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J I Mechanick

Publications and source records attributed to J I Mechanick.

36 records · Page 2Linked to original sources

Unusual scintigraphic findings in a thyroid adenoma.

Thallium imaging is increasingly being used to evaluate the thyroid. Uptake patterns of 201Tl in benign and malignant thyroid nodules have been described. Thallium localizes all thyroid tissue with possibly different rates of washout in benign and malignant nodules. This case demonstrates a follicular adenoma presenting 123I as a clinically palpable nodule with nonvisualization of the remainder of the thyroid gland consistent with the diagnosis of an autonomously hyperfunctioning module. Subsequent thallium scanning revealed a complete reversal of tracer distribution with lack of uptake of 201Tl in the nodule while the rest of the gland showed normal thallium accumulation. Surgical excision of the nodule demonstrated follicular adenoma.

Adenoma↗

Proopiomelanocortin gene expression in a distinct population of rat spleen and lung leukocytes.

Existence of proopiomelanocortin (POMC) messenger RNA (mRNA) and related peptides in extrapituitary sites has been demonstrated in immune cells, although the particular type of immune cell has been the source of considerable debate. Specifically, double labeling studies have shown that POMC peptide expressing cells in the spleen represent a subpopulation of red pulp macrophages, while splenic lymphocyte areas are POMC negative. In addition, it has also been reported that peripheral blood leukocytes express the POMC gene. Using a sensitive solution hybridization technique with a POMC exon-1 RNA probe, we detected 70 +/- 20 fg and 65 +/- 5 fg POMC mRNA per microgram total RNA in whole spleen and lung, respectively, approximately 20,000-fold lower concentrations than found in the neurointermediate lobe of the pituitary. The presence of nuclease protected full length exon-1 bands, rather than the 5' truncated POMC RNAs seen in many nonpituitary tissues, indicates transcription initiation at the normal pituitary POMC promoter site in lung and spleen. In order to localize POMC gene expression in these tissues we employed an in situ hybridization method. There was an intense signal in a small population of large mononuclear cells scattered throughout the splenic red pulp and lung parenchyma. In the lung, these cells were concentrated in the periarteriolar zone in a manner suggestive of migration from the intravascular lumen. These cells had a histomorphology suggestive of monocyte-macrophages. POMC mRNA was undetectable in the splenic white pulp and bronchus-associated lymphoid tissue, indicating an absence of POMC gene expression in splenic and lung lymphocytes. Immunocytochemical studies suggested that POMC-positive cells made up a subpopulation of cells expressing the rat monocyte-macrophage markers ED1 and ED2. Similarly, the distribution of Jenner-Giemsa stained monocyte-macrophages appeared to overlap with POMC positive cells. Studies with anti-rat beta-endorphin antisera revealed scattered cells in the splenic red pulp and lung parenchyma, suggesting that the POMC mRNA is translated in these cells. In summary, POMC mRNA is expressed in a small population of monocyte-macrophage-like cells in lung and spleen but not in lymphocytes in these tissues.

Animals↗

A C version of Fourier-derived affinity spectrum analysis (FASA) to resolve binding heterogeneity.

The computer program described in this paper facilitates resolution of binding affinity heterogeneity by transforming binding curve data (bound versus free) into affinity spectra (density versus affinity). The original program, written in FORTRAN, is extended and presented here in the language C. New applications include an ability to transform competition curves into affinity spectra and to evaluate the effects of sampling and experimental error on spectrum analysis. We propose that this program be incorporated in the routine evaluation of binding systems.

Binding, Competitive↗

Cyclic therapy of osteoporosis with neutral phosphate and brief, high-dose pulses of etidronate.

