A performance-dependent adjustment of the retention interval in a delayed non-matching-to-position paradigm differentiates effects of amnestic drugs in rats.

Operant delayed non-matching-to-position (delayed non-matching-to-position) tasks have been widely used as tests of working memory in rats, but have suffered some loss in sensitivity to differentiating selective mnemonic from non-mnemonic deficits due to floor and ceiling effects. To circumvent this problem, a novel delayed non-matching-to-position was developed in which the retention interval was adjusted on a trial-by-trial basis to hold performance accuracy at an intermediate value. The present study assessed the effects of three amnestic drugs in this delayed non-matching-to-position. Rats were administered (i.p.) NMDA receptor antagonist ((5R,10S)-(+)-5-Methyl-10, 11-dihydro-5H-dibenzo[a,d,] cyclohepten-5,10-imine (Dizocilpine or MK-801), muscarinic receptor antagonist (-)-scopolamine hydrobromide (scopolamine), or cannabinoid receptor agonist ((R)-(+)-[2, 3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1, 4-benzoxazin-6-yl]-1-naphthalenylmethanone) (WIN 55, 212-2). At high doses, both MK-801 (0.12-0.25 mg/kg) and scopolamine (0.25 mg/kg) produced deficits not selective to working memory. At low doses, scopolamine (0.06-0.12 mg/kg) and MK-801 (0.06 mg/kg) produced no deficits in any mnemonic or secondary measures. WIN 55, 212-2 produced deficits at 2.0 mg/kg that were consistent with a specific impairment of working memory. Using this particular delayed non-matching-to-position revealed that consistent changes in performance accuracy at the short retention interval were evident for scopolamine and MK-801, at times in the absence of changes in response tendency, which are consistent with an interpretation that these drugs produce general deficits in reference or procedural memory. In contrast, cannabinoid-induced deficits in choice accuracy support previous reports of delay-dependent deficits. Together, these data suggest that this delayed non-matching-to-position task is able to differentiate deficit patterns of amnestic drugs, and isolate the effects of motivational side effects of drugs from working memory measurement.

Specificity of memory measures in an adjusting delayed nonmatching-to-position task for rats.

While the delayed nonmatching-to-position (DNMTP) behavioral paradigm has often been used by neuroscientists to assess working memory in rats, its measure of working memory is compromised by floor and ceiling effects. Specifically, these floor and ceiling effects undermine the ability to detect a significant interaction in a two-factor repeated-measures ANOVA, which is required in order to conclude that impaired performance has resulted from disrupted working memory and not from a change in another psychological process (i.e. that the impairment is 'specific' to working memory). The present study was conducted to evaluate if these limitations could be overcome in a DNMTP by adjusting the length of time that the rat was required to remember (the 'delay') so as to avoid the floor and ceiling. The general procedure for two experiments presented subjects with trials where there was either a minimal (1 s) delay or a longer delay of varying length, with the goal of maintaining nonmatch-to-position accuracy near 75%. The procedure was such, that if the average accuracy was at or above 75%, then the next trial would be a long-delay trial. If it were below 75%, then the next trial would be a 1 s delay trial. In the first experiment, the subjects were presented with trials where the value of the longer delay was systematically varied between-sessions. This was done to simulate the faster rate of forgetting found in persons with amnesia. DNMTP accuracy diminished at the longer delay but not the short delay as the second interval was lengthened. However, other measures, including accuracy at the 1 s delay, discrimination accuracy during the sample phase, and the number of trials completed per session, did not change. This experiment suggested that this DNMTP could precisely measure small changes in the rate of forgetting. In a second experiment, a potential non-mnemonic confound, the level of motivation, was directly manipulated by giving the water-restricted subjects access to water immediately prior to the start of the session. The number of trials completed per session diminished, but the accuracy at both the 1 s and the longer delays did not change. These results indicated that the measures of working memory in this DNMTP were insensitive to changes in motivation. Together, these experiments confirmed that adjusting the delay in the DNMTP improves the validity of the measures in this task.

99mTc-human serum albumin: an effective radiotracer for identifying sentinel lymph nodes in melanoma.

