Evolution of cortical neurons supporting human cognition.

Human cognitive abilities are generally thought to arise from cortical expansion over the course of human brain evolution. In addition to increased neuron numbers, this cortical expansion might be driven by adaptations in the properties of single neurons and their local circuits. We review recent findings on the distinct structural, functional, and transcriptomic features of human cortical neurons and their organization in cortical microstructure. We focus on the supragranular cortical layers, which showed the most prominent expansion during human brain evolution, and the properties of their principal cells: pyramidal neurons. We argue that the evolutionary adaptations in neuronal features that accompany the expansion of the human cortex partially underlie interindividual variability in human cognitive abilities.

Verbal and General IQ Associate with Supragranular Layer Thickness and Cell Properties of the Left Temporal Cortex.

The left temporal lobe is an integral part of the language system and its cortical structure and function associate with general intelligence. However, whether cortical laminar architecture and cellular properties of this brain area relate to verbal intelligence is unknown. Here, we addressed this using histological analysis and cellular recordings of neurosurgically resected temporal cortex in combination with presurgical IQ scores. We find that subjects with higher general and verbal IQ scores have thicker left (but not right) temporal cortex (Brodmann area 21, BA21). The increased thickness is due to the selective increase in layers 2 and 3 thickness, accompanied by lower neuron densities, and larger dendrites and cell body size of pyramidal neurons in these layers. Furthermore, these neurons sustain faster action potential kinetics, which improves information processing. Our results indicate that verbal mental ability associates with selective adaptations of supragranular layers and their cellular micro-architecture and function in left, but not right temporal cortex.

Food intake inhibition and reduction in body weight gain in lean and obese rodents treated with GW438014A, a potent and selective NPY-Y5 receptor antagonist.

Numerous reports have implicated theY5 receptor as the 'feeding' receptor mediating the orexigenic action of neuropeptide Y (NPY). This notion is supported by the correlation between the in vitro functional and binding activities of different peptide agonists and their potent stimulation of food intake in rodents. We have discovered a series of small molecule heterocycles with high affinity, selectivity, and functional antagonism for Y5 receptors. Intraperitoneal (i.p.) administration of GW438014A into rodents, resulted in a potent reduction of NPY-induced and normal overnight food intake. Brain levels of GW438014A were detected well in excess of its binding IC(50) for up to 3 h post-dosing. Daily (i.p., BID, 10 mg/kg) administration of this compound to Zucker Fatty rats for a period of 4 days resulted in a marked decrease in the rate of weight gain and a reduction in fat mass. No effect on food intake was observed following oral administration of GW438014A (25-100 mg/kg), consistent with the poor oral bioavailability (<3%) and low brain levels observed.

Food intake inhibition and reduction in body weight gain in rats treated with GI264879A, a non-selective NPY-Y1 receptor antagonist.

Neuropeptide Y has been proposed to play a major role in the hypothalamic regulation of feeding behavior through the activation of specific, central NPY receptor(s). In an effort to design small molecule antagonists of NPY receptors, we have synthesized a series of substituted dipeptides based on defined pharmacophores, previously identified by us and others as essential for the interaction with the peptide receptors. GI264879A behaves as a functional antagonist of Y1 receptors while displaying no binding selectivity for the different NPY receptor subtypes. We demonstrate here that administration of GI264879A to rats causes a significant decrease in food intake and body weight partly through a mechanism dependent on the integrity of the vagus nerve.

Hypertrophy of basal forebrain neurons and enhanced visuospatial memory in perinatally choline-supplemented rats.

The effects of choline supplementation during two time-frames of early development on radial-arm maze performance and the morphology of basal forebrain neurons immunoreactive for the P75 neurotrophin receptor (NTR) in male and female Sprague-Dawley rats were examined. In the first experiment, rats were supplemented with choline chloride from conception until weaning. At 80 days of age, subjects were trained once a day on a 12-arm radial maze for 30 days. Compared to control littermates, supplemented rats made fewer working and reference memory errors; however, the memory enhancing effects of choline supplementation were greater in males than females. A morphometric analysis of NTR-immunoreactive cell bodies at three levels through the medial septum/diagonal band (MS/DBv) of these rats revealed that perinatal choline supplementation caused the somata of cells in the MS/DBv to be larger by 8-15%. In a second experiment, choline supplementation was restricted to embryonic days 12-17. A developmental profile of NTR immunoreactive cell bodies in the MS/DBv of 0-, 8-, 16-, 30- and 90-day old male and female rats again revealed that cell bodies were larger in choline-supplemented rats than controls. As in the behavioral studies, the effect of choline supplementation was greater in male than female rats. These data are consistent with the hypothesis that supplementation with choline chloride during early development leads to an increase in the size of cell bodies of NTR-immunoreactive cells in the basal forebrain and that this change may contribute to long-term improvement in spatial memory.