We have designed a cyclic regimen for the treatment of osteoporosis based on the activate, depress, free, and repeat (ADFR) concept. Osteoclastic bone resorption is activated by 7 days of oral neutral phosphate and inhibited with a brief pulse (5 days) of etidronate disodium at a high dose (20 mg/kg body weight). Patients next take calcium supplements for 48 days before resuming phosphate to enter the next cycle. Osteoporotic women increased the bone mineral density of the lumbar spine at 6 months by 7.2 +/- 5.2% (mean +/- SD, N = 14) and at 12 months by 8.2 +/- 4.0% (N = 8). Control observations in regularly exercising postmenopausal women (N = 30) showed no significant change in spine mineral density after 20 months (0.5 +/- 3.2%), confirming the stability of the measurement technique. The two patients who responded poorly to the cyclic regimen each showed a blunted rise in serum PTH during oral phosphate administration, suggesting that the rise in PTH induced by oral phosphate may be an important component of this cyclic regimen. This preliminary study does not identify which component or components of the regimen are responsible for the increase in bone mass but provides positive encouragement for randomized studies designed to determine the optimum dosage, duration, and timing of each component of the regimen.

Adult↗

Altered estrogen receptor system in estrogen-unresponsive human endometrial adenocarcinoma cells.

Previous studies from our laboratories demonstrated that cells from a human endometrial adenocarcinoma cell line (Ishikawa) responded to estradiol whereas cells from another endometrial cancer line (HEC-50) did not. In an attempt to identify factors responsible for the observed estrogen insensitivity we compared the characteristics of the estradiol receptor (ER) systems in Ishikawa and HEC-50 cells. Saturation analyses of cytosolic estrogen binders were performed over a 0.1-70 nM range of [3H]estradiol concentrations. Equilibrium dissociation constants and number of binding sites were determined by graphic analysis of Scatchard plots or computed by applying Fourier-derived affinity spectrum analysis (FASA) of the binding data. No significant differences were noted in the dissociation constants (Kd approx. 0.6 nM) or number of binding sites (approx. 6-10 fmol/mg protein) for the single binder that could be evaluated by the graphic method in cytosol from the two cell lines. However, 2 binders in Ishikawa cells (Kd approx. 0.2 and 6 nM) could be detected by the FASA method; the higher affinity binder in HEC-50 cells could not be clearly demonstrated. Structural differences in the specific estrogen binders which might distinguish HEC-50 from Ishikawa cells or normal endometrial tissue were investigated by using the anti-ER monoclonal antibody JS 34/32. Interaction of the antibody with [3H]estradiol binders of estrogen-responsive cells and tissue was evident from the formation of labeled complexes that were shown to sediment faster in glycerol density gradients and could be immunoprecipitated with Protein A attached to Sepharose beads. In contrast, the antibody did not recognize labeled specific binders in the HEC-50 cells. Furthermore, [3H]estradiol receptors in Ishikawa cells could be transformed into a species that exhibited increased hydrophilicity, evident from its binding to DNA-cellulose, whereas binders from HEC-50 could not. These results indicate that the lack of responsiveness of HEC-50 cells to estrogens might be due to structural or functional alterations in the ER protein resulting in a loss of its capability to undergo estrogen-directed conformational changes required for biological activity.

Adenocarcinoma↗

Ultrasonographic study of ovaries of 19 women with weight loss-related hypothalamic oligo-amenorrhea.

A study of 19 nonhirsute women with weight loss-related hypothalamic oligo-amenorrhea revealed evidence of multifollicular ovaries in 17. Enlarged ovaries greater than 10 cm3 were found in 8 of these subjects (42.1%). High-resolution real-time ultrasonography of the pelvis of 19 weight loss-related oligo-amenorrheic subjects revealed a mean +/- SD maximum ovarian volume (MOV) of 11.8 +/- 7.0 cm3, which was significantly different from those of control subjects whose mean +/- SD MOV was 5.2 +/- 1.9 cm3 (P = less than 0.001). The data do not allow a specific ultrasonographic distinction between hyperandrogenic women with polycystic ovarian disease and women with weight loss-related hypothalamic amenorrhea.

Adolescent↗

Distribution of 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylglycol (DOPEG) in microdissected brain structures and the pituitary gland: metabolite changes in the median eminence in response to hyperprolactinemia and suckling.

