Loneliness Predicts Progression of Frailty in Married and Widowed, but Not Unmarried Community Dwelling Older Adults.

BACKGROUND: Loneliness is highly prevalent among older adults and is associated with frailty. Most studies consider loneliness in isolation without consideration for structural and functional measures of social relationships - and longitudinal studies are scarce. OBJECTIVES: This study examined longitudinal associations between loneliness and frailty and analyzed how structural and functional social measures influence these associations. DESIGN: Linear mixed effects models examined longitudinal associations between loneliness and frailty assessed with the frailty index (scale 0-100). Models were adjusted for baseline age, gender, education, depressive symptoms, global cognition, and structural (e.g., social network, marital status), and functional social measures (e.g., social, cognitive, and physical activity, and social support). PARTICIPANTS: Loneliness and frailty data from 1,931 older adults without dementia at baseline from the Rush Memory and Aging Project were examined (mean age 79.6 ± 7.7 years, 74.9% female). MEASUREMENTS: Baseline loneliness assessed by the de Jong Gierveld Loneliness Scale was the predictor of interest. RESULTS: Frailty increased significantly over a mean follow-up period of 4.6 years. Effects of loneliness on frailty were modified by marital status. Loneliness predicted an additional accumulation of 0.37 and 0.34 deficits on the frailty index per year in married and widowed individuals respectively, compared to those who were not lonely (married: p=0.009, CI 0.09, 0.64; widowed: p=0.005, CI 0.1, 0.58). Loneliness did not predict frailty progression in unmarried individuals. CONCLUSIONS: Loneliness predicts frailty progression, highlighting the importance of social determinants on physical health in aging.

Diabetes mellitus por mutación en el gen de glucokinasa: caso clínico / Diabetes mellitus caused by a mutation of glucokinase gene: report of an affected family

Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose. Subsequently, continuous glucose monitoring at 4 months of age revealed 47% of tissue glucose levels above 140 mg/dl, with fasting glucose levels between 120 and 166 mg/dl. The genetic analysis revealed a previously reported mutation in heterozygous state of the GCK gene (c.148C>T; p.His50Tyr). This mutation was also identified in more than one affected relative in the last two generations, with a transmission pattern suggestive of dominant inheritance. GCK gene sequencing led to a correct molecular diagnosis of MODY 2 while bioinformatic analysis indicated the possible molecular causes of the enzyme dysfunction. The knowledge of the molecular diagnosis allowed an adequate medical treatment for this disease.

[Diabetes mellitus caused by a mutation of glucokinase gene. Report of an affected family]. / Diabetes mellitus por mutación en el gen de glucokinasa. Caso clínico.

Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose. Subsequently, continuous glucose monitoring at 4 months of age revealed 47% of tissue glucose levels above 140 mg/dl, with fasting glucose levels between 120 and 166 mg/dl. The genetic analysis revealed a previously reported mutation in heterozygous state of the GCK gene (c.148C>T; p.His50Tyr). This mutation was also identified in more than one affected relative in the last two generations, with a transmission pattern suggestive of dominant inheritance. GCK gene sequencing led to a correct molecular diagnosis of MODY 2 while bioinformatic analysis indicated the possible molecular causes of the enzyme dysfunction. The knowledge of the molecular diagnosis allowed an adequate medical treatment for this disease.

Diabetes autoinmune (latente) del adulto / Latent autoimmune diabetes in adults

Backgroud: Latent Autoimmune Diabetes in Adults (LADA) is the term used to describe adults who have a slowly progressive form of diabetes mellitus (DM) of autoimmune etiology, but that may be treated initially without insulin. Although it shares some immunological and genetic aspects with type 1 DM, it affects an age group that is typically affected by type 2 DM. Therefore, it could be considered an intermediate type. Diagnosis is based on clinical and laboratory criteria: age of onset, initial response to oral hypoglycemic agents and the presence of specific antibodies for diabetes. Although the definitive treatment is insulin, glitazones may be useful in early stages of the disease. Currently, its management represents a challenge for the physician, including specialists, and it is a form of DM to keep in mind.

Sensorineural hearing loss and enamel hypoplasia with subtle nail findings: another family with Heimler's syndrome.

