Bariatric surgery, osteoarthritis and arthroplasty of the hip and knee in Swedish Obese Subjects - up to 31 years follow-up of a controlled intervention study.

OBJECTIVE: To study the long-term effect of obesity and bariatric surgery on incidences of osteoarthritis and arthroplasty of hip and knee. DESIGN: Hazard ratios (HR) and incidence rates (IR) of osteoarthritis and arthroplasty of hip and knee were studied in the prospective, controlled, non-randomized Swedish Obese Subjects (SOS) study (bariatric surgery group, n = 2007; matched controls given usual obesity care, n = 2040) and the SOS reference cohort (n = 1135, general population). Osteoarthritis diagnosis and arthroplasty for osteoarthritis were captured from the National Swedish Patient Register. Median follow-up time was 21.2 (IQR 16.4-24.8), 22.9 (IQR 19.1-25.7), and 20.1 years (IQR 18.7-20.9) for the control group, surgery group and reference cohort, respectively. RESULTS: The surgery group displayed lower incidence of hip osteoarthritis (IR 5.3, 95% CI 4.7-6.1) compared to controls (IR 6.6, 95% CI 5.9-7.5, adjHR 0.83, 95% CI 0.69-1.00) but similar incidence of hip arthroplasty. Similar incidence of knee osteoarthritis was observed in the surgery group and controls, but knee arthroplasty was more common in the surgery group (IR 7.4, 95% CI 6.6-8.2 and 5.6, 95% CI 4.9-6.4, adjHR 1.45, 95% CI 1.22-1.74). The reference cohort displayed lower incidences of osteoarthritis and arthroplasty of hip and knee compared with the surgery group and controls. CONCLUSION: Bariatric surgery did not normalize the increased risk of knee and hip osteoarthritis in patients with obesity but was associated with an increased incidence of knee arthroplasty compared to the control group. With the limitations inherent to the present data, additional studies are needed to confirm these results. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01479452.

Remission and progression of pre-existing micro- and macroalbuminuria over 15 years after bariatric surgery in Swedish Obese Subjects study.

BACKGROUND: Bariatric surgery reduces incidence of albuminuria and end-stage renal disease in patients with obesity. Effects of bariatric surgery on long-term remission and progression of pre-existing obesity-related renal damage are mainly unexplored. Here we investigate the long-term effects of bariatric surgery compared with conventional obesity care on remission and progression of albuminuria. METHODS: 4047 patients were included in the Swedish Obese Subjects study. Inclusion criteria were age 37-60 years, BMI ≥ 34 kg/m2 in men and BMI ≥ 38 kg/m2 in women. Our analysis comprised 803 patients (19.8% of total population, 357 control, 446 surgery) with pre-existing albuminuria including 693 patients (312 control, 381 surgery) with microalbuminuria, and 110 patients (45 control, 65 surgery) with macroalbuminuria. Surgery patients were treated with banding, vertical banded gastroplasty, or gastric bypass. Control patients received conventional obesity care. RESULTS: Total urinary albumin excretion was 36.5% lower in all patients with albuminuria after 15 years, 44.5% lower in patients with microalbuminuria after 15 years, and 27.8% lower in patients with macroalbuminuria after 2 years following bariatric surgery compared with conventional care. In surgery patients with microalbuminuria, remission to normoalbuminuria was higher (OR, 5.9, 2.2, 3.2, p < 0.001) and progression to macroalbuminuria was lower (OR, 0.28, 0.26, 0.25, p ≤ 0.02) at 2, 10, and 15 years, respectively, compared with control patients. In surgery patients with macroalbuminuria remission to normo- or microalbuminuria was higher (OR, 3.67, p = 0.003) after 2 years. No differences between surgery and control patients with macroalbuminuria were observed after 10 and 15 years. Surgery slowed progression of eGFR decline after 2 years in patients with microalbuminuria and macroalbuminuria (treatment effect: 1.0 ml/min/1.73 m2/year, p = 0.001 and 1.4 ml/min/1.73 m2/year, p = 0.047, respectively). CONCLUSION: Bariatric surgery had better effects than conventional obesity care on remission of albuminuria and prevention of eGFR decline, indicating that patients with obesity-related renal damage benefit from bariatric surgery.

