Adequacy of the epinephrine autoinjector needle length in delivering epinephrine to the intramuscular tissues.

BACKGROUND: Epinephrine injected by an autoinjector in the anterolateral aspect of the thigh is the standard of care in the emergency self-treatment of anaphylaxis. In the United States, the autoinjector EpiPen is widely used for the self-treatment of anaphylaxis. OBJECTIVE: To investigate whether EpiPen autoinjector, with a needle length of 1.43 cm, is sufficient for intramuscular delivery of epinephrine in men and women. METHODS: The distance from skin to muscle in the anterolateral aspect of the thigh was measured in 50 men and 50 women who had undergone computed tomography of the thighs for other medical reasons. For each individual, body mass index (BMI; a measure of weight in kilograms divided by the square of height in meters) was also calculated, and the individuals were classified as underweight (BMI, < 18.5), normal (BMI, 18.5-24.9), overweight (BMI, 25.0-29.9), and obese (BMI, > or = 30.0) using standard definition. RESULTS: In the study participants the mean +/- SD distance from skin to muscle was 0.66 +/- 0.47 cm for men and 1.48 +/- 0.72 cm for women (P < .001). One man (obese at a BMI of 42.2) and 21 women (11 obese with a mean BMI of 35.2, 6 overweight with a mean BMI of 30.1, and 4 normal with a mean BMI of 24.5) had a greater distance from skin to muscle than the EpiPen needle length of 1.43 cm. CONCLUSION: The distance from skin to muscle for the anterolateral aspect of the thigh is higher in women compared with men. This difference suggests that EpiPen may not deliver epinephrine to the intramuscular tissue in many women.     

Ethyl-EPA in Huntington disease—Potentially relevant mechanism of action

The pathomechanisms involved in the neuronal dysfunction in Huntington disease (HD) are still unresolved and may be heterogeneous. One potential mechanism might be related to the induction of mitochondrial dysfunction in the CNS. This might lead firstly to neuronal dysfunction and finally to the activation of apoptotic pathways. Several compounds, which should alleviate mitochondrial dysfunction, have been tested in preclinical models as well as in clinical trials of different scale. Recently we reported the efficacy of Ethyl-eicosapentaenoic acid (Ethyl-EPA) in patients with HD. Ethyl-EPA is a polyunsaturated fatty acid from the n − 3 group, which is in clinical development for HD and melancholic depression. In our trial with Ethyl-EPA in HD responding patients could be characterized by either a lower CAG repeat number or a chorea-predominant clinical expression of the disease. Here we would like to describe some evidence on the potential mechanism of action of Ethyl-EPA in HD. We specifically focus on pathways, which are known to be influenced in HD and are modified by Ethyl-EPA and which points to an involvement of mitochondrial function as a common target. Some attention is given to the NF-kappa B pathway and the c-Jun amino-terminal kinases (JNK) pathway, which both may lead to an activation of the antiproliferative factor p53 and consequently mitochondrial dysfunction. Further the effects of EPA or Ethyl-EPA in preclinical models of HD are described. The evidence from these studies led to the design of phase III clinical trials, which are ongoing.     

Decrease of glucose in the human visual cortex during photic stimulation.

Localized proton NMR spectroscopy was used to study cerebral metabolism in the visual cortex of healthy adults during rest and photic stimulation. Basal lactate levels showed considerable interindividual differences ranging from below detectability (less than 0.3 mM) to about 1 mM without consistent alteration during photic stimulation. Local brain glucose levels were significantly reduced (approximately 50%) during the entire period of photic stimulation and recovered to resting levels (approximately 0.8 mM) within 10 min after the end of stimulation. This decrease reflects the establishment of a new equilibrium due to enhanced delivery (blood flow) and enhanced consumption. The absence of lactate accumulation supports the hypothesis of a rapid efflux of lactate from brain tissue under activated conditions.     

Detection of local recurrence of soft-tissue sarcoma with positron emission tomography using [18F]fluorodeoxyglucose