We report a pair of siblings who exhibit findings similar to those described in Heimler's syndrome, namely sensori- neural hearing loss diagnosed after the first year of life and enamel hypoplasia with normal primary dentition. Nail findings of Beau's lines and leukonychia which were described in the previous cases are absent to questionable in our patients. Our findings support the theory of autosomal recessive inheritance for Heimler's syndrome. To our knowledge there have been only three cases reported previously and the gene location has yet to be determined.

Determinación del índice de resistencia insulínica mediante HOMA en una población de la Región Metropolitana de Chile / Measurement of insulin resistance using the homeostasis model

Background: Insulin resistance is defined as an inappropriate high level of plasma insulin required to maintain metabolic homeostasis. It is associated with type 2 diabetes and cardiovascular diseases. The glucose clamp technique is the standard method for the measurement of insulin resistance. However, this method is laborious, expensive and impractical to perform in epidemiological investigations. The homeostasis model assessment (HOMA) has been proposed to assess insulin resistance and secretion, using fasting glucose and insulin concentrations. Aim: To measure insulin resistance using HOMA (HOMAir) in a population sample from the Metropolitan Region in Chile. Material and Methods: One hundred twenty subjects (59 female) with a normal body mass index and fasting blood glucose were studied. Fasting plasma glucose was measured by a glucose oxidase method and serum insulin was measured by radio immunoassay. Results: Fasting blood glucose was 81.6ñ9.4 mg/dl and serum insulin was 9.7ñ2.4 µU/ml. Mean HOMA insulin resistance was 1.96ñ0.57 (range 0.5 and 3.0). Conclusions: These HOMA values can be used as reference for Chilean non obese individuals

Chemical solution-deposited PbZr 0.53 Ti 0.47 O3 on La 0.5 Sr 0.5 Co O3. SIMS investigation of the effect of different precursor additives on the layer structure.

Chemical solution-deposited thin films of PbZr(0.53)Ti(0.47)O(3)/La(0.5)Sr(0.5)CoO(3) on Pt/TiO(2)/SiO(2)/Si substrates have been investigated by dynamic SIMS. The PbZr(0.53)Ti(0.47)O(3) (PZT) is intended to serve as a ferroelectric layer for microelectronic or microelectromechanical applications; conducting La(0.5)Sr(0.5)CoO(3) (LSCO) is a buffer layer intended to eliminate fatigue effects which usually occur at the Pt/PZT interface. Depth profiles of the main components were obtained and revealed that significant diffusion occurred during the deposition and crystallisation processes. Two types of sample, with different thickness of PZT and different types of poly(vinyl alcohol) (PVA) added to the LSCO precursor, were investigated.

Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study.

OBJECTIVE: To assess the efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis (MS). METHODS: Patients aged 18-65 years with a diagnosis of MS, a stable disability level < or =6 on the Kurtzke extended disability status scale (EDSS), and a mean score >4 on the fatigue severity scale (FSS) were eligible for the 9 week, single blind, phase 2, two centre study. Exclusion criteria included a diagnosis of narcolepsy, sleep apnoea, or clinically significant major systemic disease and recent use of medications affecting fatigue. All patients, who remained blinded for the treatment regimen, received placebo during weeks 1-2, 200 mg/day modafinil during weeks 3-4, 400 mg/day modafinil during weeks 5-6, and placebo during weeks 7-9. Safety was evaluated by unblinded investigators. Efficacy was evaluated by self rating scales, using the FSS, the modified fatigue impact scale (MFIS), a visual analogue scale for fatigue (VAS-F), and the Epworth sleepiness scale (ESS). Adverse events were recorded. RESULTS: Seventy two patients (MS type: 74% relapsing-remitting; 7% primary progressive; 19% secondary progressive) received treatment. After treatment with 200 mg/day modafinil for 2 weeks, a significant improvement in fatigue versus placebo run in was demonstrated. Mean scores after treatment with 200 mg/day modafinil were: FSS, 4.7 versus 5.5 for placebo (p<0.001); MFIS, 37.7 versus 44.7 (p<0.001); and VAS-F, 5.4 versus 4.5 (p=0.003). Fatigue scores for 400 mg/day modafinil were not significantly improved versus placebo run in. Mean ESS scores were significantly improved (p<0.001) with 200 mg/day modafinil (7.2) and 400 mg/day (7.0) versus the score at baseline (9.5). Serious adverse events were not found at either dose. The most common adverse events were headache, nausea, and aesthenia. Sixty five patients (90%) completed the study. CONCLUSIONS: These data suggest that 200 mg/day modafinil significantly improves fatigue and is well tolerated in patients with MS.

