Clinical predictors of mortality and cause of death in lymphangioleiomyomatosis: a population-based registry.

PURPOSE: Lymphangioleiomyomatosis (LAM) is a rare, progressive, frequently lethal cystic lung disease that almost exclusively affects women. Prognostic information in LAM has been limited by small numbers and heterogeneous study methodology. Early retrospective cohorts cited 5- and 10-year mortality of 40 and 80 %, respectively. More recently, mortality at 10 years has been estimated to be approximately 10-20 % from the onset of symptoms and 30 % at 10 years from the time of lung biopsy but varies widely in individual patients. Given the heterogeneous disease course, it would be useful to establish which clinical characteristics are associated with survival to develop prediction models for disease outcome. METHODS: The LAM Foundation maintains a population-based registry of 1,149 registered self-identified LAM patients. Of these, 590 have completed a "General Information/Clinical History Questionnaire" with limited demographic and clinical data, 410 of whom were identified as U.S. residents and provided date of birth. Vital status was obtained on all 410 participants through December 31, 2007 by linking patient identifiers and the National Death Index. Survival time was calculated as the time since first lung-related symptom or physician diagnosis until censoring (still alive, received lung transplant, or died). Cox proportional hazard analysis evaluated the association of demographic and clinical features with survival. RESULTS: Among the 410 subjects, there were 50 deaths and 55 lung transplantations during a median of 10.4 years of observation time. The estimated median transplant-free survival time for LAM patients in the United States is 29 years from symptom onset and 23 years from diagnosis. The estimated 10-year survival transplant-free was 86 %. Age at disease onset, smoking status, race, presence of tuberous sclerosis, occurrence of pneumothorax, and pregnancy did not demonstrate an association with survival or transplant. Greater age at presentation and presence of angiomyolipoma were associated with less risk of mortality. Treatment with hormonal therapy was associated with an increased risk of death/transplant (hazard ratio (HR) 2.93; 95 % confidence interval (CI), 1.54-5.58; p = 0.001), particularly progesterone therapy (HR 2.17; 95 % CI 1.26-3.75, p = 0.005), and may represent confounding by indication. Patients who required oxygen therapy had a worse outcome (HR 4.53; 95 % CI 2.76-7.42; p < 0.001). CONCLUSIONS: Our population-based study showed that the median survival in patients with LAM from the onset of symptoms or diagnosis is much longer than previously described. This has important implications for life choices and treatment decisions regarding medication use and lung transplantation for patients with LAM.

Interaction effects of emotional status and sexual abuse on adult sexuality.

This study examined the additive, interaction effects of emotional status with sexual abuse on adult sexual functioning and sexual responsibility. The Golombok Rust Inventory of Sexual Satisfaction (GRISS; Rust & Golombok, 1986), the Personality Assessment Inventory (PAI; Morey, 1991), and a questionnaire regarding sexual experiences, number of unwanted pregnancies, number of unsafe sexual partners, and sexual abuse history, were administered to 200 psychology students. One hundred and forty-three participants were retained in the study. Two-way multivariate analyses of variance (MANOVA) were conducted for the sexual functioning variables (as measured by the GRISS), while two-way analyses of variance (ANOVA) were conducted for the sexual irresponsibility variables (as measured by the sexual experiences questionnaire). It was found that women who have high anxiety scores on the PAI and have a history of sexual abuse reported higher numbers of unwanted pregnancies, while sexual abuse history was not associated with numbers of unwanted pregnancies for women with lower levels of anxiety. Results were not significant, however, for the sexual functioning variables. In addition, depression and alcoholism did not have interacting effect on the association between sexual abuse history and any of the sexuality variables. These results may suggest that the effects of sexual abuse on adult sexuality may not be as pervasive as was once thought.

Inhibition of protein phosphatase 1 decreases PTH secretion from isolated dispersed parathyroid cells.

To investigate the regulation of parathyroid hormone secretion by phosphatases we examined the effect of okadaic acid, a selective inhibitor of protein phosphatases (PP)-1 and -2A, on isolated, dispersed parathyroid cells. Okadaic acid inhibited secretion from intact bovine, intact human and streptolysin-O permeabilized bovine cells. Approximately 10(-6) M okadaic acid resulted in a 50% decrease in parathyroid hormone (PTH) secretion from both intact and permeabilized cells, consistent with PP-1 being the target of inhibition. Upon subcellular fractionation, PP-1 overlapped but was not identical to either PTH, a marker of the secretory granule, or Na+/K+-ATPase, a plasma membrane marker. In summary, PP-1 activity is involved in Ca2+-dependent but not basal PTH secretion.

