Muscarinic and nicotinic cholinergic agonists: structural analogies and discrepancies

Acetylcholine, the first identified neurotransmitter acts on both types of cholinergic receptors. Both rigid and flexible derivatives of acetylcholine could either be selective muscarinic or selective nicotinic agonists while some compounds show activity at both receptor subclasses. Earlier structure-activity considerations are revisited. Ligand and receptor based calculations have been applied in the hope to identify characteristic geometrical and steric requirements for the activity on the receptor subtypes. Results are treated critically and applied cautiously for predicting selective structural requirements by the cholinergic receptor subclasses.     

Familial hypocalciuric hypercalcemia

INTRODUCTION: Familial hypocalciuric hypercalcemia is often considered but rarely proved during evaluation for hypercalcemia. The disorder is characterized by lifelong persisting hypercalcemia and hypocalciuria. CASE REPORT: In this study, the authors analyzed a 25-yr-old Hungarian woman with mild hypercalcemia detected by routine laboratory testing. Evaluation revealed hypercalcemia, relative hypocalciuria and non-suppressed serum intact parathormone level. The diagnosis of hypocalciuric hypercalcemia was confirmed by the low ratio of calcium clearance/creatinine clearance. Genetic studies for calcium-sensing receptor gene mutations were performed in blood DNA samples. After polymerase chain reaction amplification, DNA sequencing of exons 2-7 were performed. The proband and her father had the same mutation (CCG-->CTG) at codon 55 of exon 2, leading to a conversion of the proline to a leucine. DISCUSSION: This case report presents the first case of familial hypocalciuric hypercalcemia, published in a Hungarian patient.     

Physiologic mechanisms in extremity veins supporting chronic orthostatic tolerance

As a consequence of chronic orthostatic load of the organism several long-term antigravitation defense mechanism are activated in the lower extremity veins and microvessels. The following adaptive mechanisms are brought into focus: acute pressure-induced myogenic tone and its augmentation which promote the venous capacity autoregulation, potassium channels counterregulating the depolarization of the venous smooth muscle membrane, functional and structural remodeling of sympathetic innervation in the vascular wall, changes in venous network properties, decreased capillary supply in oxidative muscles of the extremities, and probably transendothelial homeostatic water transport in the wall of veins.     

Somatostatin receptor scintigraphy in the management of cerebral malignant ectomesenchymoma: a case report

A 10-year-old girl presented with a cerebral malignant ectomesenchymoma (MEM), a very unusual tumour with undifferentiated mesenchymal as well as ectodermal elements. Somatostatin receptor scintigraphy (SRS) was performed during the diagnostic workup. The recurrent residual tumour mass was exactly visualized with SRS, and was negative after successful treatment of the patient. The potential application of SRS in initial staging, follow-up and therapy planning in MEM is discussed. This is the first application of SRS in MEM. Received: 14 May 1999 Accepted: 8 May 2000     

Intracochlear injection of pseudorabies virus labels descending auditory and monoaminerg projections to olivocochlear cells in guinea pig

Pseudorabies virus was used to label transneuronally descending auditory projections following intracochlear injections. At different time points after injection, virus-infected cells were detected immunohistochemically in the central nervous system. Initially (25 h), virus was transported retrogradely to olivocochlear cells in the pons. At 32-72 h after injection, labelling occurred in higher order auditory brainstem nuclei as well as in the locus coeruleus and pontine dorsal raphe. At 90-108 h, virus-infected neurons were found bilaterally in the medial geniculate body and in layer V of the auditory cortex. Viral transneuronal labelling in the auditory cortex after intracochlear application confirms the existence of a continuous descending chain of neurons from the auditory cortex to the cochlea, via the medial and lateral olivocochlear systems. The transneuronal labelling of the locus coeruleus and pontine dorsal raphe suggests that noradrenergic and serotonergic inputs may substantially influence the activity of olivocochlear cells, and thus the cochlea.     

Leptin and Puberty: A Review

Pituitary - Over the last few years, many studies have focused on leptin, the product of the LEP (ob) gene, searching for a possible link between energy balance and reproduction. The involvement of...     

Electron and High-Dose-Rate Brachytherapy Boost in the Conservative Treatment of Stage I-II Breast Cancer First Results of the Randomized Budapest Boost Trial