[Imaging methods in traumatology of the shoulder- and elbow joint]. / Bildgebende Verfahren in der Traumatologie des Schulter- und Ellenbogengelenkes.

Radiological diagnostics (diagnostic imaging) of the traumatised shoulder and elbow joint has expanded considerably and has become increasingly meaningful in recent years. The introduction of computed tomography and magnetic resonance imaging has enabled a significantly better assessment of soft parts and of the inner spatial structure of the joints. Hence, focus of diagnosis has now shifted from the assessment of the bones (which was previously the main aspect of diagnosis) to a different analysis of the joint as a functional unit of bone and soft part structures, an analysis that can also detect subtle changes such as additive micro-traumas. The article reviews the conventional imaging methods and the present state of the art in tomographic imaging technique, and illustrates this by means of several representative examples of diagnostic imaging.

Structure-activity relationship of novel pentapeptide neuropeptide Y receptor antagonists is consistent with a noncontinuous epitope for ligand-receptor binding.

We report the first systematic study on short peptide structure affinity and activity for the neuropeptide Y (NPY) receptor. A series of linear pentapeptides has been synthesized that display affinities in the low micromolar range toward rat brain NPY receptors. Furthermore, some of these compounds competitively antagonize the Y1-type NPY receptor-mediated increase in cytosolic Ca2+ in human erythroleukemic (HEL) cells. The inactive NPY carboxyl-terminal pentapeptide (Thr-Arg-Gln-Arg-Tyr-NH2; IC50 > 100 microM) was modified by replacing threonine with an aromatic amino acid and glutamine with leucine. This resulted in a series of pentapeptides with dramatically improved affinity (IC50 = 0.5-4 microM) for the rat brain receptor. The structure-affinity data suggest that these peptides may represent a noncontinuous epitope containing the amino-terminal tyrosine and the carboxyl-terminal residues Arg-35 and Tyr-36 of NPY.

High-affinity neuropeptide Y receptor antagonists.

Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats.

Interstitial high-dose rate brachytherapy with iridium-192 in patients with oral squamous cell carcinoma.

Thirty-four patients with recurrent oral and oropharyngeal carcinomas were treated over a period of 4 years, by interstitial high-dose rate (HDR) brachytherapy (BT) using an iridium-192 source (Gammamed 2i and 12i equipment, Sauerwein, Germany) and fractionated application (1 up to 3 times, weekly recovery phases, single maximum dose 10 Gy). Pretreatment characteristics of patients in terms of irradiation (RT) and surgery differed (22 had external RT alone, with a total dose between 60.0 and 75.6 Gy; RT and surgery: 7; surgery alone: 1). The initial TNM-stages (UICC, Hermanek et al., 1987) of patients were: I = 2, II =3, III = 7, IV = 22. In the majority of cases, clinical indications for HDR-BT included tumour recurrence or progression following external RT, and second primary tumours of the oral cavity. Therapy was successful in most cases, i.e. complete remission: 11, partial remission: 16, no change: 2, progression: 5. Local control and overall survival rates, including patients surgically treated after BT, were at 6 months 58% and 62%, and 44% and 53% at 12 months, respectively. This type of treatment is recommended in patients with local recurrence or second primary tumours after previous external RT in the head and neck region. However, the benefit of interstitial HDR-BT remains questionable, particularly in patients with large tumours and lymph node metastases.

[Results of neutron therapy in recurrent malignant salivary gland tumors in the head and neck area]. / Ergebnisse der Neutronentherapie bei rezidivierenden malignen Speicheldrüsentumoren im Kopf-Hals-Bereich.