Genetic and biochemical screening for endocrine disease: II. Ethical issues.

The ability to test for specific genes conferring susceptibility to a variety of diseases has profound ethical implications for the way in which we care for patients. Legislators and health care insurers are scrambling to address the aspects of genetic screening that they believe fall within their purview. Critical to the development of appropriate societal regulations regarding genetic screening is a fundamental understanding of the ethical issues involved. A review of those concerns and the areas in which they interface with legal and insurance issues is the topic of this paper.

Effects of child and adult sexual abuse on adult sexuality.

The differential effects of child and adult sexual abuse on adult sexual functioning were examined. The Golombok Rust Inventory of Sexual Satisfaction (GRISS) and a sexual experiences questionnaire were administered to 201 psychology students at the University of South Florida, 175 of whom were retained in the study. GRISS variables that were analyzed consisted of anorgasmia, sexual avoidance, sexual dissatisfaction, sexual noncommunication, nonsensuality, and vaginismus. Women who were sexually abused in adulthood were more sexually dissatisfied and nonsensual than women who had no history of sexual abuse. In addition, women who had a history of sexual abuse in childhood or adulthood were less satisfied with the overall quality of their most recent sexual relationship than non-abused women and had higher numbers of unsafe sexual partners.

Detection of thyroglobulin, thyroid peroxidase, and RET/PTC1 mRNA transcripts in the peripheral blood of patients with thyroid disease.

PURPOSE: Detection of mRNA transcripts for thyroglobulin (TG), thyroid peroxidase (TPO) and RET/PTC1 in the peripheral blood of patients with thyroid disease. PATIENTS AND METHODS: TG, TPO, and RET/PTC1 mRNA were analyzed in 52 peripheral-blood samples from 44 patients diagnosed with thyroid carcinoma (24 patients), adenoma (five patients), and nodular hyperplasia (15 patients) by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: TG and TPO were identified in 13 patients (54.2%) with thyroid carcinoma, which includes five of eight patients with no clinical evidence of disease at the time of blood collection. Four of 5 patients had cervical lymph node metastases and/or extrathyroid extension at the time of the initial surgery. RET/PTC1 mRNA was detected in the peripheral blood of only one patient with papillary thyroid carcinoma. This sample was also positive for TG and TPO. TG and TPO were detected in two patients (10%) with benign thyroid nodules. All positive samples from patients with benign thyroid lesions were collected before surgery, whereas all samples collected after surgery were negative. RET/PTC1 mRNA was not detected in any of the patients with benign thyroid nodules. RT-PCR positivity for TG and TPO mRNA was higher in patients with carcinoma than in patients with benign lesions (P = .002). CONCLUSION: TG, TPO, and RET/PTC1 mRNA are detectable in the peripheral blood of patients with thyroid disease, which correlates with a diagnosis of carcinoma.

An investigation of malingering posttraumatic stress disorder on the Personality Assessment Inventory.

Utilizing the Personality Assessment Inventory (PAI; Morey, 1991), this study aimed to isolate a pattern of responding that is indicative of an attempt to malinger posttraumatic stress disorder (PTSD). The PAI profiles of 116 male participants were examined. Profiles of a group of 29 alcohol-abusing veterans with a primary Axis I (American Psychiatric Association, 1994) diagnosis of PTSD and a group of 30 alcohol-abusing veterans with no other diagnoses were compared to those of 27 undergraduate men instructed to feign PTSD. Control data were obtained from another group of 30 undergraduates. The student malingerers produced PAI profiles that were significantly different from the veterans with PTSD. Seven scales distinguished the malingerers from the veterans with an actual diagnosis of PTSD. Malingerers tended to overexaggerate pathology, inflating their scores on many clinical scales greater than the mean of the PTSD sample. Malingerers also scored higher on Morey's (1993) 8-item Malingering Index than either group of veterans and the controls. Only 2 scales reliably differentiated alcohol-abusing veterans with PTSD from those without the disorder. The implications of these findings in the diagnosis of PTSD are discussed.

