Extracellular truncations of h beta c, the common signaling subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5, lead to ligand-independent activation

The hypothesis that extracellular truncation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony- stimulating factor, and IL-5 (h beta c) can lead to ligand-independent activation was tested by infecting factor-dependent hematopoietic cell lines with retroviruses encoding truncated forms of h beta c. A truncation, resembling that in v-Mpl, and retaining 45 h beta c-derived extracellular residues, led to constitutive activation in the murine myeloid cell line, FDC-P1. However, infection of cells with retrovirus encoding a more severely truncated receptor, retaining only 7 h beta c- derived extracellular residues, did not confer factor independence on these cells. These experiments show that truncation activates the receptor and define a 37-amino acid segment of h beta c (H395-A431) which contains two motifs conserved throughout the cytokine receptor superfamily (consensus Y/H XX R/Q VR and WSXWS), as essential for factor-independent signaling. The mechanism of activation was also investigated in less severe truncations. A receptor that retains the entire membrane-proximal domain (domain 4) also conferred factor independent growth on FDC-P1 cells; however, a retrovirus encoding a truncated form of h beta c having two intact membrane proximal domains did not have this ability, suggesting that domain 3 may have an inhibitory role in h beta c. The ability of these receptors to confer factor independence was cell specific as demonstrated by their inability to confer factor-independent growth when introduced into the murine IL-3-dependent pro-B cell line BaF-B03. These results are consistent with a model in which activation requires unmasking of an interactive receptor surface in domain 4 and association with a myeloid- specific receptor or accessory component. We suggest that in the absence of ligand intramolecular interactions prevent inappropriate signaling.     

Male hypogonadotropic hypogonadism: factors influencing response to human chorionic gonadotropin and human menopausal gonadotropin, including prior exogenous androgens

Although testosterone (T) therapy is sufficient for maturation and maintenance of secondary sex characteristics in hypogonadal men, gonadotropins are required for stimulation of spermatogenesis. Thirteen men with hypogonadotropic hypogonadism received treatment with hCG, followed in 12 by the addition of human menopausal gonadotropin (hMG). All initially had undetectable serum LH and FSH and low T levels and were azoospermic with small testes. During therapy, all achieved normal male levels of T. Twelve of 13 had marked and continuous increase in testicular volume. Three men had sperm in the ejaculate with hCG treatment alone. All but 1 patient developed sperm in their seminal fluid during combined hCG and hMG therapy. Two men achieved three pregnancies, and 2 more had semen that produced hamster oocyte penetration assays in the fertile range during the protocol period. Four of 5 who achieved sperm densities greater than 1 million/ml while receiving combined therapy maintained or increased sperm production while receiving continued hCG therapy after hMG was withdrawn. We examined the response to gonadotropin therapy of men who had received previous T therapy and those who had not. There were no differences in rapidity or degree of response, as assessed by rise in serum T, increase in testis volume, or maximal sperm density achieved. Multiple pituitary deficits and cryptorchidism were negative prognostic factors. In summary, the prognosis for successful stimulation of spermatogenesis in men with hypogonadotropic hypogonadism treated with hCG/hMG is good and not adversely affected by prior androgen treatment. Despite undetectable serum FSH levels, hCG treatment was sufficient to both initiate and maintain spermatogenesis in some patients.     

Detection of acute pulmonary embolism: feasibility of diagnostic accuracy of MRI using a stepwise protocol

Multidetector computed tomography (MDCT) has become the imaging method of choice in patients suspected of having pulmonary embolism (PE) but has the inherent limitation of radiation dose and the side effects of contrast agents. The purpose of the study was to assess the feasibility of a stepwise MRI protocol in the clinical setting of acute PE. The stepwise approach should make it possible to diagnose acute PE in critically ill patients using fast MR sequences and included the option to add comprehensive sequences when patients were stable. Forty-five patients with acute PE (26 men, 19 women; 41?±?16 years) were included in this prospective study. The diagnosis was initially confirmed by MDCT as gold standard. MRI at 1.5 T was subsequently performed without any delay in medical treatment. The MRI protocol proceeded stepwise from robust to detailed imaging techniques (i.e., from TrueFISP and single shot HASTE sequence to MR perfusion and 3D-MR angiography) if the patient was able to tolerate additional imaging time. Diagnostic accuracy was evaluated on the central (lobar) and peripheral (segmental) levels. The complete MR protocol was applied in 40 of the 45 patients (88 %). In the remaining five patients with severe dyspnea the diagnosis of acute PE was established by using fast TrueFISP sequences that were insensitive to respiratory movement. All five patients suffered from a major central PE. Highest sensitivity was achieved by MR perfusion (lobar, 98 %; segmental, 95 %). Real-time TrueFISP and MR angiography showed the highest specificity (lobar, 90–100 %; segmental, 95–97 %). The combination of all MR sequences matched closely the results of MDCT (lobar: sensitivity 98 %, specificity 100 %; segmental: sensitivity 95 %, specificity 97 %). MRI using a stepwise protocol is a promising approach for diagnosing acute PE. The protocol can be tailored for dyspneic patients with central PE using real-time MRI sequences. The diagnostic accuracy for peripheral PE can be improved by using combined MR techniques, achieving comparable results to MDCT.     

