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Biomedical subjects

P Kramer

Publications and source records attributed to P Kramer.

At least 19 recordsLinked to original sources
PubMed1998

Involvement of the Fas/Fas ligand pathway in activation-induced cell death of mycobacteria-reactive human gamma delta T cells: a mechanism for the loss of gamma delta T cells in patients with pulmonary tuberculosis.

Although the identity of T cells involved in the protection against Mycobacterium tuberculosis (Mtb) in humans remain unknown, patients with pulmonary tuberculosis (TB) have reduced numbers of Mtb-reactive, V gamma 9+/V delta 2+ T cells in their blood and lungs. Here we have determined whether this gamma deltaT loss is a consequence of Mtb Ag-mediated activation-induced cell death (AICD). Using a DNA polymerase-mediated dUTP nick translation labeling assay, 5% or less of freshly isolated CD4+ alpha beta or gamma delta T cells from normal healthy individuals and TB patients were apoptotic. However, during culture Mtb Ags induced apoptosis in a large proportion of V gamma 9+V delta 2+ peripheral blood T cells from healthy subjects (30-45%) and TB patients (55-68%); this was increased further in the presence of IL-2. By contrast, anti-CD3 did not induce any significant level of apoptosis in gamma delta T cells from healthy subjects or TB patients. Mtb Ag stimulation rapidly induced Fas and Fas ligand (FasL) expression by gamma delta T cells, and in the presence of metalloproteinase-inhibitors >70% of gamma delta T cells were FasL+. Blockade of Fas-FasL interactions reduced the level of Mtb-mediated gamma delta T cell apoptosis by 75 to 80%. Collectively, these findings demonstrate that Mtb-reactive gamma delta T cells are more susceptible to AICD and that the Fas-FasL pathways of apoptosis is involved. AICD of gamma delta T cells, therefore, provides an explanation for the loss of Mtb-reactive T cells during mycobacterial infection.

Adolescent↗
PubMed1998

Piezoelectric response of scleral collagen.

The piezoelectric coefficients (d31) for a number of bovine and human scleral collagen samples were determined as a function of drying time at room temperature. The measured values of d31 decreased with drying time. There were significant differences in the values of the d-coefficient between the human and bovine eyes as well as in the values obtained from different regions of the eye.

Animals↗
PubMed1998

Human growth-differentiation factor 3 (hGDF3): developmental regulation in human teratocarcinoma cell lines and expression in primary testicular germ cell tumours.

We describe the cloning and initial characterization of a novel cDNA from human embryonal carcinoma (EC) cells. This cDNA, which we named human growth differentiation factor 3 (hGDF3), encodes the homologue of mouse GDF3, a TGFbeta superfamily member belonging to the Growth/Differentiation Factors. We have analysed the expression of hGDF3 in human embryonal carcinoma cell lines and in primary testicular germ cell tumours of adolescents and adults (TGCTs). Expression of hGDF3 in human EC cell lines is stem cell-specific, is down-regulated upon RA-mediated differentiation and is increased upon culture of the cells in the presence of activin A. In TGCTs, hGDF3 expression is low in seminomas, while expression in non-seminomas is readily detectable and appears to be associated with the EC and yolk sac components in the tumours. We have also mapped the hGDF3 locus to the short arm of human chromosome 12, a region consistently overrepresented in human testicular germ cell tumours. Thus, hGDF3 represents an embryonal carcinoma stem cell-associated marker both in vitro and in vivo.

Activins↗
PubMed1998

Short-term vestibulo-ocular adaptation: influence of context.

A number of mechanisms and strategies are used to help an individual compensate for loss of labyrinthine function. One important example is the ability to produce a preplanned motor response that anticipates the motion of the head and so compensates for it. Closely tied to this phenomenon is the gating, in or out, of a learned response on the basis of the context in which it must occur. This issue is particularly relevant to designing programs of physical therapy that optimize performance for natural behavior. Here we discuss a model of short-term vestibulo-ocular adaptation-adjustment of vestibulo-ocular phase (timing)-and how it can be used to study context-dependent vestibulo-ocular learning. We will show how vestibulo-ocular phase can be adjusted by selectively altering the common velocity-to-position ocular motor neural integrator for one type of eye movement (vestibular) and not for another (saccades), or for one type of head movement (sinusoidal) and not for another (step). These results are another example of the remarkable flexibility of the vestibulo-ocular adaptive mechanism and further show that the fundamental process of integration for eye movements can be modified according to the pattern of afferent information.