Reconstitution of calcium-regulated parathyroid hormone secretion from streptolysin-O-permeabilized parathyroid cells by guanosine 5'-O-(thio)triphosphate.

Intracellular Ca2+ levels determine the amount of PTH secretion from parathyroid cells. Dissociated calf parathyroid cells were permeabilized with streptolysin-O (SLO) to provide an in vitro model system to examine Ca(2+)-dependent regulation of hormone secretion. PTH release from these cells was energy dependent and increased by cytosolic cofactors. Guanosine 5'-O-(thio)triphosphate (GTP gamma S) increased PTH secretion from SLO-permeabilized cells in a dose-dependent manner from 0.1-100 microM. In the absence of GTP gamma S there was no relationship between the ambient Ca2+ concentration and the rate of PTH secretion. However, in the presence of GTP gamma S, intracellular Ca2+ inhibited PTH secretion with an EC50 of approximately 0.1 microM, corresponding to physiological intracellular Ca2+ levels. Thus, the addition of GTP gamma S to SLO-permeabilized parathyroid cells reconstituted the inverse relationship between extracellular Ca2+ and PTH secretion that is observed in vivo and in intact cells. The data indicate that this effect is mediated at least in part by heterotrimeric guanosine triphosphatases. In addition, calcium/calmodulin-dependent protein kinase II appears to mediate low Ca(2+)-dependent PTH secretion from these cells.

Research validity scales for the NEO-PI-R: development and initial validation.

The purpose of this investigation was to develop a set of research validity scales for use with the NEO Personality Inventory-Revised (NEO-PI-R; Costa & McCrae, 1992b). In study 1 we used the existing NEO-PI-R item pool to select items for three validity scales: positive presentation management, negative presentation management, and inconsistency. Several iterative item and scale analyses were conducted, using multiple criteria for item selection. These analyses resulted in 10-item scales. In Study 2, the internal consistency, interscale relationships, and normative characteristics were examined in a separate sample of working adults. In Study 3, the validity of the scales was examined by contrasting five sets of NEO-PI-R protocols: from a separate sample of working adults, from a sample of 100 NEO-PI-R protocols with randomly produced responses, and from three samples of undergraduates completing the NEO-PI-R under different instructional sets. Analyses revealed that both the research validity scales and the NEO-PI-R domain scales were sensitive to group differences. issues relating to the appropriate use of the scales are discussed.

Mechanism of technetium 99m sestamibi parathyroid imaging and the possible role of p-glycoprotein.

BACKGROUND: Localization of parathyroid glands is critical in the treatment of recurrent or persistent hyperparathyroidism. Technetium sestamibi imaging may improve localization; however, the mechanism of visualization of parathyroid tissue remains unclear. On the basis of the chemical structure of sestamibi it has been suggested that p-glycoprotein is involved in the transport of sestamibi across cell membranes. This study was designed to examine sestamibi uptake and retention and p-glycoprotein expression in normal and abnormal parathyroid tissue. METHODS: Thirty-two consecutive patients underwent 2-methoxy-isobutyl-isonitrile imaging immediately before parathyroid exploration. Tissue was obtained from normal and abnormal parathyroids and from the thyroid gland. Touch preparations gave rapid confirmation of tissue origin. Specimens were trimmed and weighed, and gamma-emission was counted. Percentage injected dose per gram of tissue was calculated. Immunohistochemistry was obtained with a battery of monoclonal antibodies to identify p-glycoprotein in parathyroid tissue submitted for permanent histologic examination. Slides were graded by a pathologist familiar with immunohistochemistry. RESULTS: Abnormal parathyroid tissue had a higher mean retention of injected dose per gram than did normal thyroid and parathyroid tissue. Immunohistochemistry revealed that abnormal parathyroid tissue expresses less p-glycoprotein. CONCLUSIONS: These results suggest that size is not the single determinant of parathyroid visualization and that p-glycoprotein expression may be involved in the mechanism of parathyroid imaging.

Localization studies in patients with hyperparathyroidism.