UNLABELLED: Sentinel lymph node (SLN) biopsy has emerged as a novel approach for identifying patients with melanoma and regional nodal micrometastasis who may benefit from full nodal basin resection. To identify the pattern of tumor lymphatic drainage and the SLN, lymphoscintigraphy has been performed using primarily 99mTc-sulfur colloid (SC). In this study, we compare the efficacy of SLN biopsy using 99mTc-human serum albumin (HSA) with SLN biopsy after SC-based lymphoscintigraphy. METHODS: One hundred and six patients with localized cutaneous melanoma were studied. Lymphoscintigraphy was performed after intradermal injection of HSA in 85 patients and SC in 21 patients. Four patients underwent lymphoscintigraphy twice, once with SC and once with HSA. Dynamic images were acquired for up to 1 h, followed by high-count images of the SLN in various projections so that the most likely site was marked on the skin for biopsy. Intraoperatively, blue dye was injected around the primary site. Twenty-four patients underwent SLN dissection directed by preoperative lymphoscintigraphy and vital blue dye mapping; in the remaining 80 patients, a gamma probe was added intraoperatively to the localization procedure. Two patients underwent mapping with gamma probe alone. RESULTS: Draining lymphatic basins and nodes were identified by lymphoscintigraphy in all patients. The SLN was identified in 95% of patients when both blue dye and intraoperative gamma probe were used. When 99mTc-HSA was used for imaging, 98% of the SLNs ultimately identified were radiolabeled, and 82% were both hot and blue. Of the SLN recovered with SC, all the nodes were radiolabeled; however, there was only 58% hot and blue concordance. Greater numbers of SLNs were removed in the SC group (median 2.0 versus 1.0, P = 0.02); however, the incidence of micrometastasis was statistically similar in both HSA and SC cohorts. In the 4 patients examined with both tracers, SLN mapping was similar. CONCLUSION: Although SC has been the radiotracer of choice for SLN mapping in melanoma, HSA appears to be a suitable alternative, with identical success rates. In fact, the higher concordance between hot and blue nodes using HSA suggests superiority of this tracer for this purpose.

Immunohistochemistry with pancytokeratins improves the sensitivity of sentinel lymph node biopsy in patients with breast carcinoma.

BACKGROUND: Sentinel lymph node (SLN) biopsy is being investigated as a staging procedure for breast carcinoma. The authors evaluated whether immunohistochemical (IHC) analysis improves the sensitivity of this procedure. METHODS: Forty-four women with breast carcinoma were recruited for SLN biopsy. Preoperative lymphoscintigraphy was followed by intraoperative localization using a handheld gamma probe and blue dye. After SLN identification, an immediate complete axillary lymph node dissection was performed in all patients. All lymph nodes were subjected to routine histology (hematoxylin and eosin [H&E]) and IHC using antibody to cytokeratins. RESULTS: The SLN was identified in 41 of 43 patients (95%). Successful SLN identification was independent of biopsy technique (open surgical [95%] vs. fine-needle aspiration/core needle biopsy [96%]). Twelve of 41 patients (29%) had evidence of lymph node metastasis in the SLN by routine histology. Of the twenty-nine patients with H&E negative SLN, 3 were found to have metastasis by IHC for a conversion rate of 10%. Fifteen of 41 patients (37%) had evidence of metastasis in SLN. All 26 patients with H&E and IHC negative SLN had negative nonsentinel lymph nodes by routine histology and IHC (100% negative predictive value). All patients with tumors < 2 cm and micrometastasis to the SLN had no additional lymph node disease, in contrast to patients with lesions > 2 cm or patients with macrometastasis to the SLN (P = 0.007). CONCLUSIONS: These results confirm that SLN biopsy is extremely accurate for patients with breast carcinoma, even after open surgical biopsy. IHC analysis or serial sectioning of SLN improves the sensitivity of this staging technique.

Focal acute tubular necrosis in a renal allograft.

