[Finnish prenatal care and Chinese medicine. Acupuncture and other treatments].
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Acupuncture Therapy↗
Biomedical subjects
M Korhonen
Publications and source records attributed to M Korhonen.
[Finnish prenatal care and Chinese medicine].
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Female↗
Antiproliferative effects of low-dose micronized progesterone.
OBJECTIVE: To study the pharmacodynamic effects of oral micronized P on endometrial maturation. DESIGN: This was a controlled, open, parallel group, pilot study. SETTING: The experiment was performed in an outpatient academic clinical research unit. PATIENTS: Twelve healthy, P-challenged, estrogen-primed, postmenopausal women participated in the study. INTERVENTIONS: Patients were given 300 mg micronized P daily (8:00 A.M.) or twice (8:00 A.M. and 4:00 P.M.) daily from study days 1 through 14 after estrogen priming for 30 days. Blood samples were taken at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after the 8:00 A.M. dose on study day 1 and 14 and again at 8:00 and 9:30 A.M. on days 3 and 5 fasting, days 7 and 9 after a fatty meal, and day 11 after a high fiber meal. Endometrial biopsies were taken on day 1 and 14. MAIN OUTCOME MEASURES: Progesterone concentrations were measured. Endometrial biopsies were studied for effects on histology, glycogen content of glands, ribosomal RNA, and nuclear estrogen receptors in glands, surface epithelium, and stroma. RESULTS: Day 1 and 14 P kinetics were similar for 8 hours. Dose-dependent increases in glandular glycogen, decrease in ribosomal RNA, and decrease in nuclear estrogen receptors were demonstrated. CONCLUSIONS: Oral micronized P can induce antiproliferative changes in the human endometrium at doses lower than those required for transformation of the endometrium to a full secretory state.
Cell Division↗
Effects of moderate salt restriction alone and in combination with cilazapril on office and ambulatory blood pressure.
The purpose of the present study was to examine the effects of salt-restriction alone and in combination with an angiotensin-converting enzyme (ACE) inhibitor (cilazapril) on both office and ambulatory blood pressure (BP) levels in free living subjects with elevated BP. The study was carried out in an out-patient setting with subjects recruited from occupational health care system mainly. After exclusions, 39 subjects (24 men, 15 women, aged 28-65 years) with mildly to moderately elevated BP completed the study. After 3 months run-in period with placebo (first month on normal-salt and the next 2 months on sodium-restricted diet) the subjects were randomised into either salt-restriction placebo or salt-restriction cilazapril (2.5 mg daily) groups for 3 months. In the whole group, 24-h urinary sodium excretion decreased (mean +/- s.d.) from 198 +/- 60 to 112 +/- 59 mmol (4 weeks vs 24 weeks, P < 0.001). Systolic and diastolic office BP decreased during the placebo-sodium-restriction phase (-7.1 [95% Cl -11.2; -3.0] and -4.2 [95% Cl -6.6; -1.8] mm Hg for systolic and diastolic BP), and similarly the daytime ambulatory BP (ABP) was reduced during this period (-2.8 [95% Cl -5.2; -0.5] and -2.8 [95% Cl -4.5; -1.2] mm Hg, systolic (SBP) and diastolic blood pressure (DBP) respectively). No changes were observed in the night time ABP. Addition of cilazapril to sodium-restriction enhanced significantly the office BP (-13.2, [95% Cl -20.2; -6.2], and -9.1 [95% Cl -13.5; -4.7]) and daytime ABP (-5.9, [95% Cl -10.1; -1.8] and -5.3, [95% Cl -8.8; -1.9]) reduction. Blood glucose, plasma insulin or serum lipids did not change during the study. Moderate sodium restriction seems to lower the office and daytime ABP levels in subjects with mild-to-moderate hypertension. The antihypertensive effect of cilazapril could be enhanced by sodium restriction.
Adult↗
[Finnish maternity care and Chinese medicine].