Accuracy of Right and Left Ventricular Functional Assessment by Short-Axis vs Axial Cine Steady-State Free-Precession Magnetic Resonance Imaging: Intrapatient Correlation With Main Pulmonary Artery and Ascending Aorta Phase-Contrast Flow Measurements

Objective

The left ventricle (LV) is routinely assessed with cardiac magnetic resonance imaging (MRI) by using short-axis orientation; it remains unclear whether the right ventricle (RV) can also be adequately assessed in this orientation or whether dedicated axial orientation is required. We used phase-contrast (PC) flow measurements in the main pulmonary artery (MPA) and the ascending aorta (Aorta) as nonvolumetric standard of reference and compared RV and LV volumes in short-axis and axial orientations.

Methods

A retrospective analysis identified 30 patients with cardiac MRI data sets. Patients underwent MRI (1.5 T or 3 T), with retrospectively gated cine steady-state free-precession in axial and short-axis orientations. PC flow analyses of MPA and Aorta were used as the reference measure of RV and LV output.

Results

There was a high linear correlation between MPA-PC flow and RV–stroke volume (SV) short axis (r = 0.9) and RV-SV axial (r = 0.9). Bland-Altman analysis revealed a mean offset of 1.4 mL for RV axial and –2.3 mL for RV–short-axis vs MPA-PC flow. There was a high linear correlation between Aorta-PC flow and LV-SV short-axis (r = 0.9) and LV-SV axial (r = 0.9). Bland-Altman analysis revealed a mean offset of 4.8 m for LV short axis and 7.0 mL for LV axial vs Aorta-PC flow. There was no significant difference (P = .6) between short-axis–LV SV and short-axis–RV SV.

Conclusion

No significant impact of the slice acquisition orientation for determination of RV and LV stroke volumes was found. Therefore, cardiac magnetic resonance workflow does not need to be extended by an axial data set for patients without complex cardiac disease for assessment of biventricular function and volumes.     

Assessment of thoracic aortic dimensions in an experimental setting: comparison of different unenhanced magnetic resonance angiography techniques with electrocardiogram-gated computed tomography angiography for possible application in the pediatric population

PURPOSE: To compare different unenhanced magnetic resonance angiography (MRA) techniques for quantitative evaluation of vessel lumen in an experimental setting in young pigs whose dimensions allow for a comparison with a pediatric population. MATERIAL AND METHODS: Magnetic resonance imaging was performed in 5 healthy ventilated pigs at 1.5 T. Three different electrocardiogram (ECG)-triggered sequences were applied for MRA: [TSE-Db] T2-weighted dark-blood TurboSpinEcho (2.0 x 1.1 x 4 mm3); [trueFISP] 2D-steady-state-free-precession (2.2 x 1.8 x 2 mm3); [NAV] respiratory-gated, T2-prepared 3D-trueFISP (1.3 x 1.3 x 1.3 mm3). ECG-gated-CT angiography (CTA) (16-row CT, 1 mm collimation) served as the standard of reference. The vessel lumen was measured at 7 positions perpendicularly angulated to the vessel wall on multiplanar reformations: ascending aorta (P1), the aortic arch before (P2) and after (P3) the origin of the first supraaortic branch, the aortic arch after the origin of the second supraaortic branch (P4), the descending aorta at the level of the diaphragm (P5), and the first and second supraaortic branches (P6, P7). RESULTS: Percentage differences in the vessel area determined by MRA reformation compared with CTA-reformation were 10% +/- 20% and 35% +/- 27% (TSE-Db), -4% +/- 13% and 20% +/- 24% (trueFISP), and -3% +/- 13% and -10% +/- 19% (NAV), for positions P1 to P5 and P6 to P7, respectively. A significant difference from CTA was found for TSE-Db at all positions, and for trueFISP only at positions P6 and P7. CONCLUSIONS: Unenhanced MRA techniques allow for a reliable assessment of the dimensions of the thoracic aorta compared with CTA as the standard of reference. Using ECG-gating and navigator techniques, the free-breathing approach showed the best agreement with CTA. This technique may therefore be the most useful in the pediatric age group allowing for true 3D data acquisition with its inherent postprocessing possibilities.     

