Uterine gland development begins postnatally and is accompanied by estrogen and progesterone receptor expression in the dog.

During neonatal and juvenile life, mammalian uteri undergo extensive structural and functional changes, including uterine gland differentiation and development. In sheep and mice, inhibition of neonatal uterine gland development induced by progestin treatment led to a permanent aglandular uterine phenotype and adult infertility, suggesting that this strategy might be useful for sterilizing dogs and other companion animals. The goal of this study was to define temporal patterns of adenogenesis (gland development), cell proliferation, and progesterone and estrogen receptor expression in uteri of neonatal and juvenile dogs as a first step toward determining whether neonatal progestin treatments might be a feasible contraceptive approach in this species. Uteri obtained from puppies at postnatal wk 1, 2, 4, 6, or 8 were evaluated histologically and immunostained for MKI67, a marker of cell proliferation, estrogen receptor-1, and progesterone receptor. Adenogenesis was under way at 1 wk of age, as indicated by the presence of nascent glands beginning to bud from the luminal epithelium, and rapid proliferation of both luminal epithelial and stromal cells. By Week 2, glands were clearly identifiable and proliferation of luminal, glandular, and stromal cells was pronounced. At Week 4, increased numbers of endometrial glands were evident penetrating uterine stroma, even as proliferative activity decreased in all cell compartments as compared with Week 2. Whereas gland development was most advanced at Weeks 6 to 8, luminal, glandular, and stromal proliferation was minimal, indicating that the uterus was nearly mitotically quiescent at this age. Both estrogen receptor-1 and progesterone receptor were expressed consistently in uterine stromal and epithelial cells at all ages examined. In summary, canine uterine adenogenesis was underway by 1 wk of age and prepubertal glandular proliferation was essentially complete by Week 6. These results provided information necessary to facilitate development of canine sterilization strategies based on neonatal progestin treatments designed to permanently inhibit uterine gland development and adult fertility.

National surveillance of surgical-site infection through register-based analysis of antibiotic use after inguinal hernia repair.

BACKGROUND: Systematic surveillance of surgical-site infections is not standard. The aim of this retrospective cohort study was to evaluate the feasibility of using existing national health registers for surveillance of postoperative antibiotic treatment suggestive of surgical-site infection. METHODS: Data from national registers on hospital admissions and drug use were combined. Antibiotic purchases by 8856 patients subject to ambulatory care for inguinal hernia repair in Sweden during 2006 were ascertained during a 30-day interval immediately after surgery (postsurgical period) and in an 11-month control period (6 months before and 5 months after the postsurgical period). RESULTS: The incidence of first purchases of skin and soft tissue antibiotics was 245 per 8697 person-months in the first postoperative month and 180 per 52 612 person-months in the preoperative control period, representing a 1-month risk difference of 2.4 (95 per cent confidence interval (c.i.) 2.0 to 2.7) per cent. Hence, a 1-month risk of 2.4 per cent could be attributed tentatively to the surgery. The rate of episodes with antibiotics used mainly for skin and soft tissue infection was sevenfold higher in the first postoperative month than in the control period (rate ratio 7.01, 95 per cent c.i. 5.94 to 8.27). CONCLUSION: The risk of antibiotic treatment during the postsurgical period was of the same order of magnitude as infection rates reported in the Swedish Hernia Register and review studies. Surveillance of postoperative antibiotic use may be considered as a resource-saving surrogate marker for surgical-site infections or an indicator of inappropriate use.

Carbohydrate-based particles reduce allergic inflammation in a mouse model for cat allergy.

