Impaired spatial information processing in aged monkeys with preserved recognition memory

Spatial information processing was examined in a non-human primate model of cognitive aging, using procedures formally similar to tasks designed for rats. The test apparatus was a large open field containing eight reward locations. Monkeys rapidly learned to visit each location once per trial, and probe manipulations confirmed that young animals navigated according to the distribution of cues surrounding the maze. In contrast, aged monkeys solved the task using a response sequencing strategy, independent of extramaze spatial information. Object recognition memory was normal in the aged group. The results reveal substantial correspondence in the cognitive effects of aging across rat and primate models, and they establish appropriate procedures for testing the long-standing proposal that the role of the hippocampus in normal spatial learning is similarly conserved.     

Controversies in the management of operated pituitary macroadenomas

The medial canthal region includes several individual aesthetic units that differ in skin quality and thickness, contour, and associated landmarks. Basal cell carcinomas commonly involve the medial canthal region and extend without respecting the boundaries between units. Reconstruction of tumor-free defects is often complicated by web formation across the medial canthal concavity. To avoid this complication, we evaluate each defect according to the anatomic units involved and develop individual flaps from each component area, anchoring each flap to the medial canthal tendon or associated deep fibrous tissue. This system has been used in 58 cases with excellent results. It allows flexibility for reconstructing the many diverse defects that oculoplastic surgeons encounter and helps to minimize postoperative deformity.     

Impaired cotranslational processing as a mechanism for type I antithrombin deficiency

Most secretory proteins, including antithrombin (AT), are synthesized with a signal peptide, which is cleaved before the mature protein is exported from the cell. The signal peptide is important in the process whereby nascent protein is recognized as requiring subsequent modification within the endoplasmic reticulum (ER). We have identified a novel mutation, 2436T-->C L(-10)P, which affects the central hydrophobic domain of the AT signal peptide, in a proband presenting with venous thrombotic disease and type I AT deficiency. We investigated the basis of the phenotype by examining expression in mammalian cells of a range of variant AT cDNAs with mutations affecting the -10 residue. Glycosylated AT was secreted from COS-7 cells transfected with wild-type AT, -10L deletion, -10V or -10M variants, but not variants with P, T, R, or G at -10. Cell-free expression of wild-type and variant AT cDNAs was then performed in the presence of canine pancreatic microsomes, as a substitute for ER. Variant AT proteins with P, T, R, or G at residue -10 did not undergo posttranslational glycosylation, and their susceptibility to trypsin digestion suggested they had not been translocated into microsomes. Our results suggest that the ability of AT signal peptide to direct the protein to ER for cotranslational processing events appears to be critically dependent on maintaining the hydrophobic nature of the region including residue -10. The investigations have defined impaired cotranslational processing as a hitherto unrecognized cause of hereditary AT deficiency.     

High plasma proopiomelanocortin in aggressive adrenocorticotropin-secreting tumors

A specific propiomelanocortin (POMC) immunoradiometric assay was developed using antibodies directed against ACTH and beta-endorphin (beta end). Partially purified standard POMC was prepared from the human small cell lung carcinoma cell line DMS-79 culture medium. Ten units (U) POMC had the same displacement ability as one pg beta end in a C-terminal beta end radioimmunoassay and thus were close if not equal to 10 pg POMC. This POMC assay was used to investigate patients with ACTH-dependent Cushing's syndrome. Plasma POMC was undetectable (< 60 U/mL) in 17 normal controls and in 4 patients with Addison's disease (concomitant ACTH plasma levels between 362 and 1058 pg/mL). Forty-two patients with Cushing's disease were studied, either before (n = 25) or after (n = 17) bilateral adrenalectomy: 7 patients with highly invasive macroadenomas had high POMC plasma levels, between 240 and 4200 U/ml (concomitant ACTH plasma levels between 77 and 5730 pg/mL); 35 patients, including one with an invasive macroadenoma, had undetectable POMC plasma levels (concomitant ACTH plasma levels between 31 and 2820 pg/mL). Among 20 patients with histologically proven ectopic ACTH syndrome, 16 had high POMC plasma levels, between 80 and 8000 U/mL (concomitant ACTH plasma levels between 45 and 9265 pg/mL); all those tumors were malignant, and the highest POMC/ACTH plasma levels ratios (taken as an index of altered POMC processing) were observed in the 3 patients with small cell carcinomas of the lung; in one of these patients, ACTH and POMC plasma levels both decreased during the course of chemotherapy, in parallel with the reduction of the tumoral mass. Four patients with ectopic ACTH syndrome had undetectable POMC plasma levels (concomitant ACTH plasma levels between 78 and 335 pg/mL): they were all typical bronchial carcinoids. These data show that high POMC plasma level is neither specific for nor constant in ectopic ACTH syndrome. Rather it should be considered as a marker of tumor aggressivity, in pituitary- and non-pituitary tumors. Its diagnostic help appears limited for the most frequent cause of occult ectopic ACTH syndrome, the typical bronchial carcinoids.     

