Localization of parathyroid tumours.
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Adenoma↗
Biomedical subjects
D A Heath
Publications and source records attributed to D A Heath.
Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.
Familial benign hypercalcemia (FBH) and neonatal hyperparathyroidism (NHPT) are disorders of calcium homeostasis that are associated with missense mutations of the calcium-sensing receptor (CaR). We have undertaken studies to characterize such CaR mutations in FBH and NHPT and to explore methods for their more rapid detection. Nine unrelated kindreds (39 affected, 32 unaffected members) with FBH and three unrelated children with sporadic NHPT were investigated for mutations in the 3,234-bp coding region of the CaR gene by DNA sequencing. Six novel heterozygous (one nonsense and five missense) mutations were identified in six of the nine FBH kindreds, and two de novo heterozygous missense mutations and one homozygous frame-shift mutation were identified in the three children with NHPT. Our results expand the phenotypes associated with CaR mutations to include sporadic NHPT. Single-stranded conformational polymorphism analysis was found to be a sensitive and specific mutational screening method that detected > 85% of these CaR gene mutations. The single-stranded conformational polymorphism identification of CaR mutations may help in the distinction of FBH from mild primary hyperparathyroidism which can be clinically difficult. Thus, the results of our study will help to supplement the clinical evaluation of some hypercalcemic patients and to elucidate further the structure-function relationships of the CaR.
Amino Acid Sequence↗
Plasma FSH, LH and immunoreactive inhibin concentrations in FecBB/FecBB and FecB+/FecB+ Booroola ewes and rams from birth to 12 months of age.
Endocrine and developmental changes were examined in Booroola FecBB/FecBB (BB, n = 16) and FecB+/FecB+ (++, n = 20) ewe lambs, and BB (n = 17) and ++ (n = 19) ram lambs from 2 to 53 weeks of age. Blood samples were taken weekly for the measurement of plasma concentrations of FSH, LH, immunoreactive inhibin, progesterone (ewe lambs) and testosterone (ram lambs). Behavioural oestrus in the ewe lambs and testicular volume and the breakdown of foreskin adhesions in ram lambs were recorded. Blood samples were taken from another flock of BB (n = 134) and ++ (n = 109) ram lambs at 20 weeks of age for the analysis of immunoreactive inhibin. In ewe and ram lambs, there appeared to be genotype differences for FSH, LH and immunoreactive inhibin at specific times during the neonatal period. In BB and ++ ewe lambs, respectively, mean FSH concentrations were 4.3 and 2.0 ng ml-1 (SED 0.54) between 4 and 6 weeks, 2.6 and 3.4 ng ml-1 (SED 0.33) between 12 and 28 weeks, and 1.8 and 1.9 ng ml-1 (SED 0.18) between 34 and 53 weeks of age. Mean plasma LH concentrations were lower in BB than in ++ ewe lambs from 26 to 53 weeks of age (P < 0.05) but not earlier. Mean concentrations of immunoreactive inhibin were also lower in BB than in ++ ewe lambs between 2 and 11 weeks (16.0 and 27.4 iu ml-1, respectively; P < 0.01), but thereafter no differences were apparent.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Expression of gonadotrophin subunit genes in sheep that were homozygous carriers and non-carriers of the Booroola fecundity gene FecB.
Homozygous carriers (BB) of the Booroola fecundity gene FecB are characterized by high plasma concentrations of immunoreactive or biologically active FSH and, to a lesser extent, of immunoreactive LH, relative to non-carriers (++). Bovine cDNA probes for the alpha gonadotrophin, FSH beta and LH beta genes were used to investigate FecB-specific differences in the mRNA species for the gonadotrophin subunits in pituitaries obtained from ++ and BB mid-luteal phase ovary-intact ewes, ovariectomized ewes and ovary-intact or ovariectomized ewes with hypothalamic-pituitary disconnection (HPD) given the same regimen of pulsatile GnRH. No FecB-specific differences in the number or size of mRNA transcripts detected by northern blotting were noted for any of these genes. Densitometry of the northern blots revealed no significant FecB-specific differences in the relative amounts of mRNA encoding alpha gonadotrophin, FSH beta or LH beta in the pituitaries from any of the experimental groups of ++ and BB sheep. Furthermore, there were no significant FecB-specific differences in the pituitary content of FSH or LH in these animals, despite significantly higher plasma concentrations of FSH in the ovary-intact and ovariectomized HPD groups. These data show that whereas the FecB gene causes increased plasma concentrations of FSH, no consistent effects can be demonstrated on pituitary gonadotrophin content or on gonadotrophin subunit gene transcription, using northern analysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Development of the sheep ovary during fetal and early neonatal life and the effect of fecundity genes.