Evaluation of the clinical efficiency of lokivetmab in client privately owned atopic dogs - multicenter study.

Atopic dermatitis (AD) is the most frequent allergic disease in dogs. AD can be treated using allergenspecific immunotherapy as well as symptomatic antipruritic treatment including the use of lokivetmab - caninized anti-interleukine-31 antibody.The aim of the study was to evaluate the effectiveness of lokivetmab over 12 weeks of treat-ment. Studies have been carried out in 89 dogs. In all affected animals, the severity of lesions was assessed using the CADESI 04 and the pruritus was assessed using the VAS.After the first dose of lokivetmab, both CADESI 04 and VAS statistical decreased by 4 weeks from 40.48 to 20.31, and from 7.42 to 2.48, respectively (p = 0.0000001) maintained significantly decresed values during the whole treatment period (CADESI 04 15.64, 15.07 after 8 and 12 weeks, respectively, PVAS 2.03, 1.95 after 8 and 12 weeks, respectively).Lokivetmab leads to a significant reduction of CADESI 04 and pruritus, within four weeks and maximum effect is achived after the second dose.

Fracture risk after three bariatric surgery procedures in Swedish obese subjects: up to 26 years follow-up of a controlled intervention study.

BACKGROUND: Previous studies have reported an increased fracture risk after bariatric surgery. OBJECTIVE: To investigate the association between different bariatric surgery procedures and fracture risk. METHODS: Incidence rates and hazard ratios for fracture events were analysed in the Swedish Obese Subjects study; an ongoing, nonrandomized, prospective, controlled intervention study. Hazard ratios were adjusted for risk factors for osteoporosis and year of inclusion. Information on fracture events were captured from the Swedish National Patient Register. The current analysis includes 2007 patients treated with bariatric surgery (13.3% gastric bypass, 18.7% gastric banding, and 68.0% vertical banded gastroplasty) and 2040 control patients with obesity matched on group level based on 18 variables. Median follow-up was between 15.1 and 17.9 years for the different treatment groups. RESULTS: During follow-up, the highest incidence rate for first-time fracture was observed in the gastric bypass group (22.9 per 1000 person-years). The corresponding incidence rates were 10.4, 10.7 and 9.3 per 1000 person-years for the vertical banded gastroplasty, gastric banding and control groups, respectively. The risk of fracture was increased in the gastric bypass group compared with the control group (adjusted hazard ratio [adjHR] 2.58; 95% confidence interval [CI] 2.02-3.31; P < 0.001), the gastric banding group (adjHR 1.99; 95%CI 1.41-2.82; P < 0.001), and the vertical banded gastroplasty group (adjHR 2.15; 95% CI 1.66-2.79; P < 0.001). CONCLUSIONS: The risk of fracture is increased after gastric bypass surgery. Our findings highlight the need for long-term follow-up of bone health for patients undergoing this treatment.

Incidence of end-stage renal disease following bariatric surgery in the Swedish Obese Subjects Study.

BACKGROUND: Obesity is a major public health problem leading to co-morbidities such as diabetes, hypertension and kidney failure. Bariatric surgery results in pronounced and maintained weight loss and prevention of obesity-related diseases and their complications. Most studies of bariatric surgery on kidney disease show improvements after surgery. However, long-term studies analyzing hard end-points are lacking. Here we report on the long-term effects of bariatric surgery compared to usual obesity care on incidence of end-stage renal disease (ESRD) alone and in combination with chronic kidney disease stage 4 (CKD4/ESRD). METHODS: 4047 patients were included in the Swedish Obese Subjects (SOS) study. Inclusion criteria were age 37-60 years and BMI ≥ 34 in men and BMI ≥ 38 in women. Patients in the bariatric surgery group (N = 2010) underwent banding (18%), vertical banded gastroplasty (69%), or gastric bypass (13%); controls (N = 2037) received usual obesity care. In this analysis, patients were followed up for a median time of 18 years. The incidence of ESRD and CKD4 was obtained by crosschecking the SOS database with the Swedish National Patient Register. RESULTS: During follow-up, ESRD occurred in 13 patients in the surgery group and in 26 patients in the control group (adjusted hazard ratio (HR) = 0.27; 95% CI 0.12-0.60; p = 0.001). The number of CKD4/ESRD events was 23 in the surgery group and 39 in the control group (adjusted HR = 0.33; 95% CI 0.18-0.62; p < 0.001). In both analyses, bariatric surgery had a more favorable effect in patients with baseline serum insulin levels above median compared to those with lower insulin levels (interaction p = 0.010). Treatment benefit of bariatric surgery was also greater in patients with macroalbuminuria at baseline compared to those without macroalbuminuria (interaction p < 0.001). CONCLUSIONS: Our study showed for the first time that bariatric surgery is associated with a long-term protection against ESRD and CKD4/ESRD.

Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease is epidemiologically associated with hepatic and metabolic disorders. The aim of this study was to examine whether hepatic fat accumulation has a causal role in determining liver damage and insulin resistance. METHODS: We performed a Mendelian randomization analysis using risk alleles in PNPLA3, TM6SF2, GCKR and MBOAT7, and a polygenic risk score for hepatic fat, as instruments. We evaluated complementary cohorts of at-risk individuals and individuals from the general population: 1515 from the liver biopsy cohort (LBC), 3329 from the Swedish Obese Subjects Study (SOS) and 4570 from the population-based Dallas Heart Study (DHS). RESULTS: Hepatic fat was epidemiologically associated with liver damage, insulin resistance, dyslipidemia and hypertension. The impact of genetic variants on liver damage was proportional to their effect on hepatic fat accumulation. Genetically determined hepatic fat was associated with aminotransferases, and with inflammation, ballooning and fibrosis in the LBC. Furthermore, in the LBC, the causal association between hepatic fat and fibrosis was independent of disease activity, suggesting that a causal effect of long-term liver fat accumulation on liver disease is independent of inflammation. Genetically determined hepatic steatosis was associated with insulin resistance in the LBC and SOS. However, this association was dependent on liver damage severity. Genetically determined hepatic steatosis was associated with liver fibrosis/cirrhosis and with a small increase in risk of type 2 diabetes in publicly available databases. CONCLUSION: These data suggest that long-term hepatic fat accumulation plays a causal role in the development of chronic liver disease.

Successful conservative treatment of an intracranial pneumatocele with post-traumatic hypoglossal nerve palsy secondary to diffuse temporal bone pneumocele: case report and review of the literature.

BACKGROUND: A pneumocele occurs when an aerated cranial cavity pathologically expands; a pneumatocele occurs when air extends from an aerated cavity into adjacent soft tissues forming a secondary cavity. Both pathologies are extremely rare with relation to the mastoid. This paper describes a case of a mastoid pneumocele that caused hypoglossal nerve palsy and an intracranial pneumatocele. CASE REPORT: A 46-year-old man presented, following minor head trauma, with hypoglossal nerve palsy secondary to a fracture through the hypoglossal canal. The fracture occurred as a result of a diffuse temporal bone pneumocele involving bone on both sides of the hypoglossal canal. Further slow expansion of the mastoid pneumocele led to a secondary middle fossa pneumatocele. The patient refused treatment and so has been managed conservatively for more than five years, and he remains well. CONCLUSION: While most patients with otogenic pneumatoceles have presented acutely in extremis secondary to tension pneumocephalus, our patient has remained largely asymptomatic. Aetiology, clinical features and management options of temporal bone pneumoceles and otogenic pneumatoceles are reviewed.

Pattern recognition receptors in microbial keratitis.

Microbial keratitis is a significant cause of global visual impairment and blindness. Corneal infection can be caused by a wide variety of pathogens, each of which exhibits a range of mechanisms by which the immune system is activated. The complexity of the immune response to corneal infection is only now beginning to be elucidated. Crucial to the cornea's defences are the pattern-recognition receptors: Toll-like and Nod-like receptors and the subsequent activation of inflammatory pathways. These inflammatory pathways include the inflammasome and can lead to significant tissue destruction and corneal damage, with the potential for resultant blindness. Understanding the immune mechanisms behind this tissue destruction may enable improved identification of therapeutic targets to aid development of more specific therapies for reducing corneal damage in infectious keratitis. This review summarises current knowledge of pattern-recognition receptors and their downstream pathways in response to the major keratitis-causing organisms and alludes to potential therapeutic approaches that could alleviate corneal blindness.