BACKGROUND: Allergen-specific immunotherapy (ASIT) is the only treatment of allergic disease that gives long-lasting relief of symptoms. However, concerns for safety and efficiency have highlighted the need for improvement of the therapy. We have previously suggested carbohydrate-based particles (CBPs) as a novel adjuvant and allergen carrier for ASIT. Our aim of this study was to evaluate the therapeutic potential of CBPs in ASIT, employing a mouse model for cat allergy. METHODS: BALB/c mice were subcutaneously immunized with the recombinant (r) cat allergen Fel d 1 followed by intranasal challenge with cat dander extract (CDE). The sensitized mice were therapeutically treated with rFel d 1 covalently coupled to CBPs (CBP-rFel d 1). Airway hyper-reactivity (AHR), infiltration of leucocytes in bronchoalveolar lavage (BAL) fluid, allergen-specific serum immunoglobulin levels and in vitro splenocyte responses were evaluated. RESULTS: Mice treated with CBP-rFel d 1 showed reduced features of allergic inflammation. They responded with (i) significantly decreased AHR and infiltration of eosinophils in BAL fluid after CDE challenge, (ii) the serum level of rFel d 1-specific IgE was reduced and the level of IgG(2)a was more pronounced after CBP-rFel d 1 treatment, and (iii) there was also a tendency of decreased allergen-specific cellular response. CONCLUSIONS: Carbohydrate-based particles are effective tools as adjuvant and allergen carriers for use in ASIT and constitutes a promising strategy to improve allergy treatment.

Antimicrobial peptide LL-37 internalized by immature human dendritic cells alters their phenotype.

The human cathelicidin LL-37 has been shown to be involved in the barrier function of the innate immunity, being released from specific cells upon challenge and exerting immunomodulatory effects. We here demonstrate that LL-37 affects immature dendritic cells, derived from human peripheral blood monocytes (MDDC). LL-37 is internalized by MDDC with subsequent localization primarily in the cytoplasmic compartment. However, LL-37 could also be detected in the nuclei of MDDC, suggesting that LL-37 may be transported into the nucleus. The uptake of LL-37 is dose, time and energy dependent, indicating that the observed internalization process involves an endocytic pathway. Incubation of immature MDDC with LL-37 caused phenotypic changes, characterized by an increased expression of the antigen-presenting molecule HLA-DR, and the costimulatory molecule CD86. Taken together, these findings suggest that LL-37 released upon triggering of the innate immunity, may affect cellular adaptive immunity through an interaction with immature dendritic cells.

The effect of platelets on fibrin gel structure formed in the presence of recombinant factor VIIa in hemophilia plasma and in plasma from a patient with Glanzmann thrombasthenia.

Fibrin gel structure has been shown to be dependent on the thrombin concentration as well as the rate of thrombin generation. Accordingly, factor VIII (FVIII)- and FIX-deficient plasma (hemophilia A and B) form loose fibrin clots with high permeability constants. By adding rFVIIa in vitro to FVIII-deficient plasma containing platelets (frozen and thawed), the fibrin gel permeability constant normalized, indicating that extra rFVIIa (1.2 microg mL(-1) or higher) induced a tight fibrin structure. Thrombin generation is highly dependent on the number of platelets, and in this study it was demonstrated that the addition of rFVIIa (5 microg mL(-1)) normalizes the fibrin gel permeability in samples containing platelets (frozen-thawed) in numbers of at least down to 20 x 10(6) mL(-1). The effect of rFVIIa was not observed when unfrozen platelets instead of frozen-thawed platelets were added. Neither was any effect on the fibrin permeability seen, in the presence of annexin V, known to block the effect of phospholipids on the platelet surface. This indicates an important role of platelet phospholipids for the effect of rFVIIa. A similar effect on the fibrin permeability of rFVIIa was observed when added to platelet-rich plasma from a patient with Glanzmann thrombasthenia. Recombinant FVIIa has been found to induce hemostasis in patients with hemophilia and inhibitors against FVIII/FIX as well as in patients with Glanzmann thrombasthenia, indicating the importance of the formation of a tight fibrin gel structure, more resistant against premature proteolysis, for maintaining hemostasis. In conclusion, the addition of rFVIIa (5 microg mL(-1)) also substantially decreased the permeability constant of fibrin gels formed in FVIII-deficient plasma in the presence of low numbers of frozen-thawed platelets (down to 20 x 10(6) mL(-1)). A similar pattern was obtained in plasma from a Glanzmann patient. No effect was found in the presence of unfrozen instead of frozen-thawed platelets. Annexin V blocked any effect of rFVIIa. A normalization of the overall fibrinolysis potential (OFP) during the same condition supports the effect of rFVIIa on the fibrin permeability in the presence of a limited number of platelets.