Adaptation, Physiological↗
PubMed1998

Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA.

Congenital cataracts are a common major abnormality of the eye that frequently cause blindness in infants. At least a third of all cases are familial; autosomal dominant congenital cataract (ADCC) appears to be the most common familial form in the Western world. We have mapped an ADCC gene in family ADCC-2 to chromosome 21q22.3 near the alpha-crystallin gene CRYAA. By sequencing the coding regions of CRYAA, we found that a missense mutation, R116C, is associated with ADCC in this family.

Amino Acid Sequence↗
PubMed1998

Effect of prenatal exposure to diethylstilbestrol on Müllerian duct development in fetal male mice.

The clinical use of diethylstilbestrol (DES) by pregnant women has resulted in an increased incidence of genital carcinoma in the daughters born from these pregnancies. Also, in the so-called DES-sons abnormalities were found, mainly, the presence of Müllerian duct remnants, which indicates that fetal exposure to DES may have an effect on male sex differentiation. Fetal regression of the Müllerian ducts is under testicular control through anti-Müllerian hormone (AMH). In male mice, treated in utero with DES, the Müllerian ducts do not regress completely, although DES-exposed testes do produce AMH. We hypothesized that incomplete regression in DES-exposed males is caused by a diminished sensitivity of the Müllerian ducts to AMH. Therefore, the effect of DES on temporal aspects of Müllerian duct regression and AMH type II receptor (AMHRII) messenger RNA (mRNA) expression in male mouse fetuses was studied. It was observed that Müllerian duct regression was incomplete at E19 (19 days post coitum), upon DES administration during pregnancy from E9 through E16. Furthermore, analysis of earlier time points of fetal development revealed that the DES treatment had clearly delayed the onset of Müllerian duct formation by approximately 2 days; in untreated fetuses, Müllerian duct formation was complete by E13, whereas fully formed Müllerian ducts were not observed in DES-treated male fetuses until E15. Using in situ hybridization, no change in the localization of AMH and AMHRII mRNA expression was observed in DES-exposed male fetuses. The mRNA expression was quantified using ribonuclease protection assay, showing an increased expression level of AMH and AMHRII mRNAs at E 13 in DES-exposed male fetuses. Furthermore, the mRNA expression levels of Hoxa 11 and steroidogenic factor-1 (SF-1) were determined as a marker for fetal development. Prenatal DES exposure had no effect on Hoxa 11 mRNA expression, indicating that DES did not exert an overall effect on the rate of fetal development. In DES-exposed male fetuses, SF-1 showed a similar increase in mRNA expression as AMH, in agreement with the observations that the AMH gene promoter requires an intact SF-1 DNA binding site for time- and cell-specific expression, although an effect of DES on SF-1 expression in other tissues, such as the adrenal and pituitary gland, cannot be excluded. However, the increased expression levels of AMH and AMHRII mRNAs do not directly explain the decreased sensitivity of the Müllerian ducts to AMH. Therefore, it is concluded that prenatal DES exposure of male mice delays the onset of Müllerian duct development, which may result in an asynchrony in the timing of Müllerian duct formation, with respect to the critical period of Müllerian duct regression, leading to persistence of Müllerian duct remnants in male mice.

Animals↗
PubMed1997

Infections after renal allograft failure in patients with or without low-dose maintenance immunosuppression.

BACKGROUND: Failed renal allografts are sometimes left in situ for additional clearance and urine production during hemodialysis or peritoneal dialysis, and low-dose immunosuppressive medication is often continued in such patients. We compared the morbidity and mortality due to infections between patients with (group A) or without (group B) low-dose immunosuppression (i.e., transplantectomy). METHODS: In a hospital-based cohort study, we analyzed data from patient files. We evaluated 37 patients who received 42 kidney transplantations between May 1975 and November 1995. RESULTS: A total of 2.28 vs. 0.68 infections/patient-year were found in groups A and B, respectively. The odds ratio of one or two infections developing for patients in group A compared with group B was 14.2 (95% confidence interval, 1.4-143.4; P<0.025) and 4.3 (95% confidence interval, 1.1-17.3; P<0.04). A total of five lethal infections were found in group A; no lethal infections were found in group B. CONCLUSIONS: The increase in serious and life-threatening infections associated with even low-dose immunosuppression argues in favor of discontinuation of these drugs. The removal of failed renal allografts should be considered.