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Female↗
Comparison of the gonadotropin-releasing hormone agonist goserelin acetate alone versus goserelin combined with estrogen-progestogen add-back therapy in the treatment of endometriosis.
OBJECTIVE: To investigate whether the addition of low-dose estrogen-P combination hormone replacement therapy (HRT) to GnRH agonist (GnRH-a) treatment for endometriosis reduces the pharmacologic side effects of such treatment without reducing efficacy and to determine the endocrinologic changes during treatment. DESIGN: Prospective, randomized, double-blind, placebo-controlled, comparative study of two drug regimens: 3.6 mg goserelin acetate in a 28-day SC depot formulation once monthly for 6 months plus either a combination of 2 mg 17 beta-E2 and 1 mg norethisterone acetate (NET) 1 mg or matching placebo tablets once daily for 6 months. SETTING: Multicenter study in three tertiary referral centers at university teaching hospitals and two central hospitals. PATIENTS: Women with laparoscopically confirmed symptomatic endometriosis were included in the study. RESULTS: Of the total of 109 patients screened, 93 were recruited and 88 patients were randomized to either the HRT or the placebo group. Four women were withdrawn because of various medical reasons, and 76 patients were followed-up for a total of 12 months. In terms of efficacy, there was no difference between the two drug regimens for objective or subjective response. There were significantly less postmenopausal symptoms in the patients treated with goserelin plus HRT compared with those treated with goserelin plus placebo. CONCLUSION: Goserelin diminished significantly the symptoms and laparoscopic scores of endometriosis. The addition of HRT did not reduce the efficacy of goserelin but diminished the postmenopausal symptoms during treatment.
Adult↗
Differential expression of laminin polypeptides in developing and adult human kidney.
We studied the expression of laminin chains in embryonic and adult human kidney by indirect immunofluorescence with monoclonal antibodies (MAbs). In embryonic human kidney, immunoreactivity for laminin alpha 1, beta 1, and gamma 1 chains was found in basement membranes (BMs) of primary vesicles, in comma- and S-shaped bodies, and in more mature stages of glomeruli and in tubules. The beta 2 chain of laminin was absent in the early glomerular structures but was prominent in BMs of maturing glomeruli (GBMs) and Bowman's capsule (BCBMs) and was also detectable in some tubules. Both the beta 2 and alpha 2 chains were variably seen in medullary tubule BMs. In adult human kidney, laminin alpha 1 chain was seen in GBMs and all tubule BMs (TBMs) as well as in arterial smooth muscle BMs (SMBMs). Laminin beta 1 chain reactivity was found in all TBMs, but not in GBMs or SMBMs. In the glomerulus, a distinct mesangial type of reaction was revealed with the MAbs to beta 1 and alpha 2 chains. The GBMs and SMBMs reacted with MAbs to the beta 2 chain, but reactivity was lacking in BCBMs. Laminin gamma 1 chain immunoreactivity was weakly present in BCBMs, GBMs, and SMBMs. The alpha 3 and beta 3 chains could not be detected in developing or adult human nephron. The results show that during development the BMs in human nephron undergo distinct changes, laminin beta 1 chain being transiently co-expressed with alpha 1 chain during early glomerular development and then becoming replaced by the beta 2 chain, which, on the other hand, disappears from the BCBMs on maturation. The alpha 2 chain appears to emerge in the mesangium late during development.
Embryonic and Fetal Development↗
Integrins and laminins in human renal carcinoma cells and tumors grown in nude mice.
