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Biomedical subjects

S Mäkelä

Publications and source records attributed to S Mäkelä.

At least 19 recordsLinked to original sources
PubMed2004

Mutational analysis of the human SLC26A8 gene: exclusion as a candidate for male infertility due to primary spermatogenic failure.

SLC26A8 is an anion transporter that is solely expressed in the testes. It interacts with MgcRacGAP that shows strong structural similarity with the Drosophila protein RotundRacGAP, which is established to have an essential role for male fertility in the fruit fly. To explore whether the SLC26A8 gene has a role in human male infertility, we performed mutational analysis in the coding region of the SLC26A8 gene in 83 male infertility patients and two groups of controls using single-strand conformational polymorphism and direct sequencing methods. We found six novel coding sequence variations, of which five lead to amino acid substitutions. All variants were found with similar frequencies in both patients and controls, thus suggesting that none of them may be causally associated with infertility. We conclude that the SLC26A8 mutations are not a common cause of male infertility.

Adult↗
PubMed2004

Estrogen receptor-beta is the predominant estrogen receptor subtype in human oral epithelium and salivary glands.

Many studies have shown that the oral mucosa and salivary glands are sensitive to estrogen action. However, the expression of estrogen receptors (ERs) within these tissues is an area of controversy. ERs exist as two subtypes (ERalpha and ERbeta), and we hypothesized that the incongruity between ER expression and estrogen sensitivity may result from differential expression of ER subtypes in oral tissues. To test this hypothesis, we analyzed oral mucosal and salivary gland samples for ERalpha and ERbeta protein expression by immunohistochemistry from a cross-section of patients attending hospital for surgical problems of the head and neck. ERalpha was not detected in oral buccal and gingival epithelium or in salivary glands. In contrast, ERbeta was widely expressed at high levels in all oral tissues studied. Within these tissues, ERbeta was observed primarily in keratinocytes and salivary gland acinar and ductal cells. Our results demonstrating the expression of only the ERbeta subtype within oral tissues may explain the contradictory results from previous studies investigating ER expression in these tissues. Importantly, these results suggest that estrogens may act via ERbeta in oral tissues and explain the effect of hormonal changes on the oral mucosa as well as on saliva secretion and composition.

Adult↗
PubMed2003

Bioreconstructive joint scaffold implant arthroplasty in metacarpophalangeal joints: short-term results of a new treatment concept in rheumatoid arthritis patients.

Swanson silicone implant is the "gold standard" of metacarpophalangeal joint reconstruction in rheumatoid arthritis (RA) patients. However, durability problems of silicone implants have led us to develop a new technique based on bioreconstructive implants. PLA96 (poly-L,D-lactide copolymer, L:D ratio of 96:4) scaffolds were engineered. Bioabsorption and substitution of porous PLA96 scaffold with living tissue eventually produce a neojoint. In the current prospective study, 23 RA patients (80 joints) were operated on, using PLA96 implants. Fifteen patients (54 joints) have been monitored for at least 1 year. Pain alleviation was well achieved. Range of motion improvement was emphasized to extension direction of functional arc. The average ulnar deviation was preoperatively 26 degrees, and at follow-up it was 6 degrees. Volar subluxation was noticeable in 56% of joints preoperatively and in 6% at 1-year follow-up. This is the first report of the formation of a living, functional joint in situ by means of a synthetic bioreconstructive joint scaffold. Results of this preliminary short-term study are comparable with previously published data on silicone arthroplasty. However, bioreconstructive prostheses can aid in preventing problems that occur with biostable prostheses. Tissue engineering has created a new era in the reconstruction of damaged joints.

Arthritis, Rheumatoid↗
PubMed2002

Upregulation of CFTR expression but not SLC26A3 and SLC9A3 in ulcerative colitis.