In female sheep fetuses, the mesonephros and genital ridge can be identified at days 20 and 23 of gestation (term = 145 days), respectively. Moreover oogonia can be observed at the genital ridge from as early as day 23. Around day 55 of gestation, some germ cells enter meiosis coincident with the arrival of mesonephric-derived somatic cells (i.e. the rete ovarii). From day 75, 100, 120 and 135 of gestation, primordial (one layer of flattened granulosa cells), primary (one complete layer of cuboidal granulosa cells; early preantral), secondary (preantral) and tertiary (antral) follicles, respectively, develop within the innermost regions of the ovarian cortex. During the early neonatal period highly variable numbers of antral follicles may be present. After examination of Booroola fetuses from day 28 of gestation, it seems that the FecBB gene is associated with retarded development of the heart (day 28) mesonephros (days 30-40) and from day 30 to early neonatal life, the ovary. With respect to the ovary, fewer oogonia (days 30-40), primordial follicles (day 75-90) and growing follicles (day 120 to 6 weeks after birth) have been observed in females carrying the FecBB gene. By contrast, the FecBB gene is not associated with differences in plasma gonadotrophin or immunoreactive inhibin until early neonatal life. In Inverdale (I) fetuses heterozygous for the FecXI gene (I+), retarded germ cell development was observed at days 40 and 90 of gestation. In putative homozygous carriers (II) of the Inverdale gene, germ cell development appeared normal until day 100, but thereafter from day 120 normal secondary follicles were not observed, although many abnormal follicular-like structures were present. In both I+ and II fetuses no obvious differences in gonadotrophin concentrations have been noted. Collectively, the evidence suggests that the fecundity genes FecBB and FecXI, which affect ovulation rate in sexually mature females, are regulating organ differentiation or germ cell maturation or both processes during fetal life.
Animals↗
Parathyroid hormone-related protein gene expression in invasive cervical tumors.
BACKGROUND: Parathyroid hormone-related protein (PTHrP) is the main tumor-derived factor responsible for the hypercalcemia of malignancy. METHODS: Using a polyclonal serum to the 37-67 region of PTHrP, and 35S-labeled riboprobes, the authors investigated the cellular expression of PTHrP mRNA and peptide in formalin fixed, paraffin embedded sections from 16 invasive cervical tumors. In addition, the relationship among the histologic cell type, degree of differentiation, pattern of invasion, and tumor expression of PTHrP were examined. RESULTS: PTHrP mRNA and peptide were identified in 10 of 10 and 16 of 16 tumors examined, respectively. Overall strong mRNA expression with moderate to intense intracellular staining for peptide was associated, with adenosquamous carcinoma displaying a spray pattern of invasion. CONCLUSION: PTHrP mRNA and peptide were observed in all cervical tumors studied. Despite their high frequency of expression of PTHrP, cervical tumors seldom give rise to humoral hypercalcemia of malignancy, but the autocrine/paracrine effects of PTHrP may be important in the growth and dedifferentiation of the malignant cell population.
Carcinoma, Adenosquamous↗
Cardiopulmonary resuscitation: who makes the decision?
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Adult↗
Parathyroid hormone related protein (PTHrP) gene expression in fetal and extra-embryonic tissues of early pregnancy.