Patients with hyperparathyroidism who have not had previous neck surgery do not require preoperative localization because of the high success rate of cervical exploration (95%) and the limited sensitivity and specificity of all imaging modalities currently in use. Successful parathyroid exploration requires knowledge of the normal and frequently encountered variations in parathyroid anatomy (Fig. 4). Experience permits recognition of often subtle multiple gland disease. In skilled surgical hands, results are excellent with minimal morbidity. When recurrent or persistent disease or previously operated patients are encountered, confirmation of the diagnosis and attempts at localization should precede operation. Technetium sestamibi SPECT imaging and ultrasonography with FNA of suspicious glands are complementary tests that are readily available, inexpensive, and well tolerated by patients. If these tests are unsuccessful, MRI, CT, and invasive procedures should be pursued until the gland is localized.

DARPP-32 (dopamine and cAMP-regulated phosphoprotein, M(r) 32,000) is a membrane protein in the bovine parathyroid.

A distinct form of DARPP-32, a protein phosphatase-1 inhibitor, has been identified in bovine calf parathyroid glands. Immunoblot analysis of parathyroid tissue revealed a 32 kDa protein present predominantly in a particulate fraction; it remained particulate after treatment with 1.0 M NaCl or 0.1 M Na2CO3. Metabolic labeling of parathyroid cells with mevalonolactone demonstrated that DARPP-32 is isoprenylated. Immunocytochemical localization studies demonstrated that DARPP-32 is present in vesicles throughout the cytoplasm of parathyroid cells, and that protein phosphatase-1 gamma is concentrated in the region of the plasma membrane. Thus, in contrast to the predominately soluble form of DARPP-32 that has been characterized in selected areas of the central nervous system, the parathyroid form is tightly associated with intracellular membranes.

Interrelationship between MMPI-2 and Rorschach variables in a sample of Vietnam veterans with PTSD.

We examined interrelationships between theoretically related MMPI-2 and Rorschach variables in a sample of Veterans Affairs outpatients with Posttraumatic Stress Disorder (PTSD). Subjects were 20 White Vietnam combat veterans diagnosed with PTSD who completed the Rorschach and MMPI-2 as part of a comprehensive evaluation. Correlations were calculated for variables in three groups: validity, depression and anxiety, and thought disturbance. Results showed strong relationships between m, MOR, and the Dramatic special score of the Rorschach and MMPI-2 indices of distress. Positive relationships were also found for some indicators of thought disturbance, whereas correlations for other depressive indicators were not significant. Findings are discussed with regard to implications for the clinical assessment of combat-related PTSD and future directions for assessment research.

Antibodies to an epitope on synapsin I detect a protein associated with the endocytic compartment in non-neuronal cells.

To detect potential substrate proteins for Ca2+/calmodulin-dependent protein kinase II outside the central nervous system, antibodies were made to a synthetic peptide corresponding to a sequence within synapsin I which is phosphorylated by this enzyme. In neural tissues, this antibody (212) identified an 86/80 kDa doublet corresponding to synapsin I. In rat liver, intestinal enterocytes and the clone 9 cell line this antibody identified two proteins of 170 and 85 kDa. These proteins were present in the particulate fraction of liver postnuclear supernatant, and were released into the soluble fraction when extracted with 100 mM NaCl. In liver, enterocytes, and clone 9 cells, these antigens were localized by immunocytochemical techniques to small intracellular vesicles. The endocytic compartment of clone 9 cells was labeled by continuous uptake of horseradish peroxidase; antibody 212-labeled vesicles exhibited overlap with the compartment. To confirm the identity of this compartment as endosomal, rat liver endosomes were labeled in vivo by intravenous injection of horseradish peroxidase. Horseradish peroxidase-containing endosomes of approximately 80 nm were recognized by antibody 212. Occasionally, larger endosomes (approximately 300-500 nm) were also labeled. In clone 9 cells, partial overlap was observed between the 212 antigen and a transferrin receptor-positive, brefeldin A-sensitive compartment. In clone 9 cells double-labeled with anti-tubulin and antibody 212, then imaged using confocal microscopy, these vesicles appeared to be associated with microtubules. This antigen has properties similar to that of CLIP-170, a membrane-associated endosomal phosphoprotein. These findings demonstrate that a 170/85 kDa antigen containing an epitope for the Ca2+/calmodulin-dependent protein kinase II phosphorylation sequence is associated with an endocytic compartment.