In inflamed colonic mucosa, the equilibrium between absorptive and secretory functions for electrolyte and salt transport is disturbed. We compared the expression of three major mediators of the intestinal salt transport between healthy and inflamed colonic mucosa to understand the pathophysiology of diarrhea in inflammatory bowel disease. Expression levels of the cystic fibrosis transmembrane regulator (CFTR) (Cl- channel), SLC26A3 (Cl-/HCO exchanger) and SLC9A3 (Na+/H+ exchanger) mRNAs were measured by real-time quantitative RT-PCR in peroperative colonic samples from controls (n = 4) and patients with ulcerative colitis (n = 10). Several samples were obtained from each individual. Tissue samples were divided into three subgroups according to their histological degree of inflammation. Expression of CFTR and SLC26A3 proteins were determined by immunohistochemistry and Western blotting from the same samples, respectively. Increased expression of CFTR mRNA was observed in all three groups of affected tissue samples, most pronounced in mildly inflamed colonic mucosa (5-fold increase in expression; P < 0.001). The expression of the CFTR protein was detected from health and inflamed colon tissue. Although the expression of the SLC26A3 mRNA was significantly decreased in severe ulcerative colitis (P < 0.05), the SLC26A3 protein levels remained unchanged in all groups. The expression of SLC9A3 mRNA was significantly changed between the mild and severe groups. Intestinal inflammation modulates the expression of three major mediators of intestinal salt transport and may contribute to diarrhea in ulcerative colitis both by increasing transepithelial Cl- secretion and by inhibiting the epithelial NaCl absorption.

Antiporters↗
PubMed2001

Estrogen receptors and proliferation markers in primary and recurrent breast cancer.

To elucidate the clinical importance of estrogen receptor (ER) beta in breast cancer, 29 archival primary breast cancer specimens, six locally recurrent cancers, and five benign mammary tumors were examined histochemically for ERalpha, ERbeta and the proliferation markers Ki67 and cyclin A. In benign tumors, most epithelial cells contained ERbeta, but ERalpha was rare. In primary cancers, both ERalpha and ERbeta occurred in epithelial cells, the presence of ERbeta being associated with elevated expression of Ki67 and cyclin A, and ERalpha with decreased levels. Thus, the highest content of proliferation markers was seen in primary cancers that were ERalpha(-) ERbeta(+). Most Ki67-containing cells coexpressed ERbeta, but few showed ERalpha. In locally recurring cancers, ERalpha, ERbeta, and Ki67 were more highly expressed than in the corresponding primary tumors, and many cells containing ERbeta, but few with ERalpha, expressed Ki67. Surprisingly, ERbeta, but not ERalpha, was seen in the stromal cells of both primary and recurrent cancers. Because the response of breast cancers to tamoxifen therapy is correlated with the presence of ERalpha, cancer cells that lack ERalpha but contain ERbeta and proliferation markers represent a novel population of apparently proliferating cells that probably are not targeted by the current antiestrogens. Thus, appropriate ERbeta-specific ligands, perhaps in combination with tamoxifen, may be useful in improving the treatment of breast cancers.

Biomarkers, Tumor↗
PubMed2001

Decreased expression of estrogen receptor beta protein in proliferative preinvasive mammary tumors.

To understand the significance of estrogen receptor beta (ERbeta) in mammary carcinogenesis, we evaluated the expression of ERbeta in preinvasive mammary tumors. The percentage of ERbeta-positive epithelial or tumoral cells was assayed by quantitative immunohistochemistry using an image analyzer in 130 lesions of varying histological risk from 118 patients [71 with benign breast disease (BBD) and 59 with carcinoma in situ (CIS)] and compared with 118 adjacent histologically normal glands. Five groups of lesions with an increasing risk of invasive cancer, from BBD without hyperplasia to high-grade CIS, were studied. Results were compared with ERalpha and Ki67 immunostaining. The percentage of ERbeta-positive cells was high (median, 85%) in "normal" mammary glands and in nonproliferative BBD and decreased significantly (P < 0.0001) in proliferative BBD without atypia and in CIS, contrasting with an inverse progression for the ERalpha level. In normal mammary glands, the ERbeta level did not vary according to the nature of the lesion at the periphery and was significantly higher (P < 0.007) than in adjacent preinvasive lesions, except in nonproliferative BBD. The ERbeta level decreased in proliferative BBD, anticipating the ERalpha increase, which was significant in BBD with atypia. In high-grade ductal carcinoma in situ, both ER levels were low. The ratio between ERbeta and ERalpha was high in normal glands, and decreased significantly in proliferative lesions. ERbeta staining was inversely correlated with Ki67 (r = -0.333; P < 0.001), more particularly in high-grade ductal carcinoma in situ (r = -0.57; P < 0.02). The marked and early decreased level of ERbeta protein associated with other criteria of cell proliferation suggests a protective effect of ERbeta against the mitogenic activity of estrogens in mammary premalignant lesions. Knowledge of the ERbeta and ERalpha content in each preinvasive lesion should help to rationalize antiestrogen preventive therapy adapted to each individual patient.