Transsphenoidal microsurgery of pituitary macroadenomas with long-term follow-up results

The authors have reported on 108 patients with pituitary macroadenomas (measuring 2 cm in at least one diameter) who underwent 117 transsphenoidal operations and five craniotomies, and were followed for periods ranging from 6 months to 14 years. Vision improved in 90% of the patients. Gross total tumor removal with no evidence of residual tumor tissue demonstrable on the postoperative computerized tomography scan was accomplished in 41% of cases. However, gross total tumor removal is not synonymous with complete tumor removal. Endocrine cure was possible in 25% of prolactin-secreting and 20% of growth hormone-secreting adenomas. The incidence of recurrence was 12%, with the majority occurring from 4 to 8 years postoperatively. Both the tumors with suprasellar extension of more than 2 cm and the hard fibrotic tumors had a higher recurrence rate. Postoperative administration of radiation therapy has been associated with a significantly lower recurrence rate than when this therapy was withheld. Transsphenoidal surgery of pituitary macroadenomas confined to the extra-arachnoid space is associated with a relatively small number of complications. The operative technique used in this series is described.     

Sturgeon proopiomelanocortin has a remnant of gamma-melanotropin

A thioesterase I gene was recloned and sequenced from Escherichia coli strain JM109. The overexpressed, matured enzyme from JM109 was purified to homogeneity. The enzyme showed broad hydrolytic activity toward three kinds of substrates including acyl-CoAs, esters, and amino acid derivatives. The enzyme had a kcat/Km value of 0.363 s-1 microM-1, for a typical thioesterase I substrate, palmitoyl-CoA. The arylesterase activity of the enzyme was observed by its ability to hydrolyze several aromatic esters including alpha-naphthyl acetate, alpha-naphthyl butyrate, phenyl acetate, benzyl acetate, and eight p-nitrophenyl esters. In kinetic studies a chymotrypsin-like substrate (an amino acid derivative), N-carbobenzoxy-L-phenylalanine p-nitrophenyl ester (L-NBPNPE), was the best substrate for the enzyme with a catalytic efficiency (kcat/Km) of 4.00 s-1 microM-1, which was 23 times higher than that of the enantiomer D-NBPNPE (0.171 s-1 microM-1). It was concluded that the thioesterase I of E. coli had arylesterase activity and it possessed stereospecificity for protease substrates.     

Impaired processing of local geometric features during navigation in a water maze following hippocampal lesions in rats.

Hippocampal damage impairs navigation with respect to information provided by the shape of an arena. Recent evidence has suggested that normal rats use local geometric information, as opposed to a global geometric representation, to navigate to a correct corner. One implication of this pattern of results is that hippocampal lesions may impair processing of 1 or more of the local geometric features of an environment. The authors therefore investigated the effects of hippocampal cell loss in rats on navigation to a hidden goal with respect to a variety of local cues in an environment with a distinctive shape. Rats with lesions of the hippocampus were impaired in discriminating a right-angled corner from its mirror image. However, they were able to use cues provided by an acute-angled corner (Experiment 1) or a local polarizing cue (Experiment 2). In contrast, lesioned rats were impaired in discriminating long versus short walls (Experiment 3). Results indicate that the hippocampus plays a role in disambiguating locations by processing (metric) information related to the distance between corners. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Toward a multiroute model of number processing: Impaired number transcoding with preserved calculation skills.