Clarification by TEM and SIMS of abnormal Ti depth distribution in chemical solution-deposited SrTiO3/La0.5Sr0.5CoO3.

A chemical solution-deposited multilayer system of SrTiO3 ("STO")/La0.5Sr0.5CoO3 ("LSCO") on a platinized wafer with a layer sequence Pt/TiO2/SiO2/Si(bulk) has been investigated by dynamic SIMS (secondary ion mass spectroscopy) and TEM (transmission electron microscopy); element determination was performed with EELS (electron energy-loss spectroscopy). The STO layer is intended to serve as a dielectric layer for a microelectronic capacitor; the conducting LSCO layer is a buffer layer intended to eliminate fatigue effects which usually occur at the STO/Pt interface. The SIMS depth profiles obtained for the main components revealed intense diffusion processes which must have occurred during the deposition/crystallization processes. Ti is found to diffuse from the (insulating) STO layer into the conductive LSCO layer where a region of constant concentration is observable. TEM-EELS experiments showed that these Ti plateaus are caused by precipitates approximately 20-80 nm in diameter.

Differential Image Distortion Correction.

Imaging techniques often suffer from distortion effects. Former methods of reducing these distortions have been based either on improving the imaging technique (i.e., to avoid distortions) or on the use of reference samples (i.e., to determine the distortion field by imaging of a known structure. We present a novel method of correcting image distortion by evaluating the imaged position changes due to two small sample position shifts. The algorithm allows us to calculate a vector field, which enables us to determine the "undistorted" position of any point of the image. The presented method has very low presuppositions about the sample, requires no reference samples, and is applicable to any type of image distortion. In addition to the presentation of the method's theoretical basis and a description of the computational method, we present corrected secondary ion mass spectroscopy (SIMS) images of a regular structure (a copper grid) as well as a stochastic distribution (sodium impurities) to show the results of empirical data.

How accurately does wrist actigraphy identify the states of sleep and wakefulness?

STUDY OBJECTIVES: Because sleep and wakefulness differ from each other by the amount of body movement, it has been claimed that the two states can be accurately distinguished by wrist actigraphy. Our objective was to test this claim in lengthy polysomnographic (psg) and actigraphic (acf) samples that included night and day components. DESIGN: Fourteen healthy young (21-35 years) and old (70-72 years) men and women lived in a laboratory without temporal cues for 7 days. Each subject continuously wore sleep-recording electrodes as well as 2 wrist-movement recorders. Act measurements were converted to predictions of sleep and wakefulness by simple-threshold and multiple-regression methods. Psg served as the gold standard for calculation of predictive values (PV, the probability that an act prediction is correct by psg criteria). SETTING: N/A. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The 7-day act recordings showed clear circadian cycles of high and low activity that respectively corresponded to subjective days, when subjects were wakeful, and subjective nights when they slept. Lower act levels corresponded to deeper states of psg sleep. Logistic regression on a 20-minute moving average of act gave the highest overall PV's. Nevertheless, the mean PV for sleep (PVS) was only 62.2% in complete, day + night samples. PVS was 86.6% in night samples. Act successfully predicted wakefulness during subjective nights (PVW = 89.6) and accurately measured circadian period length and the extent of sleep-wake consolidation, but it overestimated sleep rate and sleep efficiency. Act systematically decreased before sleep onset and increased before awakening, but reliable transitions among joint psg/act states (the Markov-1 property) were not demonstrated. CONCLUSIONS: Low PV's and overestimation of sleep currently disqualify actigraphy as an accurate sleep-wake indicator. Actigraphy may, however, by useful for measuring circadian period and sleep-wake consolidation and has face validity as a measure of rest/activity.