Nuclear imaging is used to evaluate renal allografts demonstrating delayed function after transplantation. Interpretation of the nuclear scan in the context of clinical data, provides helpful information in the management of the transplant recipient. The better quality of images obtained with technetium-99m mercaptoacetyltriglycine (Tc-99m MAG3) has made it the radiotracer of choice compared to technetium-99m diethylenetriamine pentaacetic acid (Tc-99m DTPA) for imaging of the renal allograft. Tc-99m MAG3 is cleared from the kidney by tubular secretion, whereas Tc-99m DTPA is cleared by glomerular filtration. In this report, we discuss a unique abnormality found on nuclear imaging of a renal allograft. Utilizing our understanding of the characteristic handling of various radiotracers by the kidney, we were able to demonstrate that the renal scan was consistent with an area of focal acute tubular necrosis in the newly transplanted kidney.

Thyroid and parathyroid gland pathology. Role of imaging.

There are many imaging modalities available for studying thyroid and parathyroid masses. For the thyroid gland, the demonstration of a hyperfunctioning or purely cystic mass by scintigraphy and ultrasound reassures that a palpable nodule is not cancer. Solitary, cold, or solid nodules often requires biopsy because of suspicion of malignancy. Metabolic and inflammatory disorders are imaged best with nuclear medicine studies whereas congenital thyroid lesions are evaluated best with computed tomography or MR imaging. In the search for a parathyroid adenoma, MR imaging and technetium-99m sestamibi studies appear to be most accurate, but because of its low cost, ultrasound has a favorable role. In previously operated patients with persistent hyperparathyroidism, MR imaging is probably most useful, but multiple imaging studies may be needed for definitive localization of adenomas.

Ethanol-fed Sprague-Dawley rats maintain normal levels of insulin-like growth factor I.

Ethanol-fed rats do not gain weight as fast as their isoenergetically pair-fed controls; the reasons for this slower rate of growth remain uncertain. Insulin-like growth factor I (IGF-I) is a major component of the growth-promoting endocrine system. To determine whether ethanol impairs growth by interfering with this component of the endocrine system, rats were pair-fed ethanol-containing and control liquid diets. When rats were meal-fed on the day before the experiment there were no differences in serum IGF-I concentrations or hepatic IGF-I mRNA levels between ethanol-fed and control animals after 2, 3 or 4 wk. These results indicate that ethanol consumption per se does not interfere with IGF-I production and that energy derived from ethanol sustains this component of the growth-promoting endocrine system as well as carbohydrate energy. The schedule used to administer the diets, however, did have a significant effect on hepatic IGF-I mRNA levels. When after 4 wk of dietary treatment rats were not meal-fed but received their entire dietary ration in a single morning feeding on the day before the experiment, the ethanol-fed animals had significantly higher hepatic IGF-I mRNA levels than their pair-fed controls. This finding indicates that these animals are nutritionally dissimilar despite isoenergetic pair-feeding.

Effects of streptozotocin-induced diabetes mellitus on growth and hepatic insulin-like growth factor I gene expression in the rat.

Poorly controlled diabetes mellitus in humans and animals is often accompanied by impaired growth. We undertook this study in young rats to determine whether the reduction in growth rate associated with streptozotocin (STZ)-induced diabetes might be related to changes in both serum insulin-like growth factor I (IGF-I) and IGF-II levels, and, if so, whether these changes reflect alterations in serum growth hormone (GH) and in hepatic IGF-I and IGF-II gene expression. Serum rat GH (rGH) levels were variable during the first 4 days after STZ administration, but during the subsequent 5- to 11-day period the mean (+/- SEM) levels in insulin-treated (DI) (21.4 +/- 4.9 ng/mL) and untreated (D) (8.5 +/- 1.5 ng/ml) diabetic rats were significantly (P less than .001) lower than in controls (C) (117.8 +/- 22.9 ng/mL). Multiple transcripts of IGF-I (7.0, 4.0, 1.9, 1.0 kb), but barely detectable amounts of IGF-II mRNA, were found in the livers of normal and diabetic rats by Northern blot analysis. Using dot blot analysis, we have shown that the abundance of total hepatic IGF-I mRNA in untreated, growth-retarded diabetic animals decreases rapidly over a period of 3 days after STZ administration. Both serum IGF-I and IGF-II levels are also diminished during this interval in these markedly hyperglycemic rats. Insulin treatment for 3 to 4 days, started either immediately (6 hours) or within 3 days after administering STZ, blunts diabetes-induced impairment of growth and restores mean hepatic IGF-I mRNA abundance to control levels, but does not normalize serum IGF-I and IGF-II concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)