Isosteric replacement of the indole nucleus by benzothiophene and benzofuran in a series of indolylglyoxylylamine derivatives with partial agonist activity at the benzodiazepine receptor

A number of benzothienyl- and benzofurylglyoxylylamine derivatives, which are analogues of previously described indolylglyoxylylamines with a partial agonist activity, are reported in this paper. They were synthesized and tested to verify the importance of the presence of the indole NH group in the interaction of this class of compounds with the benzodiazepine agonist receptor site, since it was reported in literature that a hydrogen bond donor group such as NH was not necessary to elicit an agonist response. Several thienylglyoxylylamine derivatives were also prepared and tested. None of the compounds showed a high affinity at the BzR, demonstrating that the indole NH plays a decisive role in the interaction of the agonist glyoxylylamine ligands with the receptor site.     

Alpha-thalassemia in two Mediterranean populations

We used restriction endonuclease analysis to determine the incidence of alpha-thalassemia in two Mediterranean islands. In a random population sample, the gene frequency of deletion-type alpha-thalassemia-2 (- alpha) was 0.18 in Sardinians and 0.07 in Greek Cypriots. All cases were the rightward crossover type. From these frequencies and the known incidence of hemoglobin-H disease in these populations, we calculated the frequency of the alpha-thalassemia-1 genotype (--) and determined that it was low. We also found that beta-thalassemia homozygotes in sardinia have a higher incidence of alpha-thalassemia than normals and beta thalassemia heterozygotes because a significantly greater number of these homozygotes are also homozygous for the alpha-thalassemia-2 lesion. These findings support the theory that coinheritance of alpha- thalassemia mitigates the severity of beta-thalassemia and suggest that the protection is most pronounced when two alpha-globin genes are deleted.     

Predicting a local recurrence after breast-conserving therapy by gene expression profiling

Introduction

To tailor local treatment in breast cancer patients there is a need for predicting ipsilateral recurrences after breast-conserving therapy. After adequate treatment (excision with free margins and radiotherapy), young age and incompletely excised extensive intraductal component are predictors for local recurrence, but many local recurrences can still not be predicted. Here we have used gene expression profiling by microarray analysis to identify gene expression profiles that can help to predict local recurrence in individual patients.

Methods

By using previously established gene expression profiles with proven value in predicting metastasis-free and overall survival (wound-response signature, 70-gene prognosis profile and hypoxia-induced profile) and training towards an optimal prediction of local recurrences in a training series, we establish a classifier for local recurrence after breast-conserving therapy.

Results

Validation of the different gene lists shows that the wound-response signature is able to separate patients with a high (29%) or low (5%) risk of a local recurrence at 10 years (sensitivity 87.5%, specificity 75%). In multivariable analysis the classifier is an independent predictor for local recurrence.

Conclusion

Our findings indicate that gene expression profiling can identify subgroups of patients at increased risk of developing a local recurrence after breast-conserving therapy.     

Plasma cell immunoglobulin secretion. Arrest is accompanied by alterations the golgi complex

Conditions influencing Ig secretion by plasma cells have been studied with suspensions of murine plasma cells and myeloma cells by determining the release of (3)H-Ig after a pulse of biosynthetic labeling with L- [4,5-(3)H]-leucine. Ig secretion is insensitive to a variety of hormones, mediators, cyclic nucleotide derivatives, extracellular calcium depletion, and agents acting on mierotubules or microfilaments; i.e., to a number of factors which are involved in the regulation of secretion by cells with a storage compartment. On the other hand, Ig secretion is markedly inhibited by conditions which (a) lower intracellular calcium levels (ionophore A 23187 in Ca(++)-free medium), (b) induce partial sodium/potassium equilibration (the ionophores monensin and nigericin and, in the case of myeloma cells, ouabain and incubation in K(+)-free medium) or (c) uncouple oxidative phosphorylation. The first two situations are accompanied by striking alterations of the ultrastructural appearance of the Golgi complex, different in each case. These ultrastructural observations, together with autoradiographic experiments after a short pulse with L-[4,5-(3)H]-leucine, have led to the following hypothesis: (a) under Ca(++) depletion (3)H-Ig passes to Golgi vesicles but these vesicles are incapable of fusion or migration and therefore accumulate in exaggerated numbers in the Golgi area; (b) under partial Na(+)/K(+) equilibration, (3)H-Ig passes to Golgi vesicles which have an exaggerated tendency to fuse with other Golgi elements, thereby generating large vacuoles which store increasing amounts of Ig; (c) under energy block, multiple membrane fission and fusion events are inhibited and there is therefore, little intracellular transport of (3)H-Ig or alteration of cell ultrastructure.     