Tissue-engineered bone regeneration.

Bone lesions above a critical size become scarred rather than regenerated, leading to nonunion. We have attempted to obtain a greater degree of regeneration by using a resorbable scaffold with regeneration-competent cells to recreate an embryonic environment in injured adult tissues, and thus improve clinical outcome. We have used a combination of a coral scaffold with in vitro-expanded marrow stromal cells (MSC) to increase osteogenesis more than that obtained with the scaffold alone or the scaffold plus fresh bone marrow. The efficiency of the various combinations was assessed in a large segmental defect model in sheep. The tissue-engineered artificial bone underwent morphogenesis leading to complete recorticalization and the formation of a medullary canal with mature lamellar cortical bone in the most favorable cases. Clinical union never occurred when the defects were left empty or filled with the scaffold alone. In contrast, clinical union was obtained in three out of seven operated limbs when the defects were filled with the tissue-engineered bone.

Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia.

The present randomized, double-blind, placebo and active-drug controlled, crossover study assessed residual sedation after zaleplon 10 mg, flurazepam 30 mg (as an active control), and placebo, taken during a nocturnal awakening in patients with sleep maintenance insomnia. Twenty-two healthy sleep maintenance insomniacs (11 men; mean age, 42 y) received zaleplon, flurazepam, or placebo after an experimental awakening 3.5 hours after bedtime on two consecutive nights in each of three conditions. Residual sedation was measured with sleep latency testing (5 and 6.5 h postdrug), digit symbol substitution, symbol copying, and subjective sleepiness by visual analog scale, each twice each morning. Zaleplon did not differ from placebo on any measure of residual sedation; flurazepam showed significant sedation on all measures. No residual sedative effects were detected 5 or 6.5 hours after ingestion of zaleplon during the middle of the night by sleep maintenance insomniacs.

Channelplate Illumination Correction for Secondary Ion Mass Spectroscopy Images by Solving Apparatus Elasticity Equations.

: The SIMS channelplate used for recording image signals is characterized by local sensitivity differences caused by increasing aging of the central channelplate regions, which are subject to much more intense ion bombardment than the outer regions. These sensitivity differences lead to inhomogenous illumination of the sample, i.e., to images with disturbed intensity distributions. We present here a novel method to correct these illumination discrepancies by using the intensity changes due to sample position shifts to find the interfering background function that can be used to correct the original image. The proposed method has low presuppositions about the regarded images, and is stable with regard to noise and easy to apply. It is suitable not only for correction of channelplate local sensitivity differences but for all sorts of microscopic images that suffer from illumination inhomogeneity.

Osteogenesis with coral is increased by BMP and BMC in a rat cranioplasty.

Autologous bone marrow cells (BMC), bone morphogenetic protein (BMP) and natural coral exoskeleton (CC) were used to enhance the repair of large skull bone defects in a craniotomy model. Nine millimeter calvarial defects were created in adult rats and were either left empty (control defects) or implanted with CC alone, CC-BMC, CC-BMP, or CC-BMC-BMP. After 1 or 2 months, osteogenesis was insufficient to allow union when defects were left empty or filled with CC. Addition of BMC alone to CC had no positive influence on osteogenesis at any time and increased CC resorption at 2 months (0.1 +/- 0.1 mm2 versus 0.5 +/- 0.3 mm2). In contrast addition of BM P or BM P/BMC to CC led to a significant increase in osteogenesis and allowed bone union after 1 month. At 2 months, the combination of CC-BM P-BMC was the most potent activator of osteogenesis. Filling a defect with CC-BMP-BMC resulted in significantly increased bone surface area (11 +/- 2.7 mm2) in comparison to filling a defect with CC-BMP (7.0 +/- 1.4 mm2), CC-BMC (3.5 +/- 1.1 mm2) or CC (4.5 +/- 0.4 mm2). CC resorption was significantly decreased in the presence of BMP with or without BMC at both times. These data are in accordance with the presence of progenitor cells in bone marrow that are inducible by BMP to the osteogenic pathway in a cranial site. The increase in material resorption in defects filled with CC-BMC could suggest that cells from the granulocyte-macrophage lineage survived the grafting procedure and were still active after 2 months.