Differential regulation of the progesterone receptor A and B in the human uterine cervix at parturition.

The concept of a blockade of progesterone during human pregnancy and withdrawal of this blockade at parturition remains controversial There is no sharp fall in serum progesterone before parturition, but treatment with an antiprogestin is successful for labor induction at term pregnancy. The human progesterone receptor (PR) exists in two isoforms (PR-A and PR-B), mediating different biological responses. Here, the hypothesis of a progesterone withdrawal at parturition in terms of a change in PR isoforms was tested. Cervical biopsies were obtained at term before the onset of labor, immediately after parturition and from non-pregnant women. Solution hybridization showed a tendency for the PR mRNA level to be decreased at parturition. Immunohistochemistry displayed decreased PR(A + B) and PR-B levels (p < 0.05) immediately after parturition. The relative importance of PR-A seemed higher immediately after parturition as compared to its importance in non-pregnant and term pregnant women. Our results are consistent with the concept of a functional progesterone blockade at the receptor level at term pregnancy, and withdrawal of this blockade at parturition. These observations may have important clinical and therapeutic implications.

The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX.

Patients with hemophilia have an impaired thrombin generation and therefore form loose fibrin hemostatic plugs that are easily dissolved by fibrinolysis. This prevents maintained hemostasis in these patients, resulting in a severe bleeding disorder. Recombinant (F)VIIa has been shown to enhance thrombin generation on already thrombin-activated platelets in the absence of FVIII and FIX. An efficacy rate of 80-90% has been found in hemophilia patients with inhibitors against FVIII or FIX both in association with major surgery and in the treatment of serious bleedings. In a model measuring fibrin clot permeability in a platelet-containing system described by Blombäck et al. (1994) this was demonstrated to be dependent on the concentration of FVIII and FIX. The addition of rFVIIa in concentrations of 1.9, 4.8 and 9.6 microg mL(-1) normalized fibrin clot permeability. The concentration of 1.9 microg mL(-1) of rFVIIa normalized clot permeability in this system and the higher concentrations of rFVIIa added only slightly to the effect. No further decrease in clot permeability was found when rFVIIa in a concentration of 1.9 microg mL(-1) was added to a sample with a normal concentration (100%) of FVIII or FIX. Higher concentrations of rFVIIa added to the plasma containing 100% of FVIII or FIX induced only a slight further decrease of fibrin permeability constant, arguing against any unwanted effect of extra rFVIIa on clot permeability in the case of a normal hemostasis. Furthermore, the fibrin network was studied with 3D microscopy and the loose network found in the absence of FVIII or FIX increased in density with increasing FVIII or FIX concentrations. The addition of rFVIIa to FVIII- or FIX-deficient systems altered the network structure, making the fibers thinner and more tightly packed.

Langerhans cells that express matrix metalloproteinase 9 increase in human dermis during sensitization to diphenylcyclopropenone in patients with alopecia areata.

BACKGROUND: We know little of the initial events during the sensitization phase of contact allergy in humans. Alopecia areata (AA), a disease of unknown pathogenesis characterized by patchy hair loss, may be treated by inducing contact allergy to diphenylcyclopropenone (DPC), later followed by its topical application. OBJECTIVES: To learn more about the initial events during sensitization in human skin, we studied the early events during induction of contact allergy to DPC in patients with AA. METHODS: DPC 2% and sodium lauryl sulphate (SLS) 4% were applied on the backs of eight patients with AA. Punch biopsies were taken 6 and 24 h after application. The biopsies were snap-frozen and cryostat sections were evaluated with immunohistochemistry using antibodies against CD1a, HLA-DR, CD3, CD54 and matrix metalloproteinase 9 (MMP-9). RESULTS: After 24 h all subjects exhibited erythema on the DPC-treated areas. Histological evaluation of biopsies from these areas showed hydropic degeneration and a significantly increased number of MMP-9+ cells in the dermis (P < 0.0005). The MMP-9+ cells were identified with double immunofluorescence staining as CD1a + Langerhans cells. The expression of the other markers studied remained unaltered irrespective of treatment, including treatment with SLS. CONCLUSIONS: Our findings show that DPC induces an irritant reaction leading to an increased number of MMP-9+ CD1a+ cells in the dermis during the initial phase of sensitization.