Development of an ENT undergraduate curriculum using a Delphi survey.

OBJECTIVE: To determine an ENT undergraduate syllabus. DESIGN: Two round Delphi survey. SETTING: Email questionnaire. PARTICIPANTS: Stakeholders with a vested interest in ENT undergraduate education. MAIN OUTCOMES MEASURED: Mode and median scores for 232 learning outcomes. RESULTS: The individual learning objectives that scored most highly were related to history taking and examination, red flag symptoms, common ENT conditions including all forms of otitis, acute and chronic rhinosinusitis, thyroid disease, pharyngeal infection and airway compromise and formulation of differential diagnoses. CONCLUSIONS: Using a Delphi technique, a structured, evidence-based curriculum has been developed. This should assist those medical schools who do not currently have ENT in their curriculum but wish to reinstate it to produce a high quality teaching programme. It may also assist those medical schools who do have ENT in their curriculum to continue to develop their curriculum.

Central administration of ghrelin alters emotional responses in rats: behavioural, electrophysiological and molecular evidence.

The orexigenic and pro-obesity hormone ghrelin targets key hypothalamic and mesolimbic circuits involved in energy balance, appetite and reward. Given that such circuits are closely integrated with those regulating mood and cognition, we sought to determine whether chronic (>2 weeks) CNS exposure to ghrelin alters anxiety- and depression-like behaviour in rats as well as some physiological correlates. Rats bearing chronically implanted i.c.v. catheters were treated with ghrelin (10 µg/d) or vehicle for 4 weeks. Tests used to assess anxiety- and depression-like behaviour were undertaken during weeks 3-4 of the infusion. These revealed an increase in anxiety- and depression-like behaviour in the ghrelin-treated rats relative to controls. At the end of the 4-week infusion, brains were removed and the amygdala dissected for subsequent qPCR analysis that revealed changes in expression of a number of genes representing key systems implicated in these behavioural changes. Finally, given the key role of the dorsal raphe serotonin system in emotional reactivity, we examined the electrophysiological response of dorsal raphe neurons after a ghrelin challenge, and found mainly inhibitory responses in this region. We demonstrate that the central ghrelin signalling system is involved in emotional reactivity in rats, eliciting pro-anxiety and pro-depression effects and have begun to explore novel target systems for ghrelin that may be of importance for these effects.

Molecular architecture of the human specialised atrioventricular conduction axis.

The atrioventricular conduction axis, located in the septal component of the atrioventricular junctions, is arguably the most complex structure in the heart. It fulfils a multitude of functions, including the introduction of a delay between atrial and ventricular systole and backup pacemaking. Like any other multifunctional tissue, complexity is a key feature of this specialised tissue in the heart, and this complexity is both anatomical and electrophysiological, with the two being inextricably linked. We used quantitative PCR, histology and immunohistochemistry to analyse the axis from six human subjects. mRNAs for ~50 ion and gap junction channels, Ca(2+)-handling proteins and markers were measured in the atrial muscle (AM), a transitional area (TA), inferior nodal extension (INE), compact node (CN), penetrating bundle (PB) and ventricular muscle (VM). When compared to the AM, we found a lower expression of Na(v)1.5, K(ir)2.1, Cx43 and ANP mRNAs in the CN for example, but a higher expression of HCN1, HCN4, Ca(v)1.3, Ca(v)3.1, K(ir)3.4, Cx40 and Tbx3 mRNAs. Expression of some related proteins was in agreement with the expression of the corresponding mRNAs. There is a complex and heterogeneous pattern of expression of ion and gap junction channels and Ca(2+)-handling proteins in the human atrioventricular conduction axis that explains the function of this crucial pathway.

Changes in endovascular trophoblast invasion and spiral artery remodelling at term in a transgenic preeclamptic rat model.