This article describes a patient (S. A. M.), suffering from a progressive neurological degenerative condition of unknown origin, who showed a severe difficulty in number transcoding tasks. S. A. M. could recognize and understand arabic numerals and written number names, but he could neither read them aloud nor write them. However, he had a well maintained ability to perform oral and written calculations. The striking pattern of performance observed in S. A. M. suggests that deficits affecting the ability to produce arabic or verbal numerals can be specific to particular task demands. This observation cannot be easily accommodated by current models of numerical processing. A new multiroute model for numerical processing is proposed to account for S. A. M's pattern of performance. This model adds asemantic transcoding pathways to the semantic processing mechanisms proposed by the M. McCloskey model. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reassessment of the role of radiation therapy in the treatment of endocrine-inactive pituitary macroadenomas

OBJECTIVE: This prospective clinical trial was undertaken to assess the rate of tumor recurrence in patients with endocrine-inactive pituitary macroadenomas who underwent gross total surgical resection of their tumors and did not receive adjuvant radiotherapy. METHODS: Between December 1987 and July 1994, 45 patients with endocrine-inactive pituitary macroadenomas underwent transsphenoidal surgery. In 38 (84%) of these patients, gross total surgical resection was achieved and was confirmed by postoperative magnetic resonance imaging (n = 37) or computed tomography (n = 1). After receiving counseling from the neurosurgeon concerning the risks and benefits of radiation therapy, 32 of the 38 patients elected not to receive adjuvant radiotherapy. Patients were followed through March 1998 with radiographic imaging obtained every 6 months for the first 2 years, annually for postoperative Years 3 and 4, and then every 2 to 3 years thereafter. The study end point was defined as radiographic tumor recurrence or patient death. RESULTS: The mean follow-up duration for the study group was 5.5 years. During that time, 2 of 32 (6%) patients developed recurrence, at 18 and 24 months, respectively, after initial surgery. Both were successfully treated using radiation therapy, with one requiring additional surgery. Three additional patients died as a result of unrelated causes 9, 12, and 49 months, respectively, after initial surgery. Immunocytochemical analysis revealed 66% of the tumors to be weak gonadotroph cell adenomas, 22% to be null cell adenomas, 9% to be silent prolactinomas, and 3% to be silent corticotroph cell adenomas. CONCLUSION: This study demonstrates a 6% 5-year recurrence rate in patients with endocrine-inactive pituitary macroadenomas treated using gross total surgical resection alone. Reserving radiation therapy for the infrequent patient with recurrence and sparing the majority of patients the associated risks inherent in its use seems reasonable.     

CRF stimulates expression of multiple fos and jun related genes in the AtT-20 corticotroph cell

Pretreatment of DBA/2 mice (n = 14-15 per group) with an 18-mer antisense probe to the NMDA-receptor submit NR1 (2 x 1 micrograms, or 2 x 83 pmol, NR1 antisense probe intracerebroventricularly, -29 and -7 h before testing for seizure response) resulted in almost complete suppression of sound-induced clonic seizures. A saline-treated group gave a 100% seizures response, while the group treated with NR1 antisense probe gave a 7% seizure response to the sound stimulus. The group treated with NR1 nonsense-probe showed no anticonvulsant protection (93% seizure response). The anticonvulsant protection observed following NR1 antisense administration was of relatively short duration, with seizure response gradually returning to control levels 12 to 24 h following the termination of antisense administration. When NR1 receptor levels were assessed by receptor autoradiography ([3H]-MK 801 and -CGP 39653 binding) in the same groups of mice, significant (20%) reductions in NR1 levels were observed in the retrosplenial cortex and the overall cortex. The seizure-induced expression of c-fos and NGFI-A in thalamus, hypothalamus, inferior colliculus and medical geniculate seen in vehicle- and NR1 nonsense-treated mice was completely blocked by NR1 antisense pretreatment.     