Rh genotyping: avoiding false-negative and false-positive results among individuals of African ancestry.

High homology, variant alleles, and silent alleles have made the development of completely reliable genotyping assays for the RHD and RHC alleles difficult. An RHD pseudogene (RHDPsi) possessing a 37-bp insertion within exon 4 is common among serologically RhD-negative individuals of African descent and generates false-positive results in previously reported RhD genotyping assays. Genotyping RhC is problematic due to exon 2 homology between RHD and RHC; however, an RHC-specific 109-bp insertion within intron 2 has been reported useful for genotyping. Primers flanking the exon 4 insertion point were used for detection of RHD and RHDPsi among a total of 231 serotyped individuals: 134 African American, 85 Caucasian, and 12 RhD serotype-negative/genotype-positive, D-sensitized women. Primers flanking the RHC-specific intron 2 insertion were used to genotype 282 serotyped individuals (128 African American, 154 Caucasian) and were compared to RHC genotyping using the exon 1 RhC-specific nt48 cytosine polymorphism. Complete correlation was observed between genotyping with the RHDPsi primer pair and serotyping among 219 individuals and 10/12 previous RHD false-positive genotyping results were resolved. RHDPsi was detected in 19% (n = 4/21) of RhD seronegative African Americans and 4.4% (n = 5/113) of RhD seropositive African Americans. When using the 109-bp intron 2 insertion for genotyping of RHC, a 23.9% (n = 11/46) false-negative rate was observed among African American RhCc serotyped heterozygotes. Utilization of the exon 1 nt48 cytosine for indirect genotyping of RHC yielded a 7.2% (n = 4/55) and 56.3% (n = 45/80) false-positive rate among Rhcc Caucasians and African Americans, respectively. We conclude that these additional reactions, though not sufficient alone, can be useful supplements to existing Rh genotyping assays.

Co-localization of oestrogen receptor beta and leukocyte markers in the human cervix.

Cervical ripening during parturition is associated with rapid production of catabolic enzymes by invading leukocytes and increased collagen metabolism. The recruitment of leukocytes is regulated by various factors including inflammatory mediators, prostaglandins and matrix metalloproteinases. Sex steroids may be indirectly or directly involved in this process. This study aimed to evaluate the expression of oestrogen receptor beta (ER beta) in blood cells infiltrating the cervix during pregnancy and parturition. Cervical biopsies were obtained from term pregnant, post-partal and non-pregnant women. The ER beta protein and leukocyte markers CD45 and CD68 were evaluated by single and double labelling immunohistochemistry. Quantitative values were assessed using a microscope and a high-resolution camera connected to a computer with image analysis program. The number of CD45(+) and CD68(+) cells in the cervix increased in term pregnancy and post-partum compared with the non-pregnant state. The ER beta antigen was co-localized with CD45 leukocyte common antigen and CD68 macrophage specific antigen in blood leukocytes infiltrating the cervical tissue. The presence of ER beta in the cervical leukocytes suggests that oestrogen may directly regulate leukocyte functions in the cervix.

Different regulation of oestrogen receptors alpha and beta in the human cervix at term pregnancy.