As a follow-up to our previous study which revealed a surprisingly deeper endovascular trophoblast (ET) invasion on day 18 in a transgenic preeclamptic (PE) rat model (hAngiotensinogen female symbol x hRenin male symbol) compared to non-PE controls, we examined further changes in ET invasion and associated spiral artery (SA) remodelling at term (day 21). PE transgenic rats and non-PE reversely mated (RM) transgenic rats were compared to normal SD rats (C). Sections were stained to visualize trophoblast, fibrinoid, vascular smooth muscle (VSM) and endothelium. SA were evaluated in three depth levels in the mesometrial triangle (MT) using the KS-400 image analysis system. In separate transgenic rats, Doppler ultrasound was performed in uterine arteries, and the resistance indices (RI) were calculated. Although for the whole MT differences in ET invasion were no longer significant between the PE and C, indicating a partial catching up in C rats, there was still significantly more ET in the deepest level in the PE group as compared to the C and RM groups. At the same time the SA walls in PE rats contained significantly more fibrinoid (versus RM and C) and VSM (versus C). In all SA cross-sections, re-endothelialisation was prominent, but significantly different between PE and C group. The Doppler results showed a significantly lower RI in the arcuate uterine artery of the PE group compared to the C group. There was no evidence of elimination of deeply invaded ET at term, previously considered as a possible mechanism for restriction of vascular remodelling in human PE. The differences in vascular remodelling, previously described on day 18 by histology and Doppler data, were maintained on day 21, but there was extensive endothelial repair in the three groups. Atherosis-like lesions were observed in the three groups, most frequently in the RM group, but were never associated with placental infarcts.

On the central mechanism underlying ghrelin's chronic pro-obesity effects in rats: new insights from studies exploiting a potent ghrelin receptor antagonist.

In the present study, we explore the central nervous system mechanism underlying the chronic central effects of ghrelin with respect to increasing body weight and body fat. Specifically, using a recently developed ghrelin receptor antagonist, GHS-R1A (JMV2959), we investigate the role of GHS-R1A in mediating the effects of ghrelin on energy balance and on hypothalamic gene expression. As expected, in adult male rats, chronic central treatment with ghrelin for 14 days, when compared to vehicle-treated control rats, resulted in an increased body weight, lean mass and fat mass (assessed by dual X-ray absorptiometry), dissected white fat pad weight, cumulative food intake, food efficiency, respiratory exchange ratio and a decrease of energy expenditure. Co-administration of the ghrelin receptor antagonist JMV2959 suppressed/blocked the majority of these effects, with the notable exception of ghrelin-induced food intake and food efficiency. The hypothesis emerging from these data, namely that GHS-R1A mediates the chronic effects of ghrelin on fat accumulation, at least partly independent of food intake, is discussed in light of the accompanying data regarding the hypothalamic genes coding for peptides and receptors involved in energy balance regulation, which were found to have altered expression in these studies.

Endovascular trophoblast invasion, spiral artery remodelling and uteroplacental haemodynamics in a transgenic rat model of pre-eclampsia.

The aim of the present study was to evaluate the depth of endovascular trophoblast invasion and associated remodelling of spiral arteries in a transgenic model of pre-eclampsia in the rat, a species showing a comparable deep invasion during normal pregnancy as the human. Pre-eclamptic (PE) transgenic rats (TGR) (hAngiotensinogen female x hRenin male) and non-PE reversely mated (RM) TGR rats were compared to normal Sprague-Dawley rats (C). Day 18 implantation sites were collected and the presence of endovascular trophoblast, fibrinoid, endothelial and smooth muscle cells were evaluated in spiral arteries in three parallel layers in the mesometrial triangle using an image analysis system (KS-400). In a separate group of animals peak-systolic and end-diastolic velocities were measured by Doppler in uterine and arcuate arteries, and the resistance indices (RI) were calculated. In PE and RM rats, the entire mesometrial triangle contained significantly more endovascular trophoblast and vascular fibrinoid deposits than the C group. No difference was found between the groups in the overall amount of smooth muscle surrounding the lumen, but in the PE and RM groups significantly more muscle was present in parts of the contours covered by trophoblast. There was significantly less CD31-positive endothelium in the total lumen contours of the PE and RM groups than in the C group, but in parts of the contours covered by trophoblast more residual endothelium was present in both TGR groups. Comparison of the three layers indicated deeper invasion in both the PE and RM groups than in the C group. By Doppler analysis of the proximal uterine artery the RI was found to be significantly lower in the PE and the RM group than in the C group. In the arcuate artery, the RI was significantly lower in the PE group as compared to the RM and C groups. We conclude that in this transgenic PE rat model there is deeper endovascular invasion of spiral arteries and decreased RI of uterine arteries at day 18 of pregnancy.

