Citations

A nonlinear model of the human aural system is proposed. Utilizing a homomorphic transformation, the model is implemented in a digital computer and accounts for the Fletcher critical bands in hearing, the nonlinear relationship between input sound intensity and perceived loudness known as recruitment, as well as the thresholds of audibility and the maximum tolerance threshold. The transformed or output signal domain is identified as a perceptual space. It is shown that the model can be used to reproduce the Fletcher Munson equal loudness contours for normal hearing populations. Modification of easily measured parameters results in the generation of equal loudness contours for hearing impaired individuals. Through a combination of the forward homomorphic transformation for normal hearing to the perceptual domain and the inverse mapping utilizing parameters of a hearing impaired individual, it is shown that hearing intelligibility is dramatically improved. It is postulated that signal processing performed in the perceptual domain will produce results more pleasing and intelligible to the listener. Results of auditory testing utilizing the proposed model for both normal and hearing impaired populations are presented. Speech intelligibility scores are shown to increase by more than 40% (i.e., from 40% to over 80%) over preprocessed scores under headphones for hearing impaired subjects used in these tests.

Abstract Purpose: Most colorectal cancers that have high levels of microsatellite instability (MSI-H) show loss of immunohistochemical expression of proteins that participate in the DNA mismatch repair process, most often involving MLH1 and MSH2. Less commonly, a third DNA mismatch repair protein, MSH6, may also be lost as the primary event. Rarely, tumors with MSI-H show normal expression of these three proteins. The genetic deficiency leading to the MSI-H phenotype in such cases is unknown. PMS2 is another member of the DNA mismatch repair complex. Its expression is generally lost in tumors with MLH1 loss of expression. Rarely, there is selective loss of PMS2 expression. We sought to describe the frequency and clinical correlates of selective loss of expression of PMS2 with the MSI-H tumor phenotype. Experimental Design: Two thousand seven hundred nineteen colorectal cancers from both clinic- and research-based ascertainment were studied. Tumor MSI testing and immunohistochemistry for MLH1, MSH2, MSH6, and PMS2 were conducted. Medical records were abstracted for age at diagnosis, gender, colorectal cancer site, and family history. Results: Five hundred thirty-five of the 2,719 tumors were MSI-H. Of these, 93% showed loss of expression of MLH1, MSH2, and/or MSH6. Thirty-eight showed normal expression for these proteins. PMS2 immunohistochemical staining was successful in 32 of 38 of these tumors. Of the 32, 23 showed selective loss of expression of PMS2. This was associated with young age of diagnosis and right-sided location but not with a striking family history of cancer. Conclusions: Overall, 97% of the MSI-H tumors showed loss of expression for one or more of these four mismatch repair proteins. Selective loss of expression of PMS2 was present in 72% of cases in which colorectal cancers had an MSI-H phenotype but no alteration of expression of MLH1, MSH2, and MSH6. The underlying mechanism involved cannot be determined from this study but could involve point mutations in other DNA mismatch repair genes with retention of immunohistochemical expression, somatic inactivation of PMS2, or germ line mutation of PMS2.

Pisotriquetral arthrosis in young patients is considered rare and the diagnosis may be difficult to distinguish from other ulno-carpal problems. 12 patients under 40 years of age (15 cases) who underwent pisiformectomy were reviewed at a mean of 41 months. Patients with a good history of trauma and a positive response to intra-articular local anaesthetic injection did well. Others with an indefinite history and bilateral symptoms did not do so well. Trispiral tomography is the radiological investigation of choice.

Abstract The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) l-arginine/GHRH (to clamp low SS and high GHRH input); 2) l-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P < 0.001); 2) l-arginine/GHRH and l-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P < 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to l-arginine/GHRP-2 (r2 = 0.49, P = 0.005), whereas testosterone negatively predicted those to l-arginine/GHRH (r2 = 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.

Abstract Pheochromocytomas are rare catecholamine-producing neuroendocrine tumors that are usually benign, but which may also present as or develop into a malignancy. Predicting such behavior is notoriously difficult and there are currently no curative treatments for malignant tumors. This report follows from a workshop at the Banbury Conference Center, Cold Spring Harbor, New York, on the 16th–18th November 2003, held to review the state of science and to facilitate future progress in the diagnosis and treatment of malignant pheochromocytoma. The rarity of the tumor and the resulting fragmented nature of studies, typically involving small numbers of patients, represent limiting factors to the development of effective treatments and diagnostic or prognostic markers for malignant disease. Such development is being facilitated by the availability of new genomics-based tools, but for such approaches to succeed ultimately requires comprehensive clinical studies involving large numbers of patients, stringently collected clinical data and tumor samples, and interdisciplinary collaborations among multiple specialist centers. Nevertheless, the well-characterized hereditary basis and the unique functional nature of these neuroendocrine tumors provide a useful framework that offers advantages for establishing the pathways of tumorigenesis and malignancy. Such findings may have relevance for understanding the basis of other more common malignancies where similar frameworks are not available. As the relevant pathways leading to pheochromocytoma are established it should be possible to take advantage of the new generation of drugs being developed to target specific pathways in other malignancies. Again the success of this will require well-designed and coordinated multicenter studies.

ABSTRACT OBJECTIVE To determine the clinical presentation, imaging characteristics, microscopic and ultrastructural characteristics, and treatment outcomes of patients with clinically silent pituitary corticotroph adenomas. METHODS All silent corticotroph adenomas diagnosed at the Mayo Clinic during the years 1975 through 1997 were selected from the files of the Mayo Tissue Registry. RESULTS We studied 23 cases, occurring in 16 male and 7 female patients (age range, 11–79 yr; mean age, 48 yr), who presented with headaches (50%), visual field defects (61%), extraocular muscle paresis (13%), hypopituitarism (26%), and galactorrhea/amenorrhea (43%/29% of the female patients). No patients exhibited clinical hypercortisolism. All tumors were macroadenomas (2.4 ± 0.8 cm; range, 1.5–4.0 cm) and exhibited suprasellar extension in 87% of the cases and hemorrhage, necrosis, and/or cystic changes in 61%. All tumors stained were variably periodic acid-Schiff-, adrenocorticotropic hormone-, and β-endorphin-positive, particularly Subtype I lesions. Ultrastructural classification was performed in 19 cases. In a comparison of Subtype I and II tumors, differences were observed with respect to sex (male/female, 1.4:1 versus 6:1), preoperative hyperprolactinemia (5 of 16 versus 0 of 6 cases), preoperative hypopituitarism (9 of 16 versus 5 of 7 cases), radiographic or gross invasion (7 of 16 versus 5 of 7 cases), and partial or total postoperative pituitary failure (6 of 16 versus 6 of 6 cases). The overall median postoperative follow-up period was 4.9 years (range, 0.3–16.6 yr); 54% of the patients had persistent or recurrent tumors. CONCLUSION Clinically silent corticotroph adenomas behave in an aggressive manner and are characterized by the following: lack of clinical signs or symptoms of Cushing's syndrome and normal cortisol levels; no or only minor elevations of serum adrenocorticotropic hormone levels; macroadenomas with hemorrhagic infarction; and presentation dominated by mass effect symptoms. The high persistence/recurrence rate underscores the need for long-term follow-up.