During pregnancy, a cervical connective tissue remodelling takes place, clinically recognized as softening, effacement and dilatation. The role of oestrogens and their receptors (ER) in this process is not clear. ERalpha is a ligand-activated transcription factor involved in many physiological processes. The identification of a second oestrogen receptor, ERbeta, has led to a re-evaluation of oestrogen signalling and physiology. The aim of this study was to monitor the expression of the two ERs in the cervix from women at term pregnancy (TP) and after parturition (PP) compared with that of non-pregnant (NP). A solution hybridization assay showed that the level of ERalpha mRNA was significantly decreased in the PP group, when compared with the NP and TP groups. In contrast the ERbeta mRNA level was increased in the TP group compared with the NP and PP groups. These results were supported by reverse transcription-polymerase chain reaction (RT-PCR). Similar results were observed for the protein with immunohistochemistry. Intense ERbeta immunostaining was observed in neutrophils and the endothelial cells of blood vessels. In conclusion, this study supports a concept according to which oestrogen might be involved in the final remodelling of the cervix via the modulating effects of the two ERs. Furthermore, oestrogen may mediate some effects on cervical ripening via ERbeta present in the invading neutrophils. Further studies are needed to elucidate this finding.

The expression of glutaredoxin is increased in the human cervix in term pregnancy and immediately post-partum, particularly after prostaglandin-induced delivery.

Glutaredoxins are glutathione disulphide oxidoreductases catalysing disulphide reductions via a redox active disulphide. We have examined the presence of glutaredoxin in the human cervix, and its differential expression during cervical remodelling in term pregnancy and immediately post-partum as compared to the non-pregnant state. Cervical biopsies were obtained from 24 term-pregnant and 24 post-partal women, of which 10 were taken after spontaneous delivery, 10 after prostaglandin-induced delivery and four after mifepristone-induced delivery, all obtained within 15 min after delivery. Six non-pregnant women served as controls. The tissues were analysed for the glutaredoxin mRNA levels using a solution hybridization method. Glutaredoxin mRNA was expressed in the human cervix, the level increased > or =2-fold at term pregnancy and immediately post-partum. The level of cervical glutaredoxin mRNA from prostaglandin E(2)-treated women was 3-fold higher than after spontaneous ripening and delivery. Localization of glutaredoxin was visualized with immunohistochemistry in cervices from two post-partal women, and was compared to that of thioredoxin. We conclude that glutaredoxin may be involved in the regulation of cervical ripening in humans, particularly in the inflammatory reaction seen during this process. Glutaredoxin mRNA levels are up-regulated after prostaglandin treatment, which is effective and the most commonly used substance for cervical priming and induction of labour.

Neurochemical and cellular markers in human cervix of late pregnant, postpartal and non-pregnant women.

BACKGROUND: The aim was to evaluate the peptidergic innervation and the dendritic cell content in the cervix uteri. METHODS: Cervical biopsies were obtained from late pregnant (n=5), postpartal (n=5) and non-pregnant (n=5) women. The samples were prepared for immunohistochemistry using antibodies to protein S-100 (S-100), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), human peptide histidine isoleucine amide (PHM 27), neuropeptide tyrosine (NPY), and human histocompatibility complex class II subregion DR (HLA-DR). RESULTS: Nerve fibers positive for protein S-100, and dendritic cells positive for S-100 and HLA-DR were abundant in the cervix, especially at late pregnancy. CGRP, VIP, PHM-27 and NPY positive nerve fibers were present in non-pregnant, short nerve fibers and scattered immunoreactivity at term, and further scattered immunoreactivity after parturition. NPY positive nerve fibers were decreased at term, and after parturition a scattered immunoreactivity was observed. CONCLUSIONS: The abundant protein S-100 positive nerve fibers implies an impact of myelinated nerves in the cervix uteri during pregnancy. The abundant dendritic cells, positive for HLA-DR and S-100, especially at term, indicates a general activation of the immune system until late pregnancy and parturition. The changed occurrence and distribution of immunoreactivity for CGRP, VIP and PHM-27 suggest a release of these neuropeptides until term. The changes in NPY immunoreactivity indicate a release of NPY around parturition.