We studied by indirect immunofluorescence microscopy the distribution of integrins and laminins in four human renal cell carcinoma cell lines (CAKI-2, A498, CAKI-1, and ACHN) in vitro and in s.c. xenografts in nude mice. In vitro, all four cell lines expressed the alpha 1, alpha 3, alpha v, beta 1, beta 3, and beta 5 subunits and three expressed the alpha 6 subunit; all cell lines expressed laminin A, B1, and B2 chains. Histologically, the CAKI-2 and A498 cells formed differentiated grade 1 (G1) and G2 tumors, respectively, while the CAKI-1 and ACHN cells formed poorly differentiated G3 tumors. The described integrin profile was largely retained upon xenografting. Basal polarization of the alpha 3 and alpha 6 integrin subunits was found in the differentiated tumors, and human laminins were detected as discrete linear structures surrounding tumor cell clusters in these tumors, suggesting that the cells have retained a polarized cell-laminin interaction characteristic of normal tubular epithelial cells. A disorganized distribution of integrins and laminins was noted in the G3 tumors. We conclude that these renal carcinoma cell lines displayed an integrin repertoire similar to that of clinical renal carcinomas and retained it upon xenografting. Furthermore, the organization of integrins and laminins in the xenografts correlated with histological grade.
Animals↗
Distribution of tenascin, cellular fibronectins and integrins in the normal, hyperplastic and neoplastic breast.
We present immunolocalization data on tenascin (Ten), and extradomains A and B (EDA-, EDB-) and oncofetal (Onc-) isoforms of cellular fibronectin (cFn), and alpha 1-6 and alpha v and beta 1-4 integrin subunits on cryosections of normal human breast, the spectrum of fibrocystic disease (FCD), and benign and malignant breast neoplasms. Fetal breast ducts were surrounded by broad Ten bands; adult breast ducts and acini were encompassed by thin continuous rims. In FCD, Ten was detectable and was clearly enhanced around hyperplastic ducts. Fibroadenomas showed uneven Ten periductal reactions while in all carcinomas, the stroma showed extensive and strong reactions that were most intense at the tumors' invasive edge. EDA-cFn's distribution was similar to Ten's but the staining was stronger while EDB- and Onc-cFn were virtually restricted to fetal breasts and carcinomas. In the normal adult breast, alpha 1,2,3 and alpha 6, and B1 and beta 4 integrins were detected in myoepithelial cells; weaker staining was also noted in the basolateral aspect of luminal cells; this profile was retained--and at times enhanced--in FCD, fibroadenomas and in situ carcinomas in which myoepithelial elements were present. In carcinomas, particularly in those of high grade, integrins tended to be reduced. However, mucinous carcinomas showed enhanced expression and the emergence of alpha 5 integrin that was not in the normal repertory; also a subset of infiltrating lobular carcinomas showed prominent alpha 1 and alpha 6 and beta 1 and--rarely--beta 4 staining distributed in delicate cytoplasmic processes (kinetopodia). These data indicate that the complex cell-matrix and cell-cell interactions of the normal breast are slightly altered in hyperplastic processes and benign neoplasms whereas profound chances occur in carcinomas. The latter display enhanced Ten and EDA- and Onc-cFn expression in particular, while most integrins appear decreased. Notably, mucinous and some lobular carcinomas display enhancement of certain integrins. The conspicuous localization of integrins in kinetopodia may be significant in relation to the invasive behavior of lobular carcinomas.
Breast↗
Integrins in developing, normal and malignant human kidney.
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Carcinoma, Renal Cell↗
Integrins as receptors for extracellular matrix proteins in human cornea.
Extracellular matrix (ECM) proteins form distinct protein families that play a role during tissue maturation, wound healing and maintenance of tissue architecture. Recent studies show that there are tissue type-specific variations in their expression. ECM proteins function by complexing with each other and also by interacting with their cellular receptors, called integrins. Integrins are heterodimeric membrane glycoproteins that are partly cell type-specifically expressed in human tissues. Like other stratified epithelia, corneal epithelium expresses alpha 2 beta 1, alpha 3 beta 1, alpha 6 beta 1, 4, and alpha v beta 1 integrins that mediate attachment to the basement membrane and cell-cell interactions.
Basement Membrane↗
Integrin distributions in renal cell carcinomas of various grades of malignancy.