Parathyroid hormone related protein (PTHrP) is an important humoral factor in hypercalcaemia of malignancy. In addition there is increasing evidence that this peptide has a physiological role in fetal development, especially in cellular growth and differentiation. Both in-situ hybridization and immunohistochemistry were used together and for the first time to identify sites of PTHrP gene expression and peptide in fetal and extra-embryonic tissues of first trimester human pregnancy. PTHrP mRNA and peptide were identified in the avascular amnion and the syncytiotrophoblast while mRNA alone was expressed in the cytotrophoblast. Its expression in these extra-embryonic tissues is consistent with postulated roles for PTHrP in implantation, relaxation of endometrial muscle and regulation of vascular tone. Expression of both mRNA and peptide occurred in endo-, meso- and ectodermal structures of the fetus, consistent with local production of the peptide rather than cellular uptake from amniotic fluid and supporting a role for PTHrP in cellular growth and differentiation.
Cell Differentiation↗
Apoptosis in bovine granulosa cells in relation to steroid synthesis, cyclic adenosine 3',5'-monophosphate response to follicle-stimulating hormone and luteinizing hormone, and follicular atresia.
Apoptosis is a process of selective cell deletion implicated as a mechanism underlying the process of ovarian follicular atresia. The aims of this study were 1) to test the hypothesis that granulosa cell death during follicular (> or = 4 mm diameter) atresia in cows occurs by apoptosis and 2) to define relationships between the occurrence and degree of granulosa cell apoptosis, cAMP response to FSH or LH, extant aromatase activity, and other previously established biochemical and morphometric indices of granulosa cell function and follicular atresia in this species. Granulosa cells and follicular fluid from individual follicles 4-18 mm in diameter were collected from luteal-phase cow ovaries. Follicles were classified by morphometric criteria as "healthy" (n = 45) or atretic (n = 34). Apoptosis in granulosa cells from each follicle was inferred from detection of internucleosomal DNA cleavage by 3'-end radiolabeling; it was quantitated both subjectively from intensity of oligonucleosome labeling (apoptosis [AP] score = 0, 1, 2, or 3) and objectively by beta-counting of low-molecular weight gel fragments (labeling index; LI). Extant aromatase activity (ng estradiol produced/10(6) cells/3 h) and cAMP response (pmol/10(6) cells) to different doses of FSH or LH (1-10,000 ng/ml) was determined for granulosa cells from most healthy follicles (n = 39). Apoptosis was detected in granulosa cells from all atretic follicles as well as from 76% of healthy follicles, from 80% (16 of 20) of follicles with follicular fluid estradiol to progesterone ratios > 1, and from 71% (10 of 14) of follicles with extant aromatase activity (> 2 ng/10(6) cells/3 h). For healthy and atretic follicles, degree of DNA fragmentation was inversely related to the number of granulosa cells recovered (as percentage maximum by follicle size). In healthy follicles, FSH stimulated cAMP synthesis is a dose-dependent manner in granulosa cells from all follicles examined (> or = 4 mm), but only 36% of these had appreciable aromatase activity. The cAMP response to FSH (per cell) increased with follicle size from 4-7 mm in diameter and remained high in granulosa cells from follicles > or = 8 mm with aromatase activity; in cells without aromatase activity, cAMP response to FSH decreased with increasing follicle size > or 8 mm. The cAMP response to LH was generally low or undetectable in granulosa cells from 4-8-mm follicles; it then increased linearly with increasing follicle diameter > or = 8 mm, but to a greater degree in cells with aromatase activity than in cells without.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
An investigation of spinal bone mineral density measured laterally: a normal range for UK women.
A UK normal range for 250 volunteers was established for bone mineral density (BMD) of the lumbar spine (L2-L4) measured laterally in the decubitus position. Two software defined regions of interest ("Body" and "Mid") within the vertebral body were analysed throughout. As expected, a negative correlation of BMD with age was found for Body (r = -0.55, p < 0.001) and Mid (r = -0.56, p < 0.001). The age related bone loss from young to old (20-80 years) was 40% in L3 (Body) and 45% in L3 (Mid). In 22% of the cases only L3 could be measured owing to the influence of rib over L2 and interference of the iliac crest over L4. Age related normal ranges (+/- 2 standard deviations) for the three lumbar vertebra L2, L3, L4 for young normals (age 19-39 years) were found to be 0.54 to 1.02, 0.49 to 1.05 and 0.5 to 1.14 g cm-2 respectively for the Body region and 0.49 to 0.97, 0.45 to 1.01 and 0.45 to 1.13 g cm-2 respectively for the Mid region. These ranges can now be used as reference values for patients with suspected osteoporosis and possibly for future fracture prediction. The in vivo precision in 19 volunteers was found to be 4.2% and 5.6% on Body and Mid respectively. The short term (less than 1 week) in vitro precision was 3.1% and 2.7% respectively. From these data it appears that there is a greater measured age related drop in BMD in the vertebral body (measured laterally) than in the entire vertebra (measured anterior-posteriorly) indicating that the lateral measurement may prove to be more sensitive in predicting fracture. The precision of these results indicates that lateral measurements of the spine are not yet useful for monitoring individuals over short term periods and are less useful for studying the effects of drug treatment than the more traditional anterior-posterior measurement of the spine and femur.