Neurosteroid modulation of allopregnanolone and GABA effect on the GABA-A receptor.

The neurosteroid allopregnanolone (ALLO) or 3alpha-OH-5alpha-pregnane-20-one interacts with the GABA type A receptor chloride ion channel complex and enhances the effect of GABA. Animal and human studies suggest that ALLO plays an important role in several disorders including premenstrual syndrome, anxiety, and memory impairment. In contrast to ALLO, steroids with a hydroxy group in the 3beta position usually exert a reducing effect and have recently attracted interest due to their suggested role in counteracting the negative action of ALLO. In this study, five different 3beta-steroids were tested for their ability to modulate GABA-mediated chloride ion uptake in the absence and presence of ALLO in rat brain microsacs preparations. In addition, the effects of the 3beta-steroids and their interaction with ALLO were investigated by patch-clamp recordings of spontaneous inhibitory postsynaptic currents (sIPSCs) in rat hypothalamic neurons from the medial preoptic nucleus (MPN). All tested 3beta-steroids reduced the ALLO-enhanced GABA response in cerebral cortex, in hippocampus and in MPN. In cerebellum, only one had this effect. However, in the absence of ALLO, two of the 3beta-steroids potentiated GABA-evoked chloride ion uptake and prolonged the sIPSCs decay time, whereas the others had little or no effect. Therefore, it is possible that at least some 3beta-steroids can act as positive GABA(A) receptor modulators as well as negative modulators depending on whether or not ALLO is present. Finally, these results suggest that the 3beta-steroids could be of interest as pharmacological agents that could counteract the negative effects of ALLO.

GABA-site antagonism and pentobarbital actions do not depend on the alpha-subunit type in the recombinant rat GABA receptor.

AIM: The roles of alpha-subunits on the gamma-aminobutyric acid (GABA)-site antagonism and pentobarbital actions were examined in rat recombinant GABA(A) receptors in Xenopus oocytes. METHODS: Experiments were performed with binary and ternary GABA(A) receptors containing alpha1-, alpha4- or alpha5-subunit by the two-electrode voltage-clamp technique. RESULTS: The potency of GABA was significantly higher in the alpha1beta2, alpha4beta2 and alpha5beta2 receptors compared with the alpha1beta2gamma2L, alpha4beta2gamma2L and alpha5beta2gamma2L receptors. However, the alpha5beta2 receptor possessed significantly lower GABA efficacy compared with the alpha5beta2gamma2L receptor. While the gamma2-subunit was essential to the potency of GABA, its influence on the apparent GABA-site antagonism was less profound. The antagonist affinity constants (K(B)) of bicuculline inhibition and slopes of Schild plots were similar between all types of ternary and binary receptors except alpha5beta2 receptor which was not tested. The pK(B)s and IC(50)s of the GABA-site antagonism were not significantly different between the alpha1beta2gamma2L, alpha4beta2gamma2L and alpha5beta2gamma2L receptors. Bicuculline blocked pentobarbital-activated currents in a reversible and non-competitive manner with the alpha1beta2gamma2L, alpha4beta2gamma2L, and alpha5beta2gamma2L receptors, indicating an allosteric inhibition of the GABA-site. No significant difference of bicuculline potencies in inhibiting GABA- and pentobarbital-activated currents was found between the alpha1beta2gamma2L, alpha4beta2gamma2L and alpha5beta2gamma2L receptors. CONCLUSION: The GABA-site antagonism does not depend on the subtype of alpha-subunits. Similarly, pentobarbital activates ternary receptors composed of different alpha-subunits in a bicuculline-sensitive manner. The potencies of bicuculline to inhibit pentobarbital-activated currents are identical with receptors containing alpha1, alpha4 or alpha5-subunit. The alpha1beta2 and alpha4beta2 receptors possess higher GABA potencies compared with the alpha1beta2gamma2L and alpha4beta2gamma2L receptors.