We studied 41 renal cell carcinomas, classified according to histologic grades G1 through G3, by indirect immunofluorescence microscopy using a panel of monoclonal antibodies (MAb) against various integrin subunits, and the basement membrane (BM) components laminin and collagen type IV. Selected cases also were immunostained using the avidin-biotin-complex method. The alpha 3 and beta 1 integrin subunits were detected in tumor cells of all the carcinomas. All G1 carcinomas, like normal tubular epithelial cells, expressed the alpha 6 subunit, whereas it was lacking in 20% and 40% of G2 and G3 carcinomas, respectively. Furthermore, when alpha 6 was expressed, a lack of basally polarized organization of the subunit, coupled with disorganization of the BM components, correlated with histologic grade. Another feature that appeared to characterize the more anaplastic tumors was their high level (80%) of the alpha v subunit expression as compared with its absence in the G1 carcinomas. Stromal myofibroblasts, identified by double-labeling with anti-myosin, were often characterized by the expression of the alpha 1, alpha 3, alpha 5 and beta 1 subunits. These results indicate that changes in integrin expression in renal cell carcinomas may be correlated with their degree of histologic malignancy.
Basement Membrane↗
Distribution of the alpha 1-alpha 6 integrin subunits in human developing and term placenta.
The distribution of the alpha 1-alpha 6 as well as alpha v, beta 1, beta 3 and beta 4 integrin subunits in human first and second trimester and term placentas was studied by indirect immunofluorescence microscopy using a panel of monoclonal antibodies (mAbs). In first and second trimester villi, the alpha 1 and beta 1 integrin subunits were detected in the stromal cells, that were mostly also immunoreactive for desmin. Desmin-positive stromal cells were also found in villi of term placentas, but the stroma was negative for anti-alpha 1 and -beta 1. In the villous trophoblast, anti-alpha 6 and -beta 4 revealed a distinct basal immunoreactivity during all stages of development, whereas immunoreactivity for the alpha 3 and beta 1 subunits emerged during the second and third trimesters. Throughout placental development, endothelia of villous capillaries reacted prominently with anti-alpha 1 and -beta 1. Intermediate trophoblastic cells displayed a somewhat heterogenous immunoreactivity for the beta 1, alpha 1, alpha 3 and alpha 5 integrin subunits, and differed from villous trophoblast also in their lack of expression of the alpha 6 and beta 4 subunits. While nondecidualized endometrial cells displayed weak reactivity for the alpha 1 and beta 1 integrin subunits, the individual decidual cells presented both a basement membrane and a cell surface-confined immunoreactivity for anti-alpha 1, -alpha 3, and -beta 1. The results suggest a role for integrins in placental development, and show that expression of integrins is modulated during the differentiation of trophoblast, villous stroma, and decidual cells. Furthermore, the basal localization of alpha 6 beta 4 and alpha 3 beta 1 integrins suggests that they are employed as basement membrane receptors in the villous trophoblast, and the emergence of the alpha 3 beta 1 complex may reflect that the cytotrophoblast and syncytiotrophoblast recognize the basement membrane differently.
Capillaries↗
Immunohistochemical localization of integrins in the normal, hyperplastic, and neoplastic breast. Correlations with their functions as receptors and cell adhesion molecules.