Adult↗
PubMed1997

Autosomal dominant cerulean cataract is associated with a chain termination mutation in the human beta-crystallin gene CRYBB2.

Congenital cataracts are a common major abnormality of the eye that frequently cause blindness in infants. At least a third of all cases are familial; autosomal dominant congenital cataract (ADCC) appears to be the most common familial form in the Western world. Cerulean cataracts have peripheral bluish and white opacifications in concentric layers with occasional central lesions arranged radially. Although the opacities may be observed during fetal development and childhood, usually visual acuity is only mildly reduced until adulthood, when lens extraction is generally necessary. We have been studying a family (ADCC-1) with cerulean blue ADCC, in which the affected daughter of a first cousin mating was presumed to be homozygous for the cataract gene. Recently, we mapped an ADCC gene in this family to a region of chromosome 22 containing three beta-crystallin genes. Here we report that a chain-termination mutation in CRYBB2 is associated with ADCC in this family.

Amino Acid Sequence↗
PubMed1997

Induction of superovulation in cyclic rats by administration of decreasing doses of recombinant follicle stimulating hormone (Org32489).

The objective of this study was to set up a superovulation protocol in adult cyclic rats by using recombinant human follicle stimulating hormone (rhFSH; Org32489). Good results were obtained by treatment with decreasing doses of rhFSH (2.5 to 0.5 IU) during the dioestrus period. The number of corpora lutea (CL) found in rats treated with this protocol was 43.5 +/- 3.4; this is more than three times the number in saline-treated control rats (13.0 +/- 0.4). Fertilization of oocytes after superovulation was as good as after normal ovulation in terms of number of 2-cell stage embryos found 2 days after mating. The absolute number of implantations was twice the number observed in saline-treated control rats (23.3 +/- 1.8 versus 10.6 +/- 0.5); therefore the number of implantations per CL was lower in superovulated rats. The serum concentrations of luteinizing hormone (LH), endogenous FSH and oestradiol-17beta were decreased during rhFSH treatment, while the inhibin serum concentration was increased. The progesterone serum concentration was increased on the days of pro-oestrus and oestrus after treatment. No difference was observed in the testosterone serum concentration. Pretreatment with 10 IU rhFSH at oestrus before giving the decreasing doses of rhFSH during dioestrus reduced the ovulatory response. Finally, treatment with a constant low dose of rhFSH instead of a decreasing dose of rhFSH did not result in spontaneous ovulation. However, ovulation induction by means of a human chorionic gonadotrophin bolus resulted in superovulation in six out of eight rats. It is concluded that superovulation in cyclic rats can be achieved using rhFSH treatment. However, it was found that the type of rhFSH regimen was very important to achieve appropriate stimulation. The optimal protocol was treatment with decreasing doses of rhFSH during dioestrus. The oocytes retrieved could be fertilized as well as oocytes of saline-treated control rats. The results also indicate that treatment with higher doses of rhFSH might induce a desensitization for FSH and LH.

Animals↗
PubMed1997

Effects of progesterone on the secondary surge of follicle-stimulating hormone in the rat.

In the cyclic rat, the secondary surge of FSH on estrus appears to depend on the LH surge-induced fall in serum concentrations of inhibin. To investigate the involvement of progesterone in the regulation of the secondary surge of FSH, 4-day cyclic rats were treated on proestrus with an antagonist of LHRH (LHRHant) and with an ovulatory dose of ovine (o) LH, progesterone, the antiprogestin RU486, or the combination of RU486 and oLH. Serum concentrations of gonadotropins and inhibin at 1830 h on proestrus and at 0030 h on estrus were determined, and the expression of inhibin/activin subunit mRNAs in the ovary at 0030 h on estrus was analyzed by in situ hybridization. Rats receiving saline showed low expression of alpha-, beta(A)-, and beta(B)-subunit mRNAs in the ovary and low serum levels of inhibin in conjunction with the elevated serum concentrations of FSH on estrus. Administration of LHRHant blocked the decrease in the synthesis and secretion of inhibin and abolished the FSH secondary surge, whereas the injection of oLH prevented these effects. Exogenous progesterone, compared with LHRHant injection, increased alpha-, beta(A)-, and beta(B)-subunit mRNA hybridization intensity in the ovary and serum inhibin immunoreactivity, and also restored, in part, the surge of FSH on estrus. The antiprogestin RU486 did not modify the effect of oLH on either inhibin/ activin subunit mRNAs in the ovary or serum levels of inhibin, but blocked the FSH surge. These results indicate that, in the cyclic rat, 1) the secretion of progesterone on proestrous afternoon, induced by the LH surge, is not involved in the fall of ovarian inhibin synthesis and secretion; and 2) in combination with a drop in serum inhibin, a stimulatory action of progesterone on another factor, possibly pituitary activin, could be necessary to elicit a complete secondary surge of FSH.