Oculogravic illusion in response to straight-ahead acceleration of CF-104 aircraft.

Experimental subjects wore goggles that restricted monocular vision to a luminous line fixed relative to the head, and they were exposed on one occasion to a straight-ahead acceleration of an aircraft and on another occasion to a tilting chair. The magnitude of change of direction of the resultant accleration was the same on both occasions, but the perceived movement of the luminous line from the two stimuli was very different. In response to the aircraft stimulus, the oculogravic illusion was experienced and the luminous line was perceived as tilting relative to the subject, in response to the tilting chair stimulus, the line was perceived as remaining fixed relative to the subject. It was concluded that the oculogravic illusion, as experienced in the aircraft (and previously in centrifuges), is a true illusion and not merely a fact of physics.     

Periodic-compartmental distribution of acetylcholinesterase in the superior colliculus of the human brain.

The superior colliculus of the human brain was studied in autopsy material stained by the acetylthiocholinesterase methods of Geneser-Jensen &; blackstad (1971) and Karnovsky &; roots (1964). The histochemical findings suggest that in the human, as in common laboratory mammals, the superior colliculus is characterized by a periodic vertical segmentation in addition to a horizontal stratification into layers. In frontal sections through the superior colliculus in each of three human brains, acetylthiocholinesterase staining in the middle gray layer was distributed in a series of 200–400 μm wide patches separated by less densely stained zones. The patches were irregular in shape and some were composed of a core of intense enzyme activity surrounded by a rim of weaker stain. Comparable concentrations of the enzyme were not apparent in the superficial collicular layers. Dorsalview reconstructions of the enzyme patches were prepared in two cases from drawings of serial sections. The resulting planar maps showed that the patches present in frontal sections form parts of narrow bands of varying length that run in a roughly longitudinal direction through the colliculus.This pattern of banding is remarkably similar to that observed with cholinesterase methods in the intermediate gray layer of the cat superior colliculus and recalls also the bands formed by nigrotectal terminals in this layer. It is not yet clear which tissue elements are being stained by the cholinesterase method. Nevertheless, the finding of histochemically distinct repeating units in the human superior colliculus demonstrates the existence, in the brain of man, of a periodic ordering with many of the characteristics of columnar organization.     

Congenital pineoblastoma in the newborn: ultrasound evaluation

Transfontanelle, real-time ultrasound (US) examinations were performed in two newborn infants with congenital pineoblastoma. The tumors were hyperechoic relative to the surrounding cerebral tissue. Both were midline lesions that abutted on the posterior portion of the third ventricle, causing obstructive hydrocephalus. The US findings were correlated with CT, pathologic examination, and clinical follow-up study.     

Illusions of postural,visual, and aircraft motion elicited by deep knee bends in the increased gravitoinertial force phase of parabolic flight

Summary Illusions of self motion and aircraft motion are experienced when executing deep knee bends in the high force phases of parabolic flight. The occurrence of such illusions indicates that skeletomotor control is actively calibrated to a 1 g reference level and that departures from this level affect the execution and appreciation of voluntary movements. The origin of the illusory patterns is shown to be understandable in terms of mismatches between efferent control signals and expected patterns of associated muscle spindle activity. It is shown, too, that spindle activity is interpreted within an entire context of spatial information about ongoing and intended motion of the body and whether the body is laden.Supported by NASA contracts NAS9-15147 and T-9140E