PURPOSE: The records of 33 patients of recurrent salivary gland tumors of the head and neck regions were analysed. PATIENTS AND METHODS: 33 patients with recurrent salivary gland tumors were treated with fast neutrons of a 14 MeV DT generator. All patients had been operated several times. 10 patients had been irradiated before with photons or electrons. 24 patients had macroscopic tumor. In many cases advanced tumors were treated. RESULTS: The median follow-up of our patients is 33 months. 6 patients are still alive without disease. 5 patients are alive with local recurrence or tumor progression. The calculated survival rate for all patients is 45% at 5 years. The calculated control rate for all patients is 43% at 5 years. Most of the late side effects according to the RTOG/EORTC-score were moderate. Only in one case severe late side effects could be observed. CONCLUSION: According to the literature advanced recurrences of salivary gland tumors should be treated with fast neutrons.

Novel modified carboxy terminal fragments of neuropeptide Y with high affinity for Y2-type receptors and potent functional antagonism at a Y1-type receptor.

Peptide analogs of neuropeptide Y (NPY) with a Tyr-32 and Leu-34 replacement resulted in the decapeptide TyrIleAsnLeuIleTyrArgLeuArgTyr-NH2 (9; Table 1) and a 3700-fold improvement in affinity at Y2 (rat brain; IC50 = 8.2 +/- 3 nM) receptors when compared to the native NPY(27-36) C-terminal fragment. In addition, compound 9 was an agonist at Y1 (human erythroleukemia (HEL) cell; ED50 = 8.8 +/- 0.5 nM) receptors with potency comparable to that of NPY(1-36) (ED50 = 5 nM). Molecular dynamics and 1H-NMR were used to propose a solution structure of decapeptide 9 and for subsequent analog design. The replacement of Leu with Pro at position 4 of decapeptide 9 afforded an antagonist of NPY in HEL cells (18, TyrIleAsnProIleTyrArgLeuArgTyr-NH2; IC50 = 100 +/- 5 nM). Deletion of the N-terminal tyrosine of 18 resulted in a 10-fold improvement in antagonistic activity with a parallel 4-fold decrease in Y2 affinity. This potent antagonist may provide further insight into the physiological role(s) for NPY in the mammalian and peripheral nervous system.

[Dysbaric osteonecrosis in professional divers: MRT as a screening method?]. / Dysbare Osteonekrosen bei Berufstauchern: MRT als Screeningverfahren?

20 male professional divers underwent a total of 68 MR examinations of the shoulder, hip and knee joints with follow-up for 16 joint regions. Cerebral MR was performed additionally in 16 divers. 11 patients showed signal alterations of bone marrow which suggested bone infarct in 9 cases. One patient had unifocal demyelinisation of the left hemisphere. In conclusion, MR showed high sensitivity in detecting dysbaric osteonecrosis.

Regional CNS uptake of blood-borne nerve growth factor.

Nerve growth factor (NGF), in addition to being a neurotrophic substance, has effects on the endocrine and immune systems. For example, intravenous injection of NGF results in a cascade of events leading to an increase in glucocorticoid secretion. While this response appears to be mediated centrally, there has been no evidence that circulating NGF has access to the CNS. Using intravenous injections of 125I-NGF, we find specific uptake at 1 hr but none at 6 hr, into homogenates of the basal forebrain, cerebellum, frontal cortex, hippocampus, and olfactory bulb. By autoradiography, uptake is localized to circumventricular organs, deep layers of the cerebellum, and all layers of the hippocampal region CA1, but not the dentate gyrus. Thus, uptake of blood-borne NGF could affect the hypothalamic-pituitary-adrenal axis via binding to NGF receptors present in the hippocampus. However, the sources of endogenous NGF, the mechanism of access through the blood-brain barrier, the eventual fate of NGF entering from the blood, and the physiological significance of this uptake remain to be elucidated.

Present results of neutron therapy. The German experience.