Animals↗
PubMed1997

Fine localization of the torsion dystonia gene (DYT1) on human chromosome 9q34: YAC map and linkage disequilibrium.

The DYT1 gene, which maps to chromosome 9q34, appears to be responsible for most cases of early-onset torsion dystonia in both Ashkenazic Jewish (AJ) and non-Jewish families. This disease is inherited in an autosomal dominant mode with reduced penetrance (30%-40%). The abnormal involuntary movements associated with this disease are believed to be caused by unbalanced neural transmission in the basal ganglia. Previous linkage disequilibrium studies in the AJ population placed the DYT1 gene in a 2-cM region between the loci D9S62a and ASS. A YAC contig has now been created spanning 600 kb of this region including D9S62a. The location of the DYT1 gene has been refined within this contig using several new polymorphic loci to expand the linkage disequilibrium analysis of the AJ founder mutation. The most likely location of the DYT1 gene is within a 150 kb region between the loci D9S2161 and D9S63.

Adult↗
PubMed1997

Episodic secretion of parathyroid hormone in postmenopausal women: assessment by deconvolution analysis and approximate entropy.

In health young subjects, parathyroid hormone (PTH) is secreted presumptively in a dual fashion, with low amplitude pulses apparently superimposed on tonic secretion. In contrast, PTH secretion has not been as well characterized in postmenopausal women, and relationships among bone density, estrogen status, and PTH release have not been explored. It is possible that a pulsatile pattern of PTH secretion is important for bone remodeling, since exogenous PTH administered in a pulsatile manner stimulates bone formation. To assess the importance of pulsatile PTH secretion as a determinant of bone mass, we measured PTH in blood sampled every 2 minutes for 6 h in four groups of older women: (1) high bone density receiving estrogen (n = 6), (2) high bone density not receiving estrogen (n = 5), (3) low bone density receiving estrogen (n = 6), and (4) low bone density not receiving estrogen (n = 8). The plasma PTH release profiles were subjected to deconvolution analysis, which resolves measured hormone concentrations into secretion and clearance components, and to an approximate entropy (ApEn) estimate, which provides an ensemble measure of the serial regularity or orderliness of the release process. In postmenopausal subjects, PTH was secreted in a fashion similar to that observed in young adults, with significant tonic secretion and PTH pulse occurrences averaging every 18-19 minutes. Pulsatile PTH secretion accounted for approximately 25% of the total secreted PTH. There were no differences in the amplitude or frequency of pulsatile PTH secretory parameters or in ApEn values among the four groups or compared with young controls. We conclude that in postmenopausal women, PTH secretory patterns and temporal organization are similar to those in healthy young subjects and are not altered in states of low bone density or estrogen deficiency. This suggests that abnormalities in orderly pulsatile PTH secretion are unlikely to play a major role in established postmenopausal osteoporosis.

Adult↗
PubMed1997

Significance of oestradiol for follicular development in hypogonadotrophic immature rats treated with FSH and hCG.