Breast Neoplasms↗
PubMed2001

No evidence for the in vivo activity of aromatase-inhibiting flavonoids.

Measurements of the aromatase-inhibiting and antioxidative capacities of flavonoids in vitro showed that slight changes in flavonoid structure may result in marked changes in biological activity. Several flavonoids such as 7-hydroxyflavone and chrysin (5,7-dihydroxyflavone) were shown to inhibit the formation of 3H-17beta-estradiol from 3H-androstenedione (IC(50)<1.0 microM) in human choriocarcinoma JEG-3 cells and in human embryonic kidney cells HEK 293 transfected with human aromatase gene (Arom+HEK 293). Flavone and quercetin (3,3',4',5,7-pentahydroxyflavone) showed no inhibition (IC(50)>100 microM). None of the requirements for optimal antioxidative capacity (2,3-double bond with 4'-hydroxy group, 3-hydroxyl group, 5,7-dihydroxy structure and the orthodihydroxy structure in the B-ring) is relevant for the maximum inhibition of aromatase by flavonoids. After oral administration to immature rats at a dose of 50 mg/kg body weight, which considerably exceeds amounts found in daily human diets, neither aromatase-inhibiting nonestrogenic flavonoids, such as chrysin, nor estrogenic flavonoids, such as naringenin and apigenin, induced uterine growth or reduced estrogen- or androgen-induced uterine growth. The inability of flavonoids to inhibit aromatase and, consequently, uterine growth in short-term tests may be due to their relatively poor absorption and/or bioavailability.

Androstenedione↗
PubMed2001

Localization of oestrogen receptors alpha and beta in human testis.

Cellular localization of oestrogen receptor alpha (ERalpha) and beta (ERbeta) proteins were studied in human testis samples using immunohistochemistry, and the expression of the corresponding mRNA was examined with reverse transcription-polymerase chain reaction (RT-PCR). Seven men, aged 28-48 years, who underwent diagnostic testicular biopsy because of azoospermia or to give spermatozoa for intracytoplasmic injection for infertility treatment, donated tissue for the study. One of them had anejaculation but normally functioning testes, and one was diagnosed as having Sertoli cell-only syndrome (SCOS). In addition, expression of ERbeta protein was examined in one testis sample obtained from a man undergoing a sex change operation. Strong ERbeta immunoreactivity was detected in the nuclei of spermatogonia, spermatocytes and early developing spermatids. Elongating spermatids, mature spermatozoa, Sertoli and Leydig cells were all negative for ERbeta. The presence of ERbeta protein was confirmed in Western analysis. With RT-PCR, both wild-type ERbeta and ERbetacx, the isoform which represses wild-type ER function, were easily detected. In most cases, ERbetacx mRNA was more abundantly expressed than wild-type ERbeta. The patient with SCOS expressed neither ERbeta isoform. Neither ERalpha protein nor ERalpha mRNA was detected in any of the samples. We conclude that in the human testis, ERbeta is likely to be the ER that mediates the effects of oestrogen.

Adult↗
PubMed2001

Polymorphism of the cytokine genes in hospitalized patients with Puumala hantavirus infection.