Caesarean section in previously untreated acute promyelocytic leukaemia. Report of two patients.

Acute promyelocytic leukaemia (APL) is characterised by a life-threatening hemorrhagic diathesis which is attributed to a DIC-like coagulopathy. This report describes the problems of childbirth in two patients with untreated APL. It is concluded that caesarean section can be performed without major complications. A prerequisite is an active treatment of the coagulopathy and a close collaboration between the obstetrician and the haematologist.

Human cervical ripening, an inflammatory process mediated by cytokines.

An extensive remodelling process, referred to as cervical ripening, takes place in the cervical tissue during pregnancy and labour. It is recognized as softening and dilation of the cervical canal, and starts as a slow process during pregnancy, becoming rapid close to partum. In this study we focus on cytokines as possible mediators of this final remodelling. mRNA levels for interleukin (IL)-8, IL-6 and granulocyte colony-stimulating factor (G-CSF) were upregulated in the ripe postpartum cervical tissue (n = 8) compared to the unripe state (n = 9). Likewise, released cytokine concentrations increased from non-pregnant (n = 11) to the term-pregnant group (n = 13) with a further increase at partum (n = 16). IL-8 concentrations increased 4-fold from non-pregnant to term-pregnant (P<0.01), and a further 10-fold to postpartum state (P<0.0001). Concentrations of IL-6 and G-CSF were similarly increased. Specific IL-8 immunostaining was identified in the epithelia of pregnant cervical tissue (n = 7) and was most pronounced in the epithelia and stroma of postpartum tissue (n = 4). In conclusion, IL-8, IL-6 and G-CSF increase in the human cervix during the ripening process, indicating their important role in the cervical remodelling. These data demonstrate that cervical ripening is similar to an inflammatory process.

Induction of labor with mifepristone--a randomized, double-blind study versus placebo.

OBJECTIVE: To evaluate the efficacy of mifepristone in inducing labor in women with an unripe cervix, its effect on the cervix and on the status of the newborn. METHODS: In a prospective double-blind study, 36 post-term pregnant women with a Bishop score of 5 or less received either 400 mg mifepristone (n=24) or placebo (n=12). If, 48 hours after the treatment was started, labor had not begun or the Bishop score was 5 or less, the women were given 0.5 mg prostaglandin E2 intracervically, a treatment which was repeated 12 hours later, if necessary. RESULTS: During the first 48 hours following treatment, 19 (79.2%) of the women treated with mifepristone and two of the women (16.7%) treated with placebo went into labor. In addition, one and three women, respectively, had a ripe cervix at the end of the 48h period. The overall success rate was thus 83.3% for mifepristone and 41.7% for placebo (p=0.008; OR 14.8; 95% CI 2.1-107.6). The median time from the start of treatment to delivery was also shorter (mifepristone 36h23' and placebo 53h17'). Treatment with intracervical PGE2 was needed more often after the placebo. The duration of labor, however, tended to be shorter after placebo than after mifepristone in the women who delivered vaginally. The frequencies of instrumental delivery were similar in both treatment groups. The median Apgar score was slightly lower at 1 minute (p<0.05) following mifepristone treatment, but did not differ at 5 and 10 minutes. There was no difference between the two treatment groups in the umbilical pH at delivery. CONCLUSION: The results of the present study show that mifepristone is a simple and effective treatment for inducing labor in post-term women with an unripe cervix.

Cervical ripening after treatment with prostaglandin E2 or antiprogestin (RU486). Possible mechanisms in relation to gonadal steroids.