Background: It is often difficult to detect a local recurrence of soft-tissue sarcomas due to disturbance of the normal anatomy by previous surgery and radiotherapy. The aim of this study was to assess the value of positron emission tomography (PET) with [¹⁸F]fluoro-2-deoxy-d-glucose (FDG) for detecting local recurrences. Methods: In the period 1992–1995, 17 patients with proven or suspected local recurrence of soft-tissue sarcoma were examined using FDG-PET. Fifteen of these patients were ultimately proven to have a recurrence. Results: Recurrence was visualized in 14 patients (93%). Small tumors (maximum diameter 0.5 cm) were as easily visible as large lesions (maximum diameter 20 cm). In one patient the PET scan was positive, but the recurrence could not be proven histologically. Recurrence was proven 1 year later. A recurrent low-grade liposarcoma was not visualized. The two patients with benign lesions had a negative PET scan. The mean glucose metabolic rate was calculated to be 13.2 μmol/100 g/min (range 1.9–28.4). A correlation was found between the histological malignancy grade and the metabolic rate (p<0.05; Kruskal-Wallis). Conclusion: PET with FDG is a useful addition to the diagnostic armamentarium for detecting local recurrence of soft-tissue sarcomas and provides an indication of the malignancy grade of the recurrent lesion. Presented at the 47th Annual Meeting of The Society for Surgical Oncology, Houston, Texas, March 17–20, 1994.     

A method to remove artifacts in attenuation-corrected myocardial perfusion SPECT Introduced by misalignment between emission scan and CT-derived attenuation maps.

Nonuniform soft-tissue attenuation affects the diagnostic accuracy of SPECT in myocardial perfusion imaging. The attenuation map required for attenuation correction can be acquired using x-ray tomography (CT). Frequent findings in attenuation-corrected images are defects in the apical and anterior myocardial wall. We assume that these are artifacts produced by misalignment of SPECT images and the attenuation map. METHODS: One hundred forty patients underwent myocardial perfusion imaging with 99mTc-methoxyisobutylisonitrile. Twenty-seven of 140 showed pronounced defects in the apical or anterior wall only after CT-based attenuation correction. SPECT and corresponding CT slices were examined for misalignment in the ventrodorsal direction (y-direction) visually and by threshold-based delineation of the body surface. Mismatched studies were realigned and image reconstruction and analysis were redone. The effect of the correction was assessed visually and by semiquantitative analysis based on a 20-segment model using 4D-MSPECT. RESULTS: In 15 of 27 patients, the improved coregistration led to smaller and less-pronounced defects in the regions mentioned. In 6 of 27 patients, former defects were judged as normal. No improvement was seen in only 4 patients. In these 4 subjects, the mismatch in the y-direction was <1 pixel (7 mm), and visual inspection suggested a coincident mismatch in the craniocaudal direction. In 2 cases, coregistration was not possible because the body outline extended beyond the CT field of view. Semiquantitative analysis revealed a significant increase of the relative uptake in the apex; in the apical segments of the anterior, septal, and inferior wall; and in the mid-anterior and mid-anteroseptal segment. Basal segments of the anterolateral, lateral, and inferolateral wall and the middle inferolateral segment showed a significant decrease of relative uptake. CONCLUSION: Misalignment in the y-direction between SPECT and the attenuation map can lead to artifacts in the apical, septal, and anterior wall, which will appear as defects. It also can cause overcorrection in the basal inferior and lateral segments. There is evidence that mismatches along the other directions may have a similar effect. The coregistration of SPECT and the attenuation map needs to be verified for every patient, even when using integrated dual-modality imaging devices.     

Fluorine-18 fluorodeoxyglucose positron emission tomography and iodine-131 whole-body scintigraphy in the follow-up of differentiated thyroid cancer

Metastases of differentiated thyroid cancer may show different uptake patterns for fluorine-18 fluorodeoxyglucose and [¹³¹I]NaI. FDG positron emission tomography (PET), iodine-131 whole-body scintigraphy (¹³¹I WBS) and magnetic resonance imaging were performed in 58 unselected patients, and spiral computed tomography (CT) of the lung in 25 patients. Thirty-eight patients presented with papillary carcinomas, 15 patients with follicular carcinomas and five patients with variants of follicular carcinoma. Primary tumour stage (pT) was pT1 in 3, pT2 in 19, pT3 in 11 and pT4 in 25 cases. For the detection of metastases, FDG PET was found to have a sensitivity of 50%, ¹³¹I WBS a sensitivity of 61%, and the two methods combined a sensitivity of 86%. When FDG PET was limited to patients with elevated thyroglobulin (Tg) levels and negative ¹³¹I WBS, the sensitivity of this algorithm was 82%. Of the 21 patients with lymph node metastases, seven presented with FDG uptake but no iodine uptake. In four of them, a second FDG hot spot appeared in a lymph node metastasis of normal size. Five of the seven patients underwent surgery. None of the eight patients with pulmonary metastases smaller than 1 cm exhibited FDG uptake, while five of them had iodine uptake. All had positive results on spiral CT. In conclusion, FDG PET cannot be substituted for ¹³¹I WBS. If the Tg level is elevated and ¹³¹I WBS is negative, FDG PET can be used to detect lymph node metastases and complements anatomical imaging. A spiral CT of the lung is useful to exclude pulmonary metastases before planning a dissection of iodine-negative lymph node metastases. Received 2 May and in revised form 8 July 1997     

Evidence that the central noradrenergic and adrenergic pathways activate the hypothalamic-pituitary-adrenal axis in the sheep.