Sauvagine and TRH differentially stimulate proopiomelanocortin biosynthesis in the Xenopus laevis intermediate pituitary

ICR mice were immunized with HTLV-I carrier T lymphocytes (MT-2 cell line) and then inoculated intracerebrally with these cells. After non-specific traumatic hemorrhage, perivascular cell infiltration was noted diffusely throughout the brain on day 2 and lasted for over 2 weeks. HTLV-I antigens were detected in both sides of the cerebral hemisphere by Western blotting analysis. Tissue damage consisting of demyelination, axonal degeneration, and astrogliosis was observed most heavily on days 10 and 14. Non-immunized mice inoculated with the cells showed only transient hemorrhage. In cases using the HTLV-I free T-cell line (MOLT-4) inflammatory cell infiltration and tissue damage was much less conspicuous and disappeared after day 10. These experiments support the hypothesis that HAM/TSP is a bystander disease initiated and progresses via HTLV-I-infected T-cell invasion into the spinal cord of a patient who has been infected and sensitized to the virus.     

Impaired biotin status in anticonvulsant therapy

In 264 epileptics undergoing long-term therapy with anticonvulsants, significantly reduced plasma biotin levels were found compared with a normal control group: 74% of the epileptics had biotin levels of 250 ng/L or less. In patients undergoing single-drug therapy, the mean plasma biotin levels for those treated with sodium valproate were higher than for those treated with phenytoin, primidone, or carbamazepine. The observed reduction in biotin levels might be a factor influencing the efficacy of these three anticonvulsants.     

Impaired implicit learning in schizophrenia.

Schizophrenia patients consistently show deficits on tasks of explicit learning and memory. In contrast, their performance on implicit processing tasks often appears to be relatively intact, although most studies have focused on implicit learning of motor skills. This study evaluated implicit learning in 59 medicated schizophrenia outpatients and 43 controls using 2 different cognitive skill tasks. Participants completed a probabilistic classification task to assess procedural habit learning and an artificial grammar task to assess incidental learning of complex rule-based knowledge, as well as an explicit verbal learning and memory task. In addition to performing worse than controls on the explicit learning task, patients showed worse overall performance on the probabilistic classification task, which involves gradual learning through trial-by-trial performance feedback. However, patients and controls showed similar levels of learning on the artificial grammar task, suggesting a preserved ability to acquire complex rule-based knowledge in the absence of performance feedback. Discussion focuses on possible explanations for schizophrenia patients' poor probabilistic classification task performance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired kidney function in lithium therapy

Long-term therapy with lithium may be associated with a broad spectrum of functional and structural side-effects in the kidney. Among these features, nephrogenic diabetes insipidus is the most frequent and it can be expected to occur in 20-70% of the patients. Diabetes insipidus is the result of a lithium induced resistance of collecting ducts to antidiuretic hormone. Additional functional disturbances are represented by renal tubular acidosis and consequences of hypercalcemia. Structural alterations of the kidney have a rare occurrence. In the literature, there are accounts of chronic tubulo-interstitial nephritis, acute tubular necrosis and few cases of glomerulopathies. Our report of a patient with chronic interstital nephritis is supplemented by a brief discussion of the diverse picture of the nephrotoxicity of lithium.     

Aversive stimulation during the stress-hyporesponsive period does not affect the number of corticotroph cells in neonatal male rats

Immunohistochemistry was used to evaluate the effects of neonatal handling and aversive stimulation during the first 10 days of life on the number of corticotrophs in the anterior lobe of the pituitary of 11-day-old male Wistar rats. Since adult rats handled during infancy respond with reduced corticosterone secretion in response to stressors and with less behavior inhibition in novel environments, we assumed that neonatal stimulation could affect pituitary morphology during this critical period of cell differentiation. Three groups of animals were studied: intact (no manipulation, N = 5), handled (N = 5) and stimulated (submitted to 3 different aversive stimuli, N = 5). The percentage of ACTH-immunoreactive cells in the anterior lobe of the pituitary (number of ACTH-stained cells divided by total number of cells) was determined by examining three slices per pituitary in which a minimum of 200 cells were counted by two independent researchers. Although animals during the neonatal period are less reactive to stress-like stimulation in terms of ACTH and corticosterone secretion, results showed that the relative number of ACTH-stained cells of neonatal handled (0.25 +/- 0.01) and aversive stimulated (0.29 +/- 0.03) rats was not significantly different from intact (0.30 +/- 0.03) animals. Neonatal stimulation may have a differential effect on the various subpopulations of corticotroph cells in the anterior pituitary.