Can adrenal incidentalomas be safely observed?

We currently recommend excision of adrenal incidentalomas > or = 4 cm in size and all hormonally active tumors. The optimal management and follow-up of smaller nonfunctioning tumors are controversial. The aim of this study was to determine the clinical outcome of a well defined population of patients with incidentalomas followed without operative intervention. The study group comprised 231 patients, identified from the records of abdominal or thoracic computed tomographic (CT) scans performed between 1985 and 1989. The primary outcome variable analyzed was survival. Follow-up was obtained by office records, telephone contact, or letter. There were 101 male and 130 female patients with a mean age at diagnosis of 64 years (range 5-86 years). Most adrenal tumors were unilateral (right 113; left 98); 20 were bilateral. Mean tumor size was 2 cm (range 1-6 cm). In nine (4%) patients the tumor was > or = 4 cm. Follow-up [mean 7 years; range 1 month (patient died) to 11.7 years] was complete in 224 (97%) patients. Ninety-one (39%) patients had one or more additional CT scans performed during the follow-up period, with only four patients demonstrating a > 1 cm increase in the size of the adrenal mass. Surgical excision of these four lesions identified benign pathology. Eighty-one (35%) patients died of conditions unrelated to adrenal pathology. No patient developed subsequent adrenal hyperfunction or adrenal malignancy. Within the context of our guidelines, conservative management of adrenal incidentalomas considered benign or nonfunctioning at diagnosis is appropriate. Additional information provided by repeat CT scanning appears to confer limited benefit. This study does not support laparoscopic removal of small, nonfunctional adrenal tumors, as has been suggested.     

Evidence for dinucleotide flipping by DNA photolyase

DNA photolyases repair pyrimidine dimers via a reaction in which light energy drives electron donation from a catalytic chromophore, FADH-, to the dimer. The crystal structure of Escherichia coli photolyase suggested that the pyrimidine dimer is flipped out of the DNA helix and into a cavity that leads from the surface of the enzyme to FADH-. We have tested this model using the Saccharomyces cerevisiae Phr1 photolyase which is >50% identical to E. coli photolyase over the region comprising the DNA binding domain. By using the bacterial photolyase as a starting point, we modeled the region encompassing amino acids 383-530 of the yeast enzyme. The model retained the cavity leading to FADH- as well as the band of positive electrostatic potential which defines the DNA binding surface. We found that alanine substitution mutations at sites within the cavity reduced both substrate binding and discrimination, providing direct support for the dinucleotide flip model. The roles of three residues predicted to interact with DNA flanking the dimer were also tested. Arg452 was found to be particularly critical to substrate binding, discrimination, and photolysis, suggesting a role in establishing or maintaining the dimer in the flipped state. A structural model for photolyase-dimer interaction is presented.     

FDTD electromagnetic and thermal analysis of interstitial hyperthermic applicators. Finite-difference time-domain

In this paper, the electromagnetic and thermal behavior of interstitial applicators was analyzed by using the Finite-Difference Time-Domain method. Two configurations were considered: a simple insulated dipole antenna radiating in a layered tissue, and an air cooled applicator radiating in a tissue-equivalent phantom. The proposed approach allows a detailed modeling of the complete structure of the applicator. Furthermore, Specific Absorption Rate and temperature distributions can be determined considering real clinical or experimental conditions. The temperature distribution for the air cooled applicator has been compared with experimental results.     

Traumatic brain injury causes delayed motor and cognitive impairment in a mutant mouse strain known to exhibit delayed Wallerian degeneration

Delayed Wallerian degeneration after neuronal injury is a feature of the C57BL/Wld(s) mouse mutant. In the present study, we examined the effect of unilateral controlled cortical impact (CCI) on motor and cognitive performance in C57BL/6 and C57BL/Wld(s) mice. Performance on a beam-walking task was impaired in both injured groups over the first 3 weeks; however, between 28 and 35 days post injury, C57BL/6 mice continued to improve whereas C57BL/Wld(s) mice showed increased footfaults. In a spatial learning task, C57BL/Wld(s) animals performed consistently better than C57BL/6 mice when tested 7-10 days and 14-17 days following CCI. C57BL/Wld(s) mice also demonstrated improved working memory performance as compared with C57BL/6 mice when trained on days 21-22 after injury; this effect was lost on days 23 and 24, and was not evident in other animals tested in the same task at 28-31 days following injury. These results indicate a marked delay in motor and cognitive impairment following CCI in C57BL/Wld(s) mice compared with injured C57BL/6 controls. This is consistent with previous work showing delayed temporal evolution of neuronal degeneration in C57BL/Wld(s) mice and suggests CCI may be a suitable model for examining the functional consequences of traumatic brain injury (TBI) in genetically altered mice.     

A single midnight serum cortisol measurement distinguishes Cushing''s syndrome from pseudo-Cushing states