Results of fast neutron therapy are reviewed with special reference to the main indications for this type of treatment and the experience of five German centers. Neutron therapy seems beneficial compared to conventional radiotherapy in advanced salivary gland tumors, inoperable or unresectable soft tissue sarcomas, some bone tumors, prostate cancer stage C and some rare low-grade tumors. About 3,000 patients with malignancies have been treated with neutrons at the German centers Berlin/Rossendorf, Essen, Hamburg, Heidelberg and Münster. Treatment results and treatment-related morbidity depend on the treatment techniques and the physical selectivity of the neutron machines. A critical appraisal suggests that fast neutrons are of advantage in about 5% of all radiotherapy patients.

[Superselective interventional angiography]. / Superselektive interventionelle Angiographie.

The authors report on the clinical application of superselective interventional angiography within the framework of revascularisation and occlusion. A coaxial catheter system is used for probing, consisting of an F 5 angiography catheter as guiding catheter and an F 3 catheter as internal catheter. The internal catheter is equipped with a shaft with segments of different flexibility and can take up a guide wire of 0.018" that is sufficiently stable to be rotated and guided. The interplay between the guide wire, which can be manipulated, and the flexible internal catheter enables superselective probing even of peripheral vascular areas. As may be required by the basic disease, the necessary interventional measures can be taken via the superselectively placed microcatheter. Superselective interventional angiography is indicated as an occlusive measure in preoperative vascular occlusion followed by palliative tumour resection, embolisation in haemangioma, chemoembolization in tumours of the liver. Superselective angiography is used for revascularisation in the local lysis of peripheral vessels. Due to the on-target superselective approach, side effects are markedly less than those observed with the interventions performed to date.

Localization of NGF receptors in normal and Alzheimer's basal forebrain with monoclonal antibodies against the truncated form of the receptor.

Four new monoclonal antibodies to the extracellular domain of the nerve growth factor receptor (NGFR) have been evaluated for their specificity to NGFR and their utility in localizing NGFR in human brain. All four antibodies, as well as Me20.4, show similar cellular localization and patterns of immunoreactivity in basal forebrain neurons. NGFR monoclonal antibody XIF1 stains optimally over the widest range of concentrations, with staining being reduced only slightly at less than 10 pg/ml or more than 100 ng/ml, and produces the lowest background of those tested. Staining with all NGFR monoclonal antibodies is blocked by the addition of as little as 5-fold excess human recombinant truncated NGFR protein. The distribution of NGFR-containing neurons is similar to that previously described in normal human forebrain, as is the reduction in cell size in nucleus basalis (Ch4am) in brains from patients with Alzheimer's disease. In addition, we find evidence in the two Alzheimer's cases examined for a previously unreported loss of cells in the horizontal limb nucleus of the diagonal band (Ch3) in Alzheimer's disease. The loss of these neurons, which in normal brain have characteristic varicose dendritic processes extending to the pial surface adjacent to the cisternal space, may indicate a change in the relationship of NGF-sensitive neurons to the vasculature. Since these neurons project to olfactory bulb and cortex in rodent and primate brains, their loss may also reflect damage to the olfactory system in Alzheimer's disease.

[Computed tomographic differential diagnosis of primary pelvic osteo-, chondro- and Ewing's sarcomas]. / Computertomographische Differentialdiagnose primär pelviner Osteo-, Chondro- und Ewing-Sarkome.

The value of CT for the differential diagnosis of primary malignant tumours in the pelvis was investigated in the case of three types of tumour: osteosarcomas, chondrosarcomas and Ewing's sarcomas. A total of 78 CT examinations in 29 patients was used. The results show that CT, using suitable techniques (high resolution etc.) constitutes a valuable diagnostic method for differentiating these bone tumours. This applies not only for the localisation of the tumour and for defining its extent, but also for showing the morphology of intra- and extra-osseous soft tissue components and their patterns of calcification. It is possible to recognise patterns of growth and of tissue destruction that are typical of individual tumours.

Results of fast neutron therapy of adenoidcystic carcinomas of the head and neck at the neutron facility Hamburg-Eppendorf.

Between July 1977 and March 1988, 31 patients with an adenoidcystic carcinoma were treated with fast neutrons of a 14 MeV-DT-generator at our department. Primary locations were: parotid gland eight cases, paranasal sinus five cases, submandibular gland five cases, trachea four cases and other locations nine cases. The median follow-up of our patients was 16 months. Most of the patients had advanced tumors. The calculated local control rate is 65% at two years.