BACKGROUND: Nephropathia epidemica (NE) is a mild type of haemorrhagic fever with renal syndrome caused by Puumala (PUU) hantavirus. The clinical course of NE varies from asymptomatic to fatal. The aim of this study was to establish whether polymorphisms in the cytokine genes are associated with susceptibility to and outcome of NE. METHODS: The genotypes of the genes of tumour necrosis factor alpha (TNFalpha), interleukin-1alpha (IL-1alpha), IL-1beta and IL-1 receptor antagonist (IL-1RA) were analysed by polymerase chain reaction in 87 subjects, all hospital-treated for serologically confirmed acute NE. The control group comprised 400 healthy blood donors. Nineteen out of these 400 (5%) controls were PUU virus-seropositive. RESULTS: IL-1RA allele 2 and IL-1beta (base exchange polymorphism at position -511) allele 2 were strongly associated with each other in both groups. NE patients were more often IL-1RA-2 negative/IL-1beta-2 negative than PUU-seronegative blood donors (38 vs 27%, odds ratio 1.65, 95% confidence interval 1.0-2.7). However, there were no differences in the clinical severity of NE between the IL-1RA-2 negative/IL-1beta-2 negative and the other patients. The other allele frequencies studied evinced no statistically significant differences between the groups. Thirty-three out of 87 (38%) patients and 121 out of 381 (32%) seronegative controls were carriers of the high-producer genotype TNF2 allele. Several parameters showed the clinical course of NE to be more severe in TNF2 carriers than in non-carriers. CONCLUSIONS: These data suggest that non-carriage of the IL-1RA allele 2 and IL-1beta (-511) allele 2 may contribute to susceptibility to NE. Furthermore, TNFalpha polymorphism seems to be associated with the outcome of NE.

Adolescent↗
PubMed2001

Regulation of progesterone receptors and decidualization in uterine stroma of the estrogen receptor-alpha knockout mouse.

Regulation of progesterone receptor (PR) in uterine stroma (endometrial stroma plus myometrium) by estrogen was investigated in estrogen receptor-alpha (ERalpha) knockout (alphaERKO) mice. 17 beta-Estradiol (E(2)) increased PR levels in uterine stroma of ovariectomized alphaERKO mice, and ICI 182 780 (ICI) inhibited this E(2)-induced PR expression. Estrogen receptor-beta(ER beta) was detected in both uterine epithelium and stroma of wild-type and alphaERKO mice by immunohistochemistry. In organ cultures of alphaERKO uterus, both E(2) and diethylstilbestrol induced stromal PR, and ICI inhibited this induction. These findings suggest that estrogen induces stromal PR via ERbeta in alphaERKO uterus. However, this process is not mediated exclusively by ERbeta+, because in ERbeta knockout mice, which express ERalpha, PR was up-regulated by E(2) in uterine stroma. In both wild-type and alphaERKO mice, progesterone and mechanical traumatization were essential and sufficient to induce decidual cells, even though E(2) and ERalpha were also required for increase in uterine weight. Progesterone receptor was strongly expressed in decidual cells in alphaERKO mice, and ICI did not inhibit decidualization or PR expression. This study suggests that up-regulation of PR in endometrial stroma is mediated through at least three mechanisms: 1) classical estrogen signaling through ERalpha, 2) estrogen signaling through ERbeta, and 3) as a result of mechanical stimulation plus progesterone, which induces stromal cells to differentiate into decidual cells. Each of these pathways can function independently of the others.

Animals↗
PubMed2001

Mechanisms of estrogen action.

Our appreciation of the physiological functions of estrogens and the mechanisms through which estrogens bring about these functions has changed during the past decade. Just as transgenic mice were produced in which estrogen receptors had been inactivated and we thought that we were about to understand the role of estrogen receptors in physiology and pathology, it was found that there was not one but two distinct and functional estrogen receptors, now called ER alpha and ER beta. Transgenic mice in which each of the receptors or both the receptors are inactive have revealed a much broader role for estrogens in the body than was previously thought. This decade also saw the description of a male patient who had no functional ER alpha and whose continued bone growth clearly revealed an important function of estrogen in men. The importance of estrogen in both males and females was also demonstrated in the laboratory in transgenic mice in which the aromatase gene was inactivated. Finally, crystal structures of the estrogen receptors with agonists and antagonists have revealed much about how ligand binding influences receptor conformation and how this conformation influences interaction of the receptor with coactivators or corepressors and hence determines cellular response to ligands.

Animals↗
PubMed2001

Mesangiocapillary glomerulonephritis caused by Puumala hantavirus infection.