PURPOSE: We report stage specific followup guidelines based on our evaluation of the pattern of recurrence in 286 patients treated for local N0 or Nx renal cell carcinoma. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 286 patients with pT1 to pT3N0 or Nx renal cell carcinoma who underwent nephrectomy at our center between February 1985 and December 1994. In cases of later metastases the median interval to first metastasis, site of metastasis and method of diagnosis were correlated with the primary lesion stage. RESULTS: Metastases developed in 68 patients a median of 23 months after nephrectomy. Eight of the 113 patients with pT1 disease had metastases (median time to diagnosis 38 months), while 17 of 64 with pT2 disease and 43 of 109 with pT3 disease had metastases (medians 32 and 17 months, respectively). Of the 92 metastases 59 (64%) were asymptomatic, including 44 detected on routine chest x-rays (32) and blood tests (12). Isolated asymptomatic intra-abdominal metastases were diagnosed by surveillance computerized tomography in only 6 patients (9%). The remaining patients with metastases had associated clinical symptoms and/or abnormal results on interval tests that prompted further diagnostic studies. CONCLUSIONS: We confirmed that the risk of metastatic renal cell carcinoma is stage dependent. Therefore, surveillance protocols should be based on the pathological stage of the primary tumor. We recommend an annual chest x-ray, and serum liver function and alkaline phosphatase level tests for patients with pT1 disease. These studies are indicated beginning at 6 and 3 months for pT2 and pT3 disease, respectively, continuing every 6 months for 3 years and then annually. Surveillance computerized tomography should be performed at 24 and 60 months in patients with pT2 and pT3 disease or earlier when the results of any routine study are abnormal or clinical symptoms are present. Bone and brain surveillance studies should be prompted by site specific symptoms, elevated alkaline phosphatase levels or the diagnosis of metastasis at another site.     

Dendritic and synaptic effects in systems of coupled cortical oscillators

We explore the influence of synaptic location and form on the behavior of networks of coupled cortical oscillators. First, we develop a model of two coupled somatic oscillators that includes passive dendritic cables. Using a phase model approach, we show that the synchronous solution can change from a stable solution to an unstable one as the cable lengthens and the synaptic position moves further from the soma. We confirm this prediction using a system of coupled compartmental models. We also demonstrate that when the synchronous solution becomes unstable, a bifurcation occurs and a pair of asynchronous stable solutions appear, causing a phase lag between the cells in the system. Then using a variety of coupling functions and different synaptic positions, we show that distal connections and broad synaptic time courses encourage phase lags that can be reduced, eliminated, or enhanced by the presence of active currents in the dendrite. This mechanism may appear in neural systems where proximal connections could be used to encourage synchrony, and distal connections and broad synaptic time courses could be used to produce phase lags that can be modulated by active currents.     

Water-soluble nicotinic acetylcholine receptor formed by alpha7 subunit extracellular domains

Water-soluble models of ligand-gated ion channels would be advantageous for structural studies. We investigated the suitability of three versions of the N-terminal extracellular domain (ECD) of the alpha7 subunit of the nicotinic acetylcholine receptor (AChR) family for this purpose by examining their ligand-binding and assembly properties. Two versions included the first transmembrane domain and were solubilized with detergent after expression in Xenopus oocytes. The third was truncated before the first transmembrane domain and was soluble without detergent. For all three, their equilibrium binding affinities for alpha-bungarotoxin, nicotine, and acetylcholine, combined with their velocity sedimentation profiles, were consistent with the formation of native-like AChRs. These characteristics imply that the alpha7 ECD can form a water-soluble AChR that is a model of the ECD of the full-length alpha7 AChR.     

Inhibition of IL-1 induced tissue factor (TF) synthesis and procoagulant activity (PCA) in purified human monocytes by IL-4, IL-10 and IL-13

Exposure of monocytes to pro-inflammatory cytokines or lipopolysaccharide (LPS) may induce synthesis and expression of tissue factor (TF). In this paper we have focused on the induction of TF-activity in human monocytes by the pro-inflammatory cytokines recombinant human interleukin 1 (rhIL-1 alpha) (rhIL-1 beta) (rhIL-6) and human tumour necrosis factor alpha (rhTNF-alpha), measured as procoagulant activity (PCA) in a microtitre plate-based clot assay. In addition we have studied the modulation of IL-1 alpha/beta induced TF-mRNA and PCA by rhIL-4, rhIL-10 and rhIL13. IL-1 alpha and IL-1 beta induced a concentration dependent increase in TF-activity. Neither IL-6 nor TNF-alpha gave rise to procoagulant activity at the concentrations tested (0.2-20 ng/ml). IL-4, IL-10 and IL-13, all effectively diminished IL-1 alpha/beta induced PCA, shown at the protein- and at the mRNA-level, while cell viability was unaffected. These results add to the previously demonstrated role of IL-4 and IL-10 as inhibitors of LPS-induced TF-activity, showing that these anti-inflammatory cytokines are not specific for LPS-activation but interfere with other stimulating substances such as IL-1, which may be involved in diseases where LPS is not present.     

Noxiustoxin 2, a novel K+ channel blocking peptide from the venom of the scorpion Centruroides noxius Hoffmann

A novel peptide called Noxiustoxin 2 (NTX2) was purified from the venom of the scorpion Centruroides noxius and characterized chemically and functionally. It is composed of 38 amino acid residues linked by three disulfide bridges and its primary structure is 61% identical to that of Noxiustoxin (NTX). It is not toxic to mice (using up to 200 micrograms/20 g mouse weight) and crustaceans (up to 30 micrograms/g of crayfish), but has a paralysing effect on crickets (30 micrograms/g animal). It displaces the binding of [125I]NTX to rat brain synaptosome membranes with a Ki of 0.1 microM, in comparison NTX has a Ki of 100 pM. Similarly, using single Ca2+ activated K+ channels of small conductance obtained from cultured bovine aortic endothelial cells it was shown that NTX2 is over two logarithm units less potent than NTX in producing 50% blockade of the probability of opening the channels. NTX2 is not recognized by a panel of six distinct monoclonal antibodies against NTX, however it is recognized by polyclonal antibodies raised in mouse, with native NTX. Primary structure comparison of both NTX and NTX2 suggests that the N-terminal segments of these peptides are important for channel affinity.