TIMP-1 regulation of cell cycle in human breast epithelial cells via stabilization of p27(KIP1) protein.

Increasing evidence suggests that tissue inhibitor of metalloproteinases-1 (TIMP-1) can directly regulate cell growth and apoptosis independent of its matrix metalloproteinases (MMPs)-inhibitory activity. While TIMP-1's antiapoptotic activity has been well demonstrated, conflicting data has been reported regarding TIMP-1's role in growth regulation. Here we show that TIMP-1 reduces the growth rate of human breast epithelial (MCF10A) cells by inducing cell cycle arrest at G(1). TIMP-1-mediated cell cycle arrest is associated with its downregulation of cyclin D(1) and upregulation of p27(KIP1), resulting in inhibition of cyclin-dependent kinase activity necessary for phosphorylation of the tumor suppressor retinoblastoma protein. We further show that TIMP-1 modulation of cyclin D(1) and p27(KIP1) is achieved through TIMP-1-mediated differential regulation of protein stability independent of growth factor signaling. We also show that TIMP-1-mediated differential regulation of cyclin D(1) and p27(KIP1) is independent of cell adhesion signaling. Whereas approximately 50% of MCF10A cells with reduced TIMP-1 expression underwent cell death following loss of cell adhesion (anoikis), TIMP-1 overexpressing cells remained viable with prominent cell cycle arrest without detectable cell death. Taken together, we propose that TIMP-1-mediated cell survival independent of cell adhesion is accompanied with cell cycle arrest in human breast epithelial cells, although cell cycle regulation may not be a prerequisite for TIMP-1 regulation of apoptosis in general.

Effects of sex steroids on survival and receptor expression in ovarian epithelial tumour cells.

The factors that govern the genesis and progression of ovarian cancer remain unclear. It is thought that ovarian tumours are endocrine related and hormone dependent. We therefore investigated the effects of the sex steroids progesterone, testosterone and 17 beta-estradiol on tumour cell survival and the expression of estrogen receptors (ER) and progesterone receptors (PR) in tumour cells. The study was performed on primary cell cultures derived from patients suffering from epithelial ovarian cancer. The majority of the cells isolated expressed ER and PR to some degree, the combination ER+/PR+ was the most common. Both ER and PR expression decreased after 72-h culture, revealing an unexpectedly dynamic system. The survival rates of cells cultured in progesterone seemed to be inversely related to their PR expression. Lowering levels of 17 beta-estradiol and testosterone in cell cultures reduced cell survival, but it appears that this observation depends on factors other than ER.

Low sex steroid environment affects survival and steroid secretion of ovarian tumour cells in primary cultures.

Ovarian epithelial tumours are considered to be endocrine related. The effects of an environment with low levels of the steroid hormones 17 beta-estradiol, testosterone or progesterone on cell survival and steroid secretion were studied in primary cell cultures derived from 25 patients suffering from epithelial ovarian tumours. Tumour cells cultured in 17 beta-estradiol and testosterone showed a reduced cell survival (-10.3 +/- 2.3% and -15.6 +/- 2.7% minimum survival respectively). This reduction was inversely proportional to hormone concentrations within the range studied. No similar effect was observed in the progesterone cultures. It was found that 17 beta-estradiol was secreted from the primary cell cultures and, interestingly, the amount of 17 beta-estradiol secreted increased with increasing levels of 17 beta-estradiol in the environment. Neither progesterone nor testosterone production was observed in any of the cultures studied. It is believed that 17 beta-estradiol has an antiapoptotic effect on ovarian surface epithelial (OSE) cells. Reduction of 17 beta-estradiol in the environment may inhibit this effect, resulting in reduced cell survival. The ability of ovarian epithelial tumour cells to secrete 17 beta-estradiol suggests that epithelial ovarian tumours play an active role in altering their own hormonal environment, promoting tumour progression.