Nephropathia epidemica induced by Puumala hantavirus typically causes acute reversible renal function impairment. A typical renal biopsy finding is acute tubulointerstitial nephritis with slight glomerular mesangial changes. We describe here 5 patients who developed the nephrotic syndrome during the convalescent phase of an otherwise typical acute febrile nephropathia epidemica. Renal biopsy of all patients disclosed type I mesangiocapillary glomerulonephritis (MCGN). A clinical remission of the nephrotic syndrome was observed in 4 patients during the follow-up period, and 1 entered into chronic renal failure. Three patients had microscopic hematuria and proteinuria and 2 elevated blood pressure at the latest assessment visit. No patient had clinical or laboratory findings compatible with chronic bacterial, parasitic or viral infections (hepatitis B or C), malignancies, or other disorders known to be associated with MCGN. In conclusion, Puumala hantavirus has to be added to the list of potential agents associated with type I MCGN. Further studies are necessary to establish the incidence of MCGN caused by various hantavirus infections.

Adult↗
PubMed2001

Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase.

Aromatization of androgens is a key step in estrogen production, and it regulates the delicate balance between estrogens and androgens in the gonads and sex steroid target tissues. In the present study, we generated transgenic mice (AROM(+)) bearing the human ubiquitin C promoter/human P450 aromatase fusion gene. AROM(+) male mice are characterized by an imbalance in sex hormone metabolism, resulting in elevated serum E(2) concentrations, combined with significantly reduced testosterone and FSH levels, and elevated levels of PRL and corticosterone. AROM(+) males present a multitude of severe structural and functional alterations in the reproductive organs, such as cryptorchidism associated with Leydig cell hyperplasia, dysmorphic seminiferous tubules, and disrupted spermatogenesis. The males also have small or rudimentary accessory sex glands with abnormal morphology; a prominent prostatic utricle with squamous epithelial metaplasia, and edema in the ejaculatory ducts and vas deferens. In addition, the abdominal muscle wall is thin, and the adrenal glands are enlarged, with cortical hyperplasia. Some of the abnormalities, such as undescended testes and undeveloped prostate, resemble those observed in animals exposed perinatally to high levels of exogenous estrogen, indicating that the elevated aromatase activity results in excessive estrogen exposure during early phases of development. Some of the disorders in the reproductive organs, furthermore, can be explained by the fact that AROM(+) males are hypoandrogenic, and have elevated levels of serum PRL and corticosterone. Thus, the AROM(+) mouse model provides a novel tool to investigate the consequences of a prolonged increase in conversion of androgens to estrogens which results in complex hormonal disturbances altering the structure and function of various male reproductive organs.

Abdominal Muscles↗
PubMed2001

Nontraumatic urethral dyssynergia in neonatally estrogenized male rats.

PURPOSE: Bladder outlet obstruction develops in estrogen treated males. Because of the lack of electromyography recordings, earlier studies have not clarified the failure mechanisms of voiding. We simultaneously recorded electromyography activity of the proximal rhabdosphincter in neonatally estrogenized rats with transvesical cystometry and urethral flow, followed by morphometric analysis of the urethral structure. MATERIALS AND METHODS: Rats treated neonatally with 10 microg. diethylstilbestrol daily on days 1 to 5 after birth were used in urodynamics and morphological studies at ages 5 to 6.5 months. Using anesthesia the bladder, anterior surface of the proximal rhabdosphincter and distal urethra were exposed to record simultaneously the high frequency oscillations of intraluminal bladder pressure, and the rates of intermittent flow from the distal urethra and electromyography activity of the proximal rhabdosphincter with a suction electrode. RESULTS: Neonatally estrogenized rats had higher mean maximal bladder pressure plus or minus standard deviation (42.1 +/- 6.4 versus 37.7 +/- 4.9 mm. Hg, p = 0.01), decreased mean flow (2.3 +/- 0.1 versus 4.1 +/- 1.6 ml. per minute, p < 0.0001) and mean increment of proximal rhabdosphincter electromyography depolarization amplitude (3.0 +/- 0.78 versus 2.6 +/- 0.87 mV., p = 0.02) compared with controls, while mean transient repolarization was absent or highly decreased (-0.3 +/- 0.61 versus 0.3 +/- 0.9 mV., p = 0.04). Morphologically the proximal rhabdosphincter was atrophied with increased connective tissue. CONCLUSIONS: Alterations in the structure and electromyography activity of the urethral musculature imply that neonatal exposure to diethylstilbestrol predisposes male rats to urethral atrophy and dyssynergia, evident as altered electromyography activity of the proximal rhabdosphincter.

Animals↗
PubMed2001

Co-localization of androgen receptor with estrogen receptor beta in the lower urinary tract of the male rat.