Integrins comprise a family of transmembrane glycoproteins that modulate cell-matrix and cell-cell relationships by acting as receptors to extracellular protein ligands, and also as direct adhesion molecules. The authors studied by immunohistochemistry the distribution of the alpha 1-6,v and the beta 1,3,4 subunits of integrins in samples of normal breast, the spectrum of fibrocystic disease (FCD), and representative benign and malignant neoplasms. Monoclonal antibodies (Mabs) specific for each subunit were applied to cryosections by the avidin-biotin-complex method; selected samples were studied by double immunofluorescence microscopy with the Mabs and a polyclonal antiserum to myosin. The authors found that the alpha 1-3,6,v and the beta 1, integrin subunits were detectable in the normal breast parenchyma; myoepithelial cells were consistently more prominently stained than the basolateral aspect of the luminal cells. This immunoprofile was retained, and in cases enhanced through the spectrum of FCD, in benign tumors and in ductal and lobular carcinomas in situ. In most infiltrating ductal carcinomas, integrin staining tended to decrease except for some cases that reacted strongly for the alpha v subunit. Several mucinous carcinomas reacted strongly for alpha 2,3,6,v and beta 4 subunits, and even more so for the alpha 5 subunit that was not found in the normal breast. Subsets of infiltrating lobular carcinomas stained convincingly for alpha 1,3,6,v and beta 1 subunits in delicate but abundant kinetopodia. Our findings indicate that in hyperplasias and in benign tumors integrin expression patterns parallel those of the normal breast, whereas in carcinomas, variations include decrease, enhancement, and emergence of certain subunits that are not in the normal repertory. Alterations of integrin expression parallel phenotypic changes in breast carcinoma cells; they also reflect their disrupted interaction with the similarly disrupted extracellular matrix. Enhancement of certain integrins in some carcinomas may reflect the selection of subpopulations with increased binding capacity which in turn may impact on their invasive and metastatic properties.
Antibodies, Monoclonal↗
Integrins in human cells and tumors.
We have studied the distribution of the alpha- and beta-subunits of integrins in developing and adult human kidney as well as in selected other tissues and cultured cells. In cultured cells some of the integrin subunits (beta 1, alpha 1, alpha 2 and alpha 5) colocalize with talin at focal adhesions when plated on an appropriate ligand. Similarly, in tissues the polarization of beta 1-integrins in colocalization with talin appears to indicate adhesive complexes, as demonstrated in adult glomeruli. In human kidney, the alpha subunits of integrins were seen to be segment-specifically expressed already in fetal tissues. In glomeruli the integrin alpha 1 subunit characterized mesangial cells while the alpha 2 and alpha 3 subunits showed immunoreactivity in endothelial cells and podocytes, respectively. In renal tubuli, the alpha 6 subunit, complexed with the beta 1 subunit, showed a typical polarized distribution coaligning with the tubular basement membrane while the alpha 3 and alpha 2 subunits were expressed in distal tubular cells. These results suggested that in kidney the alpha 2 beta 1, alpha 3 beta 1, and alpha 6 beta 1 integrins can function as basement membrane receptors. The alpha 5 subunit was nearly lacking in the kidney and it appears to be mainly expressed in some smooth muscle cells. In other tissues distinct patterns in the expression of integrins were found. Thus, in many glandular epithelial cells the alpha 3 beta 1 integrin appeared to function as a basement membrane receptor while in various stratified epithelia and in the breast such a polarized localization could be found for the alpha 6 beta 4 integrin. Finally, although presenting a clearly polarized distribution for beta 1 integrins, none of the alpha subunits could be found in cardiac or skeletal muscle cells and none of the integrins could be revealed in neuronal cells of human developing and adult cerebrum or cerebellum, although neurons in peripheral tissues contained abundantly the alpha 6 beta 1 integrin complex. In human tumors, the tumor cells, including also metastastatic tumors, generally presented the same integrins as their tissues of origin. In some poorly differentiated tumors both a population heterogeneity and even a lack of expression or a disorganization of basement membrane receptor integrins was obvious.
Animals↗
The alpha 1-alpha 6 subunits of integrins are characteristically expressed in distinct segments of developing and adult human nephron.