These studies were undertaken to test the hypothesis that stimulation of the central noradrenergic and adrenergic pathways activates the hypothalamic-pituitary-adrenal axis in vivo in the conscious sheep. Blood samples were taken at 10-min intervals over 4 h to establish the baseline state, and then each animal received an intracerebroventricular (icv) injection of NaCl (control animals) or catecholamine [norepinephrine (NE) or epinephrine (EPI)]. A more frequent rate of venous sampling was used for the 30-min period after the icv injection, after which time the 10-min rate of blood sampling was continued for another 3.5 h. NaCl (n = 4) caused no change in pituitary-adrenal secretion. In contrast, 10 micrograms NE (n = 4) caused acute 1.9- and 3.2-fold increases in mean plasma ACTH and cortisol levels over the 1 h period post injection, and 1.6- and 2.3-fold increments in their concentrations over the 4 h postinjection period. Although 10 micrograms EPI (n = 4) did not elevate mean plasma ACTH, it produced significant 1.7- and 1.5-fold increases in plasma cortisol during the 1- and 4-h periods post injection. However, when 100 micrograms EPI was injected (n = 4), acute 9.5- and 5.5-fold increases in plasma ACTH and cortisol were seen over the 1 h period post injection, and 6.1- and 4.2-fold increments in their plasma concentration were noted during the entire post-injection period. To determine the predominant site of action of the catecholamines, we also examined the ability of NE and EPI to release ACTH from cultured ovine anterior pituitary cells. NE and EPI (10(-9)-10(-6) M) stimulated the release of ACTH in a dose-dependent manner, but with maximal increments only 1.5-fold greater than the basal secretion. NE and EPI also increased the maximal ACTH response to CRF, but did not alter the maximal ACTH release induced by arginine vasopressin.(ABSTRACT TRUNCATED AT 400 WORDS)     

Growth modulation of hepatocytes and rat liver epithelial cells (WB-F344) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Modulation of DNA synthesis by 2,3,7,8-tetrachlorodi-benzo-p-dioxin(TCDD) was studied in primary cultures of hepatocytes and inrat liver epithelial cells (WB-F344) to develop models for studieson the interactions between the activated Ah receptor and cellulargrowth control. In hepatocytes TCDD either positively or negativelymodulated EGF-stimulated DNA synthesis. In the presence of ethlnylestradiol10^–12 M TCDD moderately increased EGF-stimulated DNA synthyesis(     

Physiological incompatibilities of porcine hepatocytes for clinical liver support.

In fulminant hepatic failure, the use of bioartificial liver support (BAL) with porcine hepatocytes is the subject of a current and controversial debate.1 Specifically, the issue of cross-species physiological incompatibilities has not been addressed so far. We therefore investigated the effects of species-specific cytokines in single and cocultures on hepatocyte function. Hepatocyte cultures were isolated from human resection specimens and from Landrace pigs. Single and cocultures were exposed to porcine and human interleukin (IL)-6 or tumor necrosis factor (TNF)-alpha. Changes in expression of C-reactive protein (CRP), albumin, CCAAT enhancer binding protein (C/EBP)-alpha and C/EBP-beta and metabolic competence of cultured cells was studied by measuring testosterone metabolite production. After human or porcine IL-6 dosing, CRP was induced up to 100-fold in human hepatocyte cultures, while porcine hepatocytes responded marginally (2- to 5-fold). Treatment with human or porcine IL-6 or TNF-alpha resulted in reduced albumin production, albeit at different levels when human and porcine hepatocytes were compared (P = 0.001). Unlike human, porcine hepatocytes produced less of 6alpha-hydroxytestosterone (6alpha-HT) (P < 0.001) and 7alpha-HT (P < 0.001) after human or porcine IL-6 dosing and treatment with species-specific TNF-alpha induced (human hepatocytes) or decreased (porcine hepatocytes) 6beta-HT production (P = 0.021). In coculture with free exchange of metabolites, porcine hepatocytes produced less 6alpha-HT (P = 0.048) and 16alpha-HT (P = 0.033), whereas after treatment with human IL-6 reduced CRP gene and protein expression was observed with human hepatocytes (P = 0.013). In conclusion, species-specific responses of hepatocytes to cytokines and interactions with xenobiotic metabolites may limit the clinical effectiveness of porcine hepatocytes in BAL.