PURPOSE: Androgens and estrogens influence voiding. In this study their target sites in the lower urinary tract of the male rat were identified. MATERIALS AND METHODS: Cryosections of the bladder body, bladder neck, prostatic urethra, mid proximal urethra and prostatic autonomic ganglia of adult male rats were immunostained with specific estrogen receptor alpha, estrogen receptor beta (ERbeta) or androgen receptor (AR) antibodies. The sections were then examined under conventional, fluorescence or confocal fluorescence microscopy. RESULTS: Co-expression of AR and ERbeta in the urothelium, bladder smooth muscle cells, proximal urethra striated muscle cells and neurons in the autonomic ganglia of the prostatic plexus suggests that estrogen and androgen have direct effects in the lower urinary tract. CONCLUSIONS: The local interaction of AR and ERbeta in the hormonal control of voiding is an intriguing possibility.

Animals↗
PubMed2000

Differential expression of estrogen receptors alpha and beta in adult rat accessory sex glands and lower urinary tract.

Estrogens induce pronounced structural and functional changes in male accessory sex glands and the lower urinary tract in both sexes, but the exact mechanisms of estrogen action are not fully understood. This study was undertaken to localise the tissue cell types that express estrogen receptor in adult rats, and to determine the receptor subtype (ERalpha and ERbeta) in order to identify sites that may respond directly to estrogens. In the male accessory sex glands (seminal vesicles, prostatic lobes and ampullary glands), ERbeta mRNA and protein were strongly expressed in the epithelium but not in the stroma, while ERalpha mRNA was present only in the fibromuscular tissue surrounding the prostatic collecting ducts in the posterior periurethral region and in ampullary gland stroma. In the epithelium of the urinary bladder and urethra of both sexes, high level of ERbeta mRNA and protein, but no ERalpha mRNA, was detected. The connective tissue in urinary bladder of both males and females, as well as that in prostatic urethra in males expressed ERalpha mRNA. The neural cells in the autonomic ganglia of the prostatic plexus were strongly positive for ERbeta mRNA, but were completely devoid of ERalpha. We conclude that ERbeta is the predominant ER subtype in the epithelium of adult male rat accessory sex glands and the lower urinary tract of both males and females, as well as in the prostatic neural plexus regulating the function of the lower urinary tract in males, while ERalpha is present only in the stromal compartment of distinct sites. These results indicate that in these tissues in intact adults there are multiple targets for direct estrogen action. Furthermore, the differential or complementary expression of the two ER subtypes suggests that they may have specific functions, and may explain the complex structural and functional changes induced by estrogens.

Animals↗
PubMed2000

Differential expression of estrogen receptors alpha and beta in adult rat accessory sex glands and lower urinary tract.

Estrogens induce pronounced structural and functional changes in male accessory sex glands and the lower urinary tract in both sexes, but the exact mechanisms of estrogen action are not fully understood. This study was undertaken to localise the tissue cell types that express estrogen receptor in adult rats, and to determine the receptor subtype (ER alpha and ER beta) in order to identify sites that may respond directly to estrogens. In the male accessory sex glands (seminal vesicles, prostatic lobes and ampullary glands), ER beta mRNA and protein were strongly expressed in the epithelium but not in the stroma, while ER alpha mRNA was present only in the fibromuscular tissue surrounding the prostatic collecting ducts in the posterior periurethral region and in ampullary gland stroma. In the epithelium of the urinary bladder and urethra of both sexes, high level of ER beta mRNA and protein, but no ER alpha mRNA, was detected. The connective tissue in urinary bladder of both males and females, as well as that in prostatic urethra in males expressed ER alpha mRNA. The neural cells in the autonomic ganglia of the prostatic plexus were strongly positive for ER beta mRNA, but were completely devoid of ER alpha. We conclude that ER beta is the predominant ER subtype in the epithelium of adult male rat accessory sex glands and the lower urinary tract of both males and females, as well as in the prostatic neural plexus regulating the function of the lower urinary tract in males, while ER alpha is present only in the stromal compartment of distinct sites. These results indicate that in these tissues in intact adults there are multiple targets for direct estrogen action. Furthermore, the differential or complementary expression of the two ER subtypes suggests that they may have specific functions, and may explain the complex structural and functional changes induced by estrogens.

Adolescent↗