OBJECTIVE: To compare the mechanisms for cervical ripening after treatment with prostaglandin E2 or antiprogestin (RU486) to spontaneous cervical ripening, with focus on gonadal steroid receptors. STUDY DESIGN: Cervical biopsies were obtained from postpartal women after treatment with prostaglandin E2 (n=10), or antiprogestin (n=5). Postpartal women after spontaneous cervical ripening (n=10) served as controls. Levels of estrogen and progesterone receptors, their mRNAs, insulin-like growth factor I mRNA and serum estradiol and progesterone were quantitated. The collagen concentration and solubility by pepsin were determined. Statistical tests used were Kruskal-Wallis and Mann-Whitney U test. RESULTS: After prostaglandin E2 treatment the collagen concentration was higher (P<0.05) as compared to spontaneous ripening. After antiprogestin treatment the estrogen receptor concentration was higher (P<0.05) in comparison to spontaneous ripening. CONCLUSION: The elevated estrogen receptor concentration after antiprogestin treatment, in contrast to spontaneous ripening, and prostaglandin E2 treatment, indicates a that a receptor-mediated progesterone withdrawal does not explain the events behind spontaneous cervical ripening at parturition.

Protein gene product 9.5-immunoreactive nerve fibers and cells in human cervix of late pregnant, postpartal and non-pregnant women.

BACKGROUND: The aim of this study was to examine the occurrence and distribution of the general neuronal marker protein gene product (PGP) 9.5 in the cervix uteri. METHODS: Cervical biopsies were obtained from late pregnant (n=5), postpartal (n=5) and non-pregnant (n=5) women. The samples were prepared for immunohistochemistry using antibodies to PGP 9.5. RESULTS: Nerve fibers were found consistently in all biopsies. There were differences in the occurrence and distribution of PGP 9.5 immunoreactive nerve fibers and cells between the three groups. Immunoreactive nerve fibers were observed at a moderate to abundant frequency in the stroma and around arterial vessel walls, in all groups. Immunoreactive nerve fibers were also observed at high frequency within and around glandular epithelium in the late pregnant and postpartal groups. PGP 9.5 immunoreactive cells were seen occasionally in the stroma of the non-pregnant group, but at a high frequency in the stroma, around arterial blood vessel walls, around and within the glandular epithelium in the late pregnant and postpartal groups. The total frequency of immunoreactive nerve fibers and cells was the highest in the late pregnant group, slightly lower in the postpartal group, and the lowest in the non-pregnant group. CONCLUSIONS: These findings show that changes in the general innervation take place during human cervical ripening until late pregnancy and parturition.

Differential expressions of mRNA for proteoglycans, collagens and transforming growth factor-beta in the human cervix during pregnancy and involution.

During pregnancy and involution, an extensive remodelling of the human cervical connective tissue occurs. This cervical ripening is one of the most pronounced physiological remodelling processes known in human connective tissue. To investigate how the remodelling is accomplished, the levels of mRNA for collagen I and III, versican and three small proteoglycans, biglycan, decorin and fibromodulin, were evaluated using Northern blots at different stages of cervical ripening. In the corresponding biopsies the concentration of collagen and of small and large proteoglycans were determined. The role of transforming growth factor-beta (TGF-beta) as a mediator of the remodelling process was also investigated. The concentration of collagen decreased and 1 week before partus, 50% of the nonpregnant level was attained. No further decrease was noted after partus. The mRNA for collagen I and III did, however, not decrease in the term pregnant cervix 1 week before partus. Only 20-30% decrease during the final ripening just before partus was recorded. Neither did the mRNA levels of the small proteoglycans change significantly during the ripening, despite an almost 50% decrease in the concentration of the small proteoglycans. The message for versican was, however, 5-fold increased at partus and then gradually returned to nonpregnant levels within 4 days after delivery. These changes corresponded to similar changes in the concentration of the large proteoglycan. Thus, the remodelling of the cervical connective tissue is achieved by two different mechanisms, on one hand an increased turnover of collagen and the small proteoglycans, on the other a changed transcription followed by an increased production of versican. During the involution 2- to 3-fold increases in the messages for collagen I and III, and the small proteoglycans, biglycan and decorin, corresponded to increases in the concentration of the small proteoglycans and non-extractable collagen. The message for TGF-beta was increased 2-fold immediately after delivery compared with the term pregnant state. Thus, TGF-beta may be of importance for the reconstruction of the cervix, which starts immediately after partus.