Absorptiometry, Photon↗
Ontogeny of ovarian follicle development in Booroola sheep fetuses that are homozygous carriers or non-carriers of the FecB gene.
The aims of this study were to examine the effects of the Booroola FecB gene on ovarian development and reproductive hormones (FSH, LH and inhibin) at days 90, 100, 120 and 135 of gestation (term = 147 days). The effects of litter size were eliminated by transferring equal numbers of homozygous BB and control (++) embryos to recipient ewes. The ovary, but not the body, pituitary, adrenal, kidney or thymus, was heavier (P < 0.05) in BB compared with ++ fetuses at day 90 but not thereafter. In the ovary, gene-specific differences were observed in the total number of germ cells present at days 90 (P < 0.01) and 135 (P < 0.05) with the same tendency being noted at day 100 (P < 0.07); at all of these ages the mean numbers of germ cells in the BB genotype exceeded those in ++ animals. Gene-specific differences were observed in the numbers of oogonia and isolated oocytes at day 90 (i.e. BB > ++), in the number of primordial follicles at days 100 (BB > ++) and 135 (BB > ++), and also in the number of primary or secondary follicles (++ > BB) at day 135. At each gestational age examined no differences were noted with respect to the plasma concentrations of FSH, LH or inhibin between the BB and ++ fetuses. However, the highest mean plasma concentrations of FSH and LH occurred at days 90 and 100 of gestation, which coincided with the first developing primary follicles.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Developing innovative programs for unique student populations.
BACKGROUND: Optometric education has been faced with ever-increasing expectations. These include the ability to educate students and practitioners to care for new patient populations, deal with more diverse and complex clinical problems, to be significant participants in the research community and to fulfill leadership positions within the profession. To fulfill this expectation, schools and colleges need to diversify their program offerings to attract and educate unique student populations who come from diverse backgrounds and bring a range of pre-existing knowledge and skills. RESULTS: This paper provides an overview of The New England College of Optometry's efforts in this area and two programs, the "Advanced Standing International Program" and the "Accelerated Doctor of Optometry Degree Program," are examined in detail. An emphasis is placed on outcomes assessment to ensure the programs are fulfilling their purpose and the results of a retrospective analysis of the two programs is provided.
Curriculum↗
Sulfasalazine induced seizures and dysphasia.
We describe the case of a 46-year-old woman with rheumatoid arthritis who developed a severe reaction to sulfasalazine, characterized by dysphasia, seizures, rash and the development of strongly positive pANCA (perinuclear antineutrophil cytoplasmic antibodies). Her condition improved spontaneously upon withdrawal of sulfasalazine. Dysphasia has not been reported as a side effect of sulfasalazine.
Antibodies, Antineutrophil Cytoplasmic↗
Hypercalcaemia associated with calcipotriol (Dovonex) treatment.
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Aged↗
Parathyroid hormone-related protein (PTHrP) gene expression in solid tumours associated with normocalcaemia and hypercalcaemia.