Administration of hCG (0.5 i.u.) to immature female rats that were made hypogonadotrophic by injections of an LHRH-antagonist at 22, 24, 26 and 28 days of age and in which follicular development was induced by FSH (10 i.u., given from day 26 until day 29) stimulates follicles to grow to their preovulatory size with a low amount of atresia. To investigate whether this effect of hCG on follicular growth is due to stimulation of oestradiol production, intraovarian concentrations of oestradiol were suppressed by an aromatase inhibitor and oestradiol action was blocked by an oestrogen antagonist; both of these were administered from day 25 until day 29. By day 30 this treatment had resulted in an increase in the percentage of atretic follicles. In turn, oestradiol benzoate (100 micrograms or 1000 micrograms day-1), given from day 26 until day 29 in rats treated with 10 i.u. FSH, resulted in (1) an increase in the total number of antral follicles, (2) an increase in follicular size and (3) a decrease in the percentage of atretic follicles. Although the administration of 1000 micrograms oestradiol benzoate can mimic the effects of 0.5 i.u. hCG on follicular growth to a large extent, the number of follicles with a diameter > 575 microns in rats treated with FSH plus oestrogen was smaller than that in rats treated with FSH plus hCG (10 +/- 2 and 24 +/- 2, respectively). Furthermore, a single injection of 10 i.u. hCG given on day 29 was used to induce ovulation: fewer ova were found in rats treated with FSH plus 1000 micrograms oestrogen than in rats treated with FSH plus hCG (15.2 +/- 2.1 and 46.5 +/- 1.6, respectively). From these studies, it is concluded that the effects of hCG on follicular growth and atresia can be largely attributed to the mitotic and anti-atretic effect of oestradiol. However, part of the effect of hCG cannot be explained on the basis of oestradiol action.

Animals↗
PubMed1997

Perceptual grouping in space and time: evidence from the Ternus display.

We report three experiments investigating the effect of perceptual grouping on the appearance of a bistable apparent-motion (Ternus) display. Subjects viewed a Ternus display embedded in an array of context elements that could potentially group with the Ternus elements. In contrast to several previous findings, we found that grouping influenced apparent motion perception. In Experiment 1, apparent motion perception was significantly affected via grouping by shape similarity, even when the visible persistence of the elements was controlled. In Experiment 2, elements perceived as moving without context were perceived as stationary without context were perceived as moving when grouped with moving elements perceived as stationary without context were perceived as moving when grouped with moving context elements. We argue that grouping in the spatial and temporal domains interact to yield perceptual experience of apparent-motion displays.

Adult↗
PubMed1996

A second gene for cerulean cataracts maps to the beta crystallin region on chromosome 22.

Congenital cataracts are one of the most common major eye abnormalities and often lead to blindness in infants. At least a third of all cases are familial. Within this group, highly penetrant, autosomal dominant forms of congenital cataracts (ADCC) are most common. ADCC is a genetically heterogeneous group of disorders, in which at least eight different loci have been identified for nine clinically distinct forms. Among these, Armitage et al. (Nature Genet. 9: 37-40, 1995) mapped a gene for cerulean blue cataracts to chromosome 17q24. Bodker et al. (Am. J. Med. Genet. 37: 54-59, 1990) described a large family with cerulean blue cataracts, in which the affected daughter of affected first cousins was presumed to be homozygous for the purported gene. We report linkage in this family to the region on chromosome 22q that includes two beta crystallin genes (CRYBB2, CRYBB3) and one pseudogene (CRYBB2P1). The affected female in question is homozygous at all markers.

Cataract↗
PubMed1996

Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13.

Hallervorden-Spatz syndrome (HSS) (OMIM #234200) is a rare, autosomal recessive neurode-generative disorder with brain iron accumulation as a prominent finding. Clinical features include extrapyramidal dysfunction, onset in childhood, and a relentlessly progressive course. Histologic study reveals massive iron deposits in the basal ganglia. Systemic and cerebrospinal fluid iron levels are normal, as are plasma levels of ferritin, transferrin and ceruloplasmin. Conversely, in disorders of systemic iron overload, such as haemochromatosis, brain iron is not increased, which suggests that fundamental differences exist between brain and systemic iron metabolism and transport. In normal brain, non-haem iron accumulates regionally and is highest in basal ganglia. Pathologic brain iron accumulation is seen in common disorders, including Parkinson's disease, Alzheimer's disease and Huntington disease. In order to gain insight into normal and abnormal brain iron transport, metabolism and function, our approach was to map the gene for HSS. A primary genome scan was performed using samples from a large, consanguineous family (HS1) (see Fig. 1). While this family was immensely powerful for mapping, the region demonstrating homozygosity in all affected members spans only 4 cM, requiring very close markers in order to detect linkage. The HSS gene maps to an interval flanked by D20S906 and D20S116 on chromosome 20p12.3-p13. Linkage was confirmed in nine additional families of diverse ethnic backgrounds.

Chromosome Mapping↗