Dopamine (DA), norepinephrine (NE), epinephrine (E), 3,4-dihydroxyphenylglycol (DOPEG) and dihydroxyphenylacetic acid (DOPAC) were determined simultaneously by a radioenzymatic, thin-layer chromatographic assay able to detect 1-10 pg of the parent compounds and 80-120 pg of their metabolites. A localization study of these compounds in 20 micro-dissected hypothalamic and limbic structures and the anterior and posterior pituitary glands of male rats was completed. DOPAC was detectable in 14 of 22 structures with the lowest DOPAC/DA ratio being found in the caudate nucleus (7.1%) and the highest in the medial aspect of the ventromedial nucleus of the hypothalamus (422.0%). There was a higher DOPAC/DA ratio in the lateral (21.5%) than in the medial (11.3%) portion of the median eminence suggesting that a greater portion of released DA in the medial median eminence enters the portal circulation. DOPEG was detectable in 6 of 22 structures with DOPEG/NE ratios ranging from 8% (interstitial nucleus of the stria terminalis, ventral aspect) to 32% (medial median eminence). A poor correlation exists between DOPAC and DA concentrations in the various brain regions while there was a stronger relationship between DOPEG and NE concentrations. Male rats were rendered hyper-prolactinemic for 48 hours with injections of ovine prolactin (oPRL) every 8 hours (4 mg/kg body weight sc). In such rats there was a suppression of endogenous rat PRL (rPRL) secretion, the DOPAC/DA ratio increased 2.2-fold in the medial (MEm) and 1.9-fold in the lateral median eminence (MEl), and the DA concentration in the anterior pituitary also increased 2.6-fold. In 10 day postpartum lactating rats, suckling produced marked increases in serum rPRL but no change in DOPAC/DA ratios in the ME or in the DA concentration in the anterior pituitary. The data reveal a wide range of DOPAC/DA ratios (7-422%) in brain regions containing cell bodies, axons and terminals of the different dopaminergic neuronal tracts in brain and pituitary. Considering the DOPAC/DA ratios in the MEm and MEl, it is suggested that a large perturbation of dopaminergic transmission produces a significant ratio change while a smaller perturbation is not detected by this index of neuronal metabolism.

3,4-Dihydroxyphenylacetic Acid↗

Heritable syndrome of pseudoxanthoma elasticum with abnormal phosphorus and vitamin D metabolism.

A patient with pseudoxanthoma elasticum was documented to be hyperphosphatemic and mildly hypercalcemic for six years. Complications included metastatic calcification, absorptive hypercalciuria, and renal insufficiency. The 1,25-dihydroxyvitamin D value was elevated, despite normal serum parathyroid hormone values, high serum phosphate levels, and renal insufficiency. Either increased dietary calcium or prednisone seemed to suppress the 1,25-dihydroxyvitamin D value. Nephrolithiasis or abnormalities suggestive of pseudoxanthoma elasticum occurred in the patient's father, daughter, and several siblings, suggesting a distinct familial syndrome in which connective tissue changes are accompanied by abnormalities of phosphorus and vitamin D metabolism that may resemble those in the syndrome of familial tumoral calcinosis. Nine similar cases were described before 1970.

Calcitriol↗

Resolution of steroid binding heterogeneity by Fourier-derived affinity spectrum analysis (FASA).

A new mathematical method of analyzing radioreceptor assay data is presented. When there are many binding classes with different affinities, the probability-density function B(p) is described by the equation B(p) = (integral negative infinity to infinity) q(k)f(p-k)dk, where q(k) is the affinity spectrum (density of a particular binding class as a function of affinity) and f(p-k) is a probability function (probability that dissociation constants will fall between k and p-k, where p is the free ligand concentration). This equation is solved for q(k) and evaluated explicitly by Fourier transformation, namely, q(w) = b(w)/f(w), where w is frequency. Since division by f(w) can amplify and high frequency noise present in the experimental data, a Gaussian smoothing function is introduced thus: qs(w) = q(w)e(-w/W0)2, where W0 is a constant. This produces an affinity spectrum defined as a plot of the number of binding sites, qs(k), versus their respective dissociation constants, k. Using a FORTRAN computer program, we verify this algorithm using simulated data. We also apply the procedure to resolve heterogeneous populations of estrogen binders in human endometrium using [3H]estradiol as ligand. Two estrogen binder classes are revealed with dissociation constants approximately 2.5 natural logarithmic units apart. We identify one high-affinity (Kd = 0.18 nM)-low density (70 pM [or 72 fmol/mg protein]) subpopulation and one low affinity (Kd = 2.5 nM)-high density (101 pM [or 102 fmol/mg protein]) subpopulation of estradiol binders. The management of experimental error, sampling limitations, and nonspecific binding are discussed. This method directly transforms experimental data into an easily interpretable representation without mathematical modeling or statistical procedures.

