal-dependent, intrinsic neuromodulator and/or neuroprotector.

[Excess of mineralocorticoids in essential hypertension: clinical-diagnostic approach]. / Exceso de mineralocorticoides en hipertensos esenciales: enfoque clínico-diagnóstico.

BACKGROUND: Primary hyperaldosteronism is more frequent among subjects with essential hypertension than previously thought. The prevalence, according to local and international evidence could fluctuate between 9 and 10%. AIM: To investigate if subjects with essential hypertension have different aldosterone and renin plasma levels than normotensive subjects. PATIENTS AND METHODS: One hundred twenty five subjects with essential hypertension, not receiving medications for at least two weeks prior to the study and 168 age and sex matched normotensive controls were studied. Blood was drawn between 9 and 10 AM during a sodium free diet to determine plasma aldosterone, plasma renin activity and potassium. RESULTS: Plasma aldosterone was higher in hypertensive subjects than controls (11.6 +/- 7.6 and 9.9 +/- 5.1 ng/dl respectively; p = 0.04). Plasma renin activity was lower in hypertensives than controls (1.42 +/- 1.28 and 1.88 +/- 1.39 ng/ml/b respectively; p < 0.001). Thus, plasma aldosterone/plasma renin activity ratio was higher in hypertensives (13.8 +/- 13.5 and 8.3 +/- 7.8; p < 0.001). A pathological ratio was defined as over 25, corresponding to the mean plus two standard deviations of the control group. Primary hyperaldosteronism was found in 5/125 hypertensives (4%) and 1/168 normotensive subject (0.6%). None had hypokalemia. CONCLUSIONS: Subjects with essential hypertension have higher plasma aldosterone and lower plasma renin activity than normal controls. A plasma aldosterone/plasma renin activity over 25 was defined as abnormal.

A(-6)G variant of angiotensinogen gene and aldosterone levels in hypertensives.

Recently, a novel mutation in the promoter region of the angiotensinogen gene that involves the presence of an adenine instead of a guanine 6 bp upstream from the transcription initiation site (A(-6)G) has been shown to induce an increase in gene transcription. The aim of this study was to determine the prevalence of the A(-6)G mutation in essential hypertensive patients and to correlate it with aldosterone and renin activity levels. We studied 191 hypertensives. We measured levels of aldosterone (plasma and urinary) and plasma renin activity. We determined the variants A and G using a mutagenically separated polymerase chain reaction technique. In 191 hypertensives, the A variant was detected in 266 of 382 (69.6%) and the G variant in 116 of 382 alleles (30.4%). Plasma aldosterone was significantly higher in patients homozygous for AA than in those homozygous for GG (369+/-208 versus 246+/-142 pmol/L). Urinary aldosterone was significantly higher in homozygous AA than in AG or GG patients (62.4+/-39.4 versus 50.8+/-25.2 and 37.4+/-22.3 nmol/d, respectively). When the patients were grouped according to the presence or absence of the A allele, the aldosterone levels and the plasma aldosterone/plasma renin activity ratio were significantly higher in patients with the A allele. The presence of the A variant was associated with higher levels of aldosterone. These results suggest that the presence of the A variant could determine the appearance of arterial hypertension through higher transcription activity of the angiotensinogen gene and concomitant aldosterone production.

Metabotropic glutamate receptors group I are involved in cochlear neurotransmission.

All three types of ionotropic glutamate receptors, AMPA, NMDA and kainate, contribute to the neurotransmission between inner hair cells (IHC) and afferent neurons in the mammalian cochlea. We used microiontophoretic techniques to investigate whether metabotropic glutamate receptors group I (mGluR I) are also involved in the transmission of IHC afferents of the guinea pig. The mGluR I agonist DHPG produced an increase in afferent firing, which lasted significantly longer than that of the ionotropic agonists AMPA and NMDA. The activation was reversibly blocked by the mGluR I antagonist AIDA in a dose-dependent manner. AIDA also diminished spontaneous activity, but only slightly affected the AMPA- or NMDA-induced firing rate. Our results suggest that mGluR I are involved in peripheral auditory processing.

New approaches for inner ear therapy with glutamate antagonists.

In the mammalian cochlea neurotransmission between inner hair cells and afferent auditory neurons is probably mediated by glutamate or another related excitatory amino acid. Neurotoxicity induced by excessive glutamate release seems to play a crucial role in some pathological conditions of the cochlea, such as ischaemia or noise trauma. Thus, glutamate antagonists may be a new therapeutic strategy for different inner ear diseases. Because of their potential severe side-effects only a few glutamate antagonists have so far been adopted for clinical use. We used microiontophoretic techniques to compare the effects of memantine and caroverine on the glutamatergic transmission of inner hair cells of the guinea pig and tested the possibility of a local administration of memantine to the cochlea with a micropump. Memantine selectively inhibited the NMDA (N-methyl-D-aspartate) stimulated activity while caroverine blocked NMDA as well as AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) induced activity of inner hair cell afferents. With a flow rate of 1 microl/h the local administration of memantine via a cochleotomy was succeeded in a reversible blockade of the spontaneous and the NMDA induced firing of inner hair cell afferents. These results suggest that local application to the cochlea could be a feasible way to administer glutamate antagonists in sufficient amounts while avoiding systemic side-effects.

GABA(A) receptor modulates the activity of inner hair cell afferents in guinea pig cochlea.

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) is mediated by two main categories of receptors: the GABA(A) and GABA(B) receptor. Recent immunocytochemical and electron microscopical studies revealed the existence of GABA at the efferent olivocochlear innervation of the guinea pig cochlea. In this microiontophoretic study we examined the effect of GABA on spontaneous and glutamate or acetylcholine induced activity of afferent fibres in the dendritic region of inner hair cells. Furthermore, the receptor subtypes being responsible for this GABA action were analysed using specific agonists and antagonists on alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) induced activity. The spike activities of the subsynaptic area were recorded in the third or fourth turn of the cochlea of anaesthetised guinea pigs. Application of GABA had little effect on spontaneous activity whereas the glutamate or acetylcholine induced firing rate could be depressed by GABA. AMPA and NMDA induced activity was reduced by the GABA(A) agonist muscimol but not by the GABA(B) agonist baclofen. The GABA(A) antagonist blocked the inhibition of both GABA and the GABA(A) agonist. In contrast, the GABA(B) antagonist saclofen was without effect. These results reveal that GABA reduces the activated firing rate of inner hair cell afferents mediated by the GABA(A) receptor subtype.