Parathyroid hormone-related protein (PTHrP) is an important humoral factor in the syndrome of humoral hypercalcaemia of malignancy (HHM) and its importance is evident by the many studies examining either PTHrP mRNA expression, intracellular peptide, or circulating PTHrP levels in patients with malignancy. However, the relationship between PTHrP mRNA expression, intracellular localization of peptide, and circulating PTHrP levels in the same group of patients with malignancy has not been examined. This study was carried out to explore this relationship in a group of patients with solid tumours associated with either normocalcaemia or hypercalcaemia. PTHrP mRNA and peptide were localized by in situ hybridization and immunohistochemistry respectively in 26 squamous carcinomas and 15 adenocarcinomas from patients who were either hypercalcaemic or normocalcaemic. Plasma PTHrP1-86 and serum PTH1-84 concentrations were measured by two-site immunoradiometric assays. PTHrP mRNA and peptide were localized in 11 (100 per cent) and 10 (91 per cent) of 11 squamous tumours from hypercalcaemic patients, all of whom had detectable circulating PTHrP levels, and in 14 (97 per cent) and 11 (73 per cent) respectively of 15 squamous tumours from normocalcaemic patients. PTHrP mRNA and peptide were localized in only two (28 per cent) and four (57 per cent) respectively of seven adenocarcinomas associated with hypercalcaemia. Since the majority of squamous tumours synthesized PTHrP irrespective of the calcium status of the patient, this suggests that the clinical expression of tumour-derived PTH-like bioactivity may depend on the rate of secretion of PTHrP rather than gene expression, and that the bioactivity of secreted PTHrP may be modulated by post-translational processing.
Adenocarcinoma↗
Osteoporosis: current controversies and future trends.
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Bone Density↗
Plasma gonadotropin concentrations and ovarian characteristics in Inverdale ewes that are heterozygous for a major gene (FecX1) on the X chromosome that influences ovulation rate.
Ewes heterozygous (I+) for the Inverdale prolificacy gene (FecX1) located on the X chromosome have ovulation rates approximately 1.0 times higher than noncarriers (++). The aims of this study were to examine, in I+ and ++ ewes, the peripheral plasma concentrations and/or ovarian secretion rates of FSH, LH, inhibin, estradiol, and progesterone during anestrus and the estrous cycle and after ovariectomy. Also examined were aspects of ovarian morphology and functions of granulosa cells in vitro. No FecX1-specific differences were noted for the ovarian hormones or for FSH or LH. However, I+ animals contained significantly more ovarian antral follicles (p < 0.05) and their granulosa cells had a higher mean LH responsiveness in vitro with respect to cAMP synthesis at smaller follicular diameters relative to ++ ewes (I+ = > 2.5 mm; ++ = > 4.5 mm). Moreover, nonatretic follicles in I+ animals compared to the ++ genotype contained fewer granulosa cells and smaller CL. Although the I+ animals had a higher ovulation rate than the controls (p < 0.05), the total weight of CL was not different between the genotypes. These findings suggest that the FecX1 gene affects ovarian function without altering ovarian hormone secretion. The findings also suggest that there are no FecX1-specific differences in the mean concentrations of gonadotropins, although further studies on temporal changes in gonadotropin secretion are warranted.
Animals↗
Ovaries of ewes homozygous for the X-linked Inverdale gene (FecXI) are devoid of secondary and tertiary follicles but contain many abnormal structures.
Ewes homozygous (II) for the Inverdale prolificacy gene (FecXI) located on the X chromosome are infertile with "streak" ovaries. The aims of this study were to examine the ovarian morphology and plasma and tissue (or extracellular fluid) hormone concentrations in II ewes in comparison to control (++) animals. All II animals (n = 11) were found to contain no normal ovarian follicles beyond the primary stage of development despite their being similar in number of germ cells to the ++ ewes. The II animals had high plasma gonadotropin levels and undetectable estradiol and progesterone, and in addition 6 of 9 ewes had undetectable plasma inhibin concentrations. II ewes contained large numbers of oocyte-free follicles ("nodules") that were often found as clusters in the innermost regions of the cortex. In addition, 6 of 11 ewes contained abnormal luteal- or granulosa cell-like structures and other unusual formations. In three II animals the abnormal structures were visible on the ovarian surface, and the plasma inhibin concentrations in these ewes were significantly higher than in the ++ ewes (p < 0.05). Collectively these findings suggest that two copies of the FecXI mutation impair the resumption of growth of primordial follicles and may in some instances lead to the development of abnormal structures having a morphology consistent with that observed for ovarian tumors.
Animals↗