Endometrium↗

Hypothalamic dysfunction following whole-brain irradiation.

The authors describe 15 cases with evidence of hypothalamic dysfunction 2 to 9 years following megavoltage whole-brain x-irradiation for primary glial neoplasm. The patients received 4000 to 5000 rads in 180- to 200-rad fractions. Dysfunction occurred in the absence of computerized tomography-delineated radiation necrosis or hypothalamic invasion by tumor, and antedated the onset of dementia. Fourteen patients displayed symptoms reflecting disturbances of personality, libido, thirst, appetite, or sleep. Hyperprolactinemia (with prolactin levels up to 70 ng/ml) was present in all of the nine patients so tested. Of seven patients tested with thyrotropin-releasing hormone, one demonstrated an abnormal pituitary gland response consistent with a hypothalamic disorder. Seven patients developed cognitive abnormalities. Computerized tomography scans performed a median of 4 years after tumor diagnosis revealed no hypothalamic tumor or diminished density of the hypothalamus. Cortical atrophy was present in 50% of cases and third ventricular dilatation in 58%. Hypothalamic dysfunction, heralded by endocrine, behavioral, and cognitive impairment, represents a common, subtle form of radiation damage.

Adult↗

Hypothesis: aberrant puberty and the Stein-Leventhal syndrome.

We hypothesize that the Stein-Leventhal syndrome (type 1 polycystic ovarian disease: SLS-PCOD-I) results from an aberrant puberty. Abnormal neural development in the brain decreases the hypophyseal set-point for negative and positive ovarian hormone feedback. This generates a condition whereby hypophyseal luteinizing hormone (LH) secretion is inappropriately elevated compared to hypophyseal follicle-stimulating hormone (FSH) secretion and is thus termed inappropriate gonadotropin secretion (IGS). The events which create an initial state of IGS are referred to as the "generator" stage. IGS is maintained by ovarian-derived hyperandrogenemia and increased peripheral aromatization of androgens yielding elevated free serum estrone (E1) and unbound estradiol (E2) levels. E1 suppresses release of hypophyseal FSH while E2 exerts positive feedback on LH pulsatile release by increasing pituitary sensitivity to gonadotropin-releasing hormone (GnRH). Diminished circulating FSH levels decrease granulosa cell aromatase activity sufficiently to cause suboptimal ovarian conversion of LH-induced thecal androgens into estrogens. Consequently, chronic local ovarian hyperandrogenemia with associated arrested follicle maturation results in chronic anovulation. Furthermore, an elevated circulating LH/FSH ratio stimulates early development and proliferation of immature follicles causing the appearance of polyfollicular ovaries. In this effector stage of PCOD-I, a vicious cycle is fashioned wherein IGS causes polyfollicular ovaries and increased ovarian androgen production which, in turn, promotes IGS. We suggest that the etiology of this disease involves an aberrant puberty that establishes a persistent faulty hypothalamic-hypophyseal-ovarian axis.

Female↗

Parenteral nutrition formulation: an integral part of the endocrinologist's metabolic support consultation service.

Endocrinologists are uniquely suited to provide consultation in the new field of metabolic support. This specialty incorporates management of electrolyte and mineral disorders, diabetes mellitus, and malnutrition. Principles of formulation of parenteral nutrition are discussed, with an emphasis on distinguishing marasmus from kwashiorkor types of cachexia, disease-specific treatment, nutritional pharmacology, and relevant controversies.

Journal Article↗

Myotonic dystrophy presenting as male infertility: a case report.

A 28-year-old man presented with azoospermia, low plasma testosterone levels, and an elevated follicle stimulating hormone (FSH) concentration. Bilateral testicular biopsies revealed tubular atrophy with normal-appearing Leydig cells. One year later, symptoms and signs consistent with myotonic dystrophy (MyD) were noted. The rarity of male hypogonadism preceding the neurological manifestations of MyD is stressed.

Adult↗