Can panic be induced in deep sleep? Examining the necessity of cognitive processing for panic.

This study examines the relative contribution of biological and psychological processes to the induction of panic attacks by a biochemical challenge agent. Panicogenic doses of caffeine were administered to 8 panic disorder (PD) patients and 11 healthy volunteers during stage 3-4 sleep, when cognitive processing is minimal and the threshold to external stimuli is high. Panic attacks were induced directly from sleep in 3 subjects and subclinical panics in an additional 3. Subjects who experienced full panic attacks spent periods of time ranging from 4 to 52 minutes in stage 2 sleep before awakening in a panic, while those who awakened in subclinical panic awakened almost directly from stage 4 sleep. PD patients experienced significantly more panic symptoms than healthy volunteers. Although limited by a small sample size, this study suggests a combined biological-psychological model of panic induction in which panic disorder patients are more biologically predisposed than healthy controls to panic symptoms but may require cognitive processing for the elaboration of a full panic attack.

Direct comparison of two widely used activity recorders.

Wrist actigraphy is increasingly used to track circadian rest-activity cycles and to identify states of wakefulness and sleep, yet the measurement characteristics of activity recorders have never been compared. Two widely used recorders are compared here: the MotionLogger from Ambulatory Monitoring, Inc (AM) and the Gaehwiler (G). They were worn together on the same wrist for periods averaging 41.5 hours by five members of a research team. Activity counts were stored every half-minute. Pairwise comparisons between recorders of each type showed both types to be reliable. Each also validly detected circadian rest/activity cycles. Both types suffered, however, from insensitivity. For the lower 75% of activity levels, the variance of data from the G was indeed so small as to be essentially uninformative. Since these levels include over 95% of all nocturnal data, the G must be less sensitive than the AM to small nocturnal movements, including those signifying arousal. An additional difference is that data from the AM but not the G were distributed in biphasic fashion. Biphasic activity levels are consistent with the common assumption that activity/wakefulness and rest/sleep are distinct neurobehavioral states. As the use of actigraphy increases, the important differences found here between two leading instruments point to an urgent need for standards by which activity recorders can be compared. Aspects of instrument design that could be quantitatively rated are reliability, validity, ruggedness and artifact rejection.

Expression of parathyroid hormone-related peptide (PTHrP) and PTH/PTHrP receptor in newborn human calvaria osteoblastic cells.

We examined the expression of parathyroid hormone-related peptide (PTHrP) and its receptor in normal newborn human calvaria osteoblastic (NHCO) cells. Northern blot analysis showed that NHCO cells express a single 1.6 kb transcript of PTHrP, which was increased within 1 h (2x) and peaked at 6 h (7x) after serum treatment. In the culture media, the release of PTHrP peptide was maximally increased (4x) 24 h after the addition of serum, as determined by immunoradiometric assay. NHCO cells exhibited a cytoplasmic immunostaining for PTHrP in the presence of serum, and most PTHrP-positive cells were alkaline phosphatase-negative, suggesting that PTHrP was expressed in undifferentiated cells. Furthermore, RT-PCR analysis showed that both PTHrP and PTH/PTHrP receptor were expressed in NHCO cells in basal conditions or after stimulation with serum. The maximal PTHrP expression induced by serum suppressed PTH/PTHrP receptor expression, suggesting that PTHrP down-regulated its receptor in NHCO cells. Treatment with 10 nM human PTH(1-34) which binds to PTH/PTHrP receptors, increased intracellular cAMP levels and alkaline phosphatase activity, and decreased cell growth, indicating that ligand binding to PTH/PTHrP receptors regulates NHCO cell proliferation and differentiation. The expression and synthesis of PTHrP and the presence of functional PTH/PTHrP receptors suggest a possible paracrine mechanism of action of PTHrP in normal human calvaria osteoblastic cells.

Circadian rest-activity rhythms in demented and nondemented older community residents and their caregivers.