5-Methoxy Psoralen, Etretinate, and UVA for Psoriasis

This first Australasian randomized trial of 5-methoxy psoralen (5-MOP) PUVA for psoriasis shows, conclusively, less acute side effects than 8-MOP PUVA. Daily addition of oral etretinate to the PUVA regimen (Re-PUVA) produces a valuable reduction in total joules and more so with 5-MOP than with 8-MOP. The clearing phase with 5-MOP Re-PUVA is quicker than with 8-MOP Re-PUVA in skin types 1, 2, and 3 (most Anglo-Saxon-Celtic Australians). Doses, when adapted to total body surface rather than mg/kg, allow superior control of therapy. Emollient creams, tar gels, nonsteroidal scalp applications, etc. allow more patient comfort.     

Acute myocardial ischemia: MR imaging with Mn-TP

Cardiac-gated magnetic resonance (MR) imaging was performed in rats to determine the effects of manganese ethylenediaminetetraphosphonate (TP). Ten normal rats received Mn-TP in a dose of 50 mumol/kg through a tail-vein injection. Spin-echo MR images were obtained before and every 10 minutes after Mn-TP injection for 1 hour. Cardiac signal intensity (SI) increased more than 70% after Mn-TP injection and remained nearly unchanged 1 hour after injection. Myocardial T1 was 517 +/- 49 msec in eight control rats and 282 +/- 61 msec (P less than .001) in six rats 81 +/- 0 minutes after injection. Nine rats underwent occlusion of the left anterior descending coronary artery prior to MR imaging. Images were obtained before and 15, 30, and 60 minutes after Mn-TP injection. In normal myocardium, SI increased up to 82% and remained elevated for 1 hour. In ischemic myocardium, SI rose 11%, leading to a marked contrast between the two tissue zones. T1 was also different in the two regions: In normal tissue, it was 206 msec +/- 54; in ischemic tissue, 338 +/- 82 (P less than .001). With T1-weighted MR imaging, Mn-TP showed a potential for delineating the jeopardized area after acute myocardial ischemia.     

Distribution of metallothionein in normal and pathological human skin

The expression and distribution of metallothionein (MT) in frozen sections of normal and pathological human skin was studied using the monoclonal antibody L2E3 directed against MT derived from human fetal liver. Immunohistochemical staining of normal fetal and adult skin revealed strong reactivity in basal keratinocytes of epidermis and outer hair root sheath, hair matrix cells and the secretory coil, but not the exocrine portion of eccrine glands; myoepithelial cells around apocrine sweat glands were similarly stained. In epidermal hyperplasia, variable numbers of suprabasal keratinocytes were stained, whereas in interface dermatitis, interrupted staining was found in the basal layer. Weak or scattered staining was observed in squamous tumours, whereas basal cell carcinomas did not show consistent staining. The distribution of MT in normal skin was in line with the germinative role of basal keratinocytes and hair matrix cells, whereas its distribution in hyperplastic epidermis was in line with experimental animal data, and reflected the increase in the germinative pool in these conditions. It is concluded that monoclonal antibody L2E3 may serve as a valuable immunohistochemical marker in diagnostic cutaneous pathology since it labels basal keratinocytes selectively, and since it discriminates between eccrine and apocrine sweat glands.     

Multidisciplinary protocol of preoperative and surgical management of patients with pituitary tumors candidates to pituitary surgery

The optimal planning of preoperative diagnosis, management and treatment of pituitary tumors (PT) candidates to pituitary surgery (PS) requires a multidisciplinary approach involving a team of endocrinologists, neurosurgeons, ENT, neuro-ophthalmologists and neuroradiologists with experience in pituitary diseases. Such teams improve surgical results, minimize complications and facilitate their correct treatment if occurring, and optimize the hormonal, ophthalmological and radiological preoperative and follow-up evaluation. We have developed a clinical practice protocol for patients with PT who are candidates to PS based on the most recent national and international guidelines and the relevant literature regarding PT published in the last years. The protocol has been elaborated by a multidisciplinary team of a Spanish Pituitary Tumor Center of Excellence (PTCE) that includes at least one neurosurgeon, ENT, neuroradiologist, neuro-ophthalmologist, endocrine pathologist and endocrinologist specialized in pituitary diseases. We elaborated this guideline with the aim of sharing our experience with other centers involved in the perioperative and surgical management of PT thereby facilitating the management of patients undergoing PS.