We studied the distribution of the alpha 1-alpha 6 subunits of beta 1 integrins in developing and adult human kidney using a panel of mAbs in indirect immunofluorescence microscopy. Uninduced mesenchyme displayed a diffuse immunoreactivity for only the alpha 1 integrin subunit. At the S-shaped body stage of nephron development, several of the alpha subunits were characteristically expressed in distinct fetal nephron segments, and the pattern was retained also in the adult nephron. Thus, the alpha 1 subunit was characteristically expressed in mesangial and endothelial cells, the alpha 2 in glomerular endothelium and distal tubules, the alpha 3 in podocytes, Bowman's capsule, and distal tubules, and the alpha 6 subunit basally in all tubules, and only transiently in podocytes during development. Unlike the alpha 3 and alpha 6 subunits, the alpha 2 subunit displayed an overall cell surface distribution in distal tubules. It was also distinctly expressed in glomerular endothelia during glomerulogenesis. The beta 4 subunit was expressed only in fetal collecting ducts, and hence the alpha 6 subunit seems to be complexed with the beta 1 rather than beta 4 subunit in human kidney. Of the two fibronectin receptor alpha subunits, alpha 4 and alpha 5, only the latter was expressed, confined to endothelia of developing and adult blood vessels, suggesting that these receptor complexes play a minor role during nephrogenesis. The present results suggest that distinct integrins play a role during differentiation of specific nephron segments. They also indicate that alpha 3 beta 1 and alpha 6 beta 1 integrin complexes may function as basement membrane receptors in podocytes and tubular epithelial cells.
Adult↗
Distribution of beta 1 and beta 3 integrins in human fetal and adult kidney.
The distribution of beta 1 and beta 3 integrins was studied in fetal and adult human kidneys by indirect immunofluorescence microscopy. In the developing kidney, the cells of the undifferentiated metanephric blastema displayed strong cell surface-confined beta 1 integrin immunoreactivity, whereas the cells of primary vesicles and comma- and S-shaped bodies reacted more weakly. In mature fetal as well as adult glomeruli, beta 1 integrins were distinctly localized, apparently confining to the basal cell surfaces of endothelial cells and podocytes abutting the glomerular basement membrane. In adult proximal tubules, beta 1 integrin immunoreactivity was strictly confined to the basal aspect of the epithelial cells, being absent laterally, which is unusual for membrane proteins of polarized epithelial cells. A more diffuse overall immunoreactivity was seen in distal tubules and collecting ducts. The epithelial cells of developing proximal and distal tubules displayed an overall distribution of beta 1 integrins. In each case, talin immunoreactivity followed that of beta 1 integrins. Compared with beta 1 integrins, beta 3 integrins showed a more restricted distribution, and differences were seen in the reactions of mono- and polyclonal antibodies. In developing glomeruli, beta 3 integrin immunoreactivity was prominently seen in the cells of Bowman's capsule, possibly revealing the presence of vitronectin receptor. Solitary cells, that reacted also with antibodies to the platelet glycoprotein IIb, were consistently detected in fetal glomeruli, suggesting the presence of megakaryocytes. The results show that during nephrogenesis, beta 1 integrins become distinctly polarized both in glomerular endothelial cells and podocytes, as well as in the epithelial cells of proximal tubules.
Adult↗
Terodiline: a dose titrated, multicenter study of the treatment of idiopathic detrusor instability in women.
Idiopathic detrusor instability is a common cause of lower urinary tract symptoms at all ages and in both sexes. Treatment initially is conservative and often includes drug therapy. Terodiline has the theoretical advantage of being a drug with anticholinergic and calcium channel blocking effects. Theoretically, by using a drug with dual action the beneficial effect of reduced detrusor overactivity might occur at a dosage below that likely to lead to the troublesome side effects experienced by patients who take pure anticholinergic agents. A total of 70 female patients completed a study characterized by extremely strict inclusion criteria and a tight protocol. Other novel elements to the study were the extensive use of urinary diaries for symptom evaluation, standardized urodynamic studies agreed upon by the participating centers and the dose titration design of the trial. Terodiline has been demonstrated to be a safe, well tolerated and effective drug in the treatment of idiopathic detrusor instability. Drug treatment led to significant decreases in urinary frequency and incontinence episodes. Pre-micturition symptoms, such as urgency, were markedly reduced and the voided volume was significantly increased. Although there were consistent trends towards greater improvement in the urodynamic measurements, when the terodiline and placebo groups were compared these did not reach statistical significance, partly due to a large improvement in the placebo group. Nevertheless, terodiline has been shown to be a useful drug for conservative management of patients with detrusor instability.
Adult↗