OBJECTIVE: Disruptive nocturnal behaviors (DNBs) of older people often threaten the caregiving arrangements on which their community tenure depends. Dementing disorders are especially prone to result in disrupted sleep and agitated behaviors ("sundowning"). The objective here was to develop an objective correlate of DNBs, by which their severity and effects on caregivers can be measured. DESIGN: Quantitative comparison of subjective sleep and motor activity patterns in older people and their caregivers. It was hypothesized that older people with reported DNBs would be more motorically active at night than their caregivers. SETTING: Subjects' homes. PARTICIPANTS: Twenty-five demented and 18 nondemented older day-care participants and their paired caregivers. MEASUREMENTS: Older subjects and caregivers simultaneously kept daily sleep logs and recorded wrist motor activity every .5 minute for 9 days. A novel method was devised to identify and exclude from analysis periods when the activity monitor was not being worn. Such periods were common. Activity data were analyzed by computing hourly means and by fitting cosine models by least squares. RESULTS: Demented older people were not significantly more active at night than their caregivers, though group differences varied by time of night. They were significantly less active in the daytime than were their caregivers. Nondemented older people were significantly more active at night than their caregivers and were as active by day as their caregivers. The caregivers of demented and nondemented older people had similar rest-activity patterns. The mean amplitudes of cosine models were smaller in the older adults. Acrophases (peaks) fell between 2 and 3 pm and did not differ significantly among the groups. CONCLUSIONS: As a result of increased nighttime motor activity and decreased daytime activity, rest-activity rhythms were flatter in older adults than in caregivers. This was not explained fully by age and does not necessarily imply that the output of a circadian pacemaker was low. Decreased daytime activity may have resulted from deficient physical stimulation or frailty. Frailty may also explain why nighttime activity was not more elevated in the demented older people. Increased nighttime activity is probably explained by depression, sleep-schedule disturbances, restless legs, or other sleep disorders. Judging by their shared variations of activity, caregivers interacted mainly with the demented older people at bedtime and at rising time in the morning.

Secretory products of breast cancer cells specifically affect human osteoblastic cells: partial characterization of active factors.

The pathogenesis of tumor-induced osteolysis (TIO) following breast cancer metastases in bone remains unclear. We postulated that osteoblasts could be target cells for the secretory products of breast cancer cells. We previously showed that serum-free conditioned medium (CM) of the breast cancer cell line MCF-7 inhibits DNA synthesis by 75% of control values in osteoblast-like cells SaOS-2 and that this effect is only in a minor part due to transforming growth factor beta secretion. To establish the specificity of our observations and to look for other biologically active factors, we have tested the effects of medium conditioned by several cancer and noncancer cell lines (breast, colon, placenta, or fibrosarcoma) on the proliferation of osteoblast-like cells (SaOS-2, MG-63), normal human osteoblasts, human fibrosarcoma cells, and normal human fibroblasts. Culture medium (1:2) of the breast cancer cell lines MCF-7, T-47D, MDA-MB-231, and SK-BR-3 inhibited by 25-50% the proliferation of osteoblast-like cells SaOS-2, MG-63, and normal osteoblasts as evaluated by the MTT survival test or [3H]thymidine incorporation. MCF-7 cells completely inhibited the proliferation of normal human osteoblasts in coculture. This inhibitory effect was reversible and not due to cytotoxicity. Moreover, the cyclic adenosine monophosphate (cAMP) response to parathyroid hormone (PTH) of osteoblast-like cells SaOS-2 was also increased by 100-240% by the same CM. Such activities were, however, not detected in medium from the breast noncancer cell line HBL-100 or in the medium conditioned by non-breast cancer cell lines (COLO 320DM, HT-29, JAR, or HT-1080). Medium from the breast cancer cells had no effect on normal human fibroblasts or fibrosarcoma cells (HT-1080), suggesting the specificity of their action on human osteoblasts. After partial purification by ultrafiltration and size-exclusion chromatography, we found that medium of T-47D cells contained at least three nonprostanoid factors of low molecular weights (apparent MW of 700, 1500, and 4000 D) which affected human osteoblast-like cells. These factors were heat stable and could be peptides without disulfide bonds. In summary, our data show that human breast cancer cells release soluble factors that inhibit osteoblast proliferation and increase their cAMP response to PTH, indicating that osteoblasts could be important target cells for breast cancer cells and could be involved in the process of TIO.