Background and Aims: To evaluate the effect of electron and high-dose-rate brachytherapy (HDR BT) boost on local tumor control (LTC), side effects and cosmesis after breast-conserving surgery (BCS) in a prospective randomized study. Patients and Methods: 207 women with stage I-II breast cancer who underwent BCS were treated by 50 Gy irradiation to the whole breast and then randomly assigned to receive either a boost to the tumor bed (n = 104) or no further radiotherapy (n = 103). Boost treatments consisted of either 16 Gy electron irradiation (n = 52) or 12-14,25 Gy HDR BT (n = 52). Breast cancer-related events, side effects, and cosmetic results were assessed. Results: At a median follow-up of 5.3 years, the crude rate of local recurrences was 6.7% (7/104) with and 15.5% (16/103) without boost. The 5-year probability of LTC, relapse-free survival (RFS), and cancer-specific survival (CSS) was 92.7% vs. 84.9% (p = 0.049), 76.6% vs. 66.2% (p = 0.044), and 90.4% vs. 82.1% (p = 0.053), respectively. There was no significant difference in LTC between patients treated with electron or HDR BT boost (94.2% vs. 91.4%; p = 0.74). On multivariate analysis, patient age < 40 years (RR: 4.53), positive margin status (RR: 4.17), and high mitotic activity index (RR: 3.60) were found to be significant risk factors for local recurrence. The incidence of grade 2-3 side effects was higher in the boost arm (17.3% vs. 7.8%; p = 0.03). However, the rate of excellent/good cosmetic results was similar for the two arms (85.6% vs 91.3%; p = 0.14). Cosmesis was rated as excellent/good in 88.5% of patients treated with HDR BT and 82.7% of patients with electron boost (p = 0.29). Conclusions: Boost dose significantly improves LTC and RFS in patients treated with BCS and radiotherapy. In spite of the higher incidence of late side effects in the boost arm, boost dose is strongly recommended for patients at high risk for local recurrence. Positive or close margin status, high mitotic activity index, and young patient age should be viewed as absolute indications for tumor bed boost. LTC and cosmesis are excellent and similar to patients boosted with either HDR BT or electrons. Hintergrund und Ziel: In einer prospektiv randomisierten Studie werden die Effekte eines Elektronenboosts und eines High-Dose-Rate-Brachytherapie-(HDR-BT-)Boosts bezüglich lokaler Tumorkontrolle (LTC), Nebenwirkungen und kosmetischer Ergebnisse nach brusterhaltender Operation (BCS) evaluiert. Patienten und Methodik: 207 Patientinnen mit Brustkarzinomen im Stadium I-II wurden einer BCS zugeführt. Postoperativ erfolgte eine perkutane Radiatio der gesamten Brust bis 50 Gy. Daran schloss sich willkürlich entweder eine Boostbestrahlung des Tumorbetts (n = 104) oder keine weitere Radiatio (n = 103) an. Die Boostbestrahlung erfolgte perkutan mit 16 Gy Elektronen (n = 52) oder in Form einer HDR-BT mit 12-14,25 By (n = 52). Untersucht wurden LTC, Nebenwirkungen und kosmetische Ergebnisse. Ergebnisse: Die mediane Nachbeobachtungszeit betrug 5,3 Jahre. Die Lokalrezidivrate lag mit Boostbestrahlung bei 6,7% (7/104), ohne Boost bei 15,5% (16/103). Die 5-Jahres-Überlebensrate für LTC, für die rezidivfreie Überlebenszeit (RFS) und für die krebsspezifische Überlebenszeit (CSS) betrugen 92,7% vs. 84,9% (p = 0,049), 76,6% vs. 66,2% (p = 0,044) und 90,4% vs. 82,1% (p = 0,053). Bezüglich der LTC bestand kein signifikanter Unterschied zwischen Patienten, die mit einem Elektronen- oder HDR-BT-Boost behandelt wurden (94,2% vs. 91,4$; p = 0,74). Die multivariate Analyse zeigte, dass Faktoren wie Patientenalter > 40 Jahre (RR: 4,53), positive Resektionsränder (RR: 4,17) und ein hoher Mitoseaktivitätsindex (RR: 3.60) das Risiko eines lokalen Rezidivs signifikant erhöhen. Die Inzidenz von Nebenwirkungen Grad 2-3 war im Boost-Arm höher (17,3% vs. 7,8%; p = 0,03). Allerdings waren die sehr guten kosmetischen Ergebnisse in beiden Armen gleich (85,6% bs. 91,3%, p = 0,14). Sehr gute kosmetische Ergebnisse wurden bei 88,5% der Patientinnen mit HDR-BT-Boost und 82,7% der Patientinnen mit Elektronenboost erreicht (p = 0,29). Schlussfolgerungen: Die Boost-Dosis verbessert signifikant LTC und RFS bei Patientinnen, die einer BCS und anschließender Radiatio zugeführt wurden. Obwohl eine höhere Inzidenz an Spätnebenwirkungen im Boost-Arm gefunden wurde, wird eine Boost-Dosis für Patientinnen mit hohem Risiko für die Entwicklung eines Lokalrezidivs empfohlen. Unserer Meinung nach ist bei Faktoren wie positive Schnittränder, schmaler Sicherheitssaum, hoher Mitoseaktivitätsindex und niedriges Patientenalter, die absolute Indikation zur Boost-Bestrahlung des Tumorbetts gegeben. LTC und die kosmetischen Ergebnisse sind sehr gut und unterscheiden sich nicht in Bezug auf Elektronenboost oder HDR-BT-Boost.