Modeling the interference between shear and longitudinal waves under high intensity focused ultrasound propagation in bone.

Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) is a noninvasive thermal technique that enables rapid heating of a specific area in the human body. Its clinical relevance has been proven for the treatments of soft tissue tumors, like uterine fibroids, and for the treatments of solid tumors in bone. In MR-HIFU treatment, MR-thermometry is used to monitor the temperature evolution in soft tissue. However, this technique is currently unavailable for bone tissue. Computer models can play a key role in the accurate prediction and monitoring of temperature. Here, we present a computer ray tracing model that calculates the heat production density in the focal region. This model accounts for both the propagation of shear waves and the interference between longitudinal and shear waves. The model was first compared with a finite element approach which solves the Helmholtz equation in soft tissue and the frequency-domain wave equation in bone. To obtain the temperature evolution in the focal region, the heat equation was solved using the heat production density generated by the raytracer as a heat source. Then, we investigated the role of the interaction between shear and longitudinal waves in terms of dissipated power and temperature output. The results of our model were in agreement with the results obtained by solving the Helmholtz equation and the frequency-domain wave equation, both in soft tissue and bone. Our results suggest that it is imperative to include both shear waves and their interference with longitudinal waves in the model when simulating high intensity focused ultrasound propagation in solids. In fact, when modeling HIFU treatments, omitting the interference between shear and longitudinal waves leads to an over-estimation of the temperature increase in the tissues.

Modelling the temperature evolution of bone under high intensity focused ultrasound.

Magnetic resonance-guided high intensity focused ultrasound (MR-HIFU) has been clinically shown to be effective for palliative pain management in patients suffering from skeletal metastasis. The underlying mechanism is supposed to be periosteal denervation caused by ablative temperatures reached through ultrasound heating of the cortex. The challenge is exact temperature control during sonication as MR-based thermometry approaches for bone tissue are currently not available. Thus, in contrast to the MR-HIFU ablation of soft tissue, a thermometry feedback to the HIFU is lacking, and the treatment of bone metastasis is entirely based on temperature information acquired in the soft tissue adjacent to the bone surface. However, heating of the adjacent tissue depends on the exact sonication protocol and requires extensive modelling to estimate the actual temperature of the cortex. Here we develop a computational model to calculate the spatial temperature evolution in bone and the adjacent tissue during sonication. First, a ray-tracing technique is used to compute the heat production in each spatial point serving as a source term for the second part, where the actual temperature is calculated as a function of space and time by solving the Pennes bio-heat equation. Importantly, our model includes shear waves that arise at the bone interface as well as all geometrical considerations of transducer and bone geometry. The model was compared with a theoretical approach based on the far field approximation and an MR-HIFU experiment using a bone phantom. Furthermore, we investigated the contribution of shear waves to the heat production and resulting temperatures in bone. The temperature evolution predicted by our model was in accordance with the far field approximation and agreed well with the experimental data obtained in phantoms. Our model allows the simulation of the HIFU treatments of bone metastasis in patients and can be extended to a planning tool prior to MR-HIFU treatments.

Activity and cellular origin of gelatinases in patients with colon and rectal carcinoma differential activity of matrix metalloproteinase-9.

BACKGROUND: Expression and enzymatic activity of gelatinases were examined in biopsy specimens from patients with colon and rectal neoplasms. The objective of this study was to determine whether the activity of these enzymes is altered between tumor areas compared with areas of noninvolved, normal mucosa and between colon and rectal carcinoma. METHODS: Matrix metalloproteinase (MMP) production was analyzed by Western immunoblot analysis and gelatin zymography. mRNA was determined by quantitative, real-time polymerase chain reaction analysis. RESULTS: Patients with colon carcinoma (n = 20 patients) showed a significant increase in levels of MMP-9 (92 kDa and 88 kDa) and MMP-2 (72 kDa and 62 kDa) in tumor areas compared with noninvolved regions. In contrast, patients with rectal carcinoma (n = 10 patients) had revealed the same high activity of MMP-9 in tumor regions and corresponding healthy tissue. Confirming activity measurements, in colon tumors, but not in rectal tumors, there was significant up-regulation of MMP-9 transcription compared with healthy tissue in the same patients. There were no significant changes in the tissue inhibitor of metalloproteinase-1 protein when colon and rectal tumor tissues were compared with the corresponding noninvolved regions. Cell culture experiments revealed fibroblasts as the cellular origin of MMPs. The findings showed that the secretion and activation of gelatinases depend on soluble factors secreted by tumor cells and are influenced by extracellular matrix components. CONCLUSIONS: This is the first report showing differences in MMP-9 activity between rectal carcinoma and colon carcinoma. Previous results indicating an active involvement of stromal cells in the generation of MMPs during tumor invasion are extended. Because the abundance of gelatinases increases in colorectal carcinoma, inhibitors of these proteases may be of therapeutic value.

Relationships of sex hormone levels to dependence in activities of daily living in the frail elderly.

OBJECTIVES: We undertook this nursing home study in order to determine the relationships between dependency in activities of daily living (ADL) and blood levels of estrone, testosterone, androstenedione, and dehydroepiandrosterone (DHEA). Little is known about this issue. METHODS: cross-sectional study of 370 nursing home residents. Hormone levels in blood specimens drawn in 1997 and 1998 were correlated with degree of ADL dependency recorded in medical charts. RESULTS: Because of multiple comparisons associations were deemed significant for P-values < or =0.017 for males and < or =0.0125 for females. In males, the following were inversely related: testosterone levels with dependency in transferring and eating; estrone with eating and a summary ADL index; and androstenedione with toileting and a summary ADL index (in all cases, r=-0.4; P=0.007-0.015). Inverse trends existed between testosterone levels and dependency in mobility and a summary ADL index; and androstenedione and eating (in all cases r=-0.3; P=0.030-0.055). Among females the following were directly related: estrone levels with dependence in mobility, toileting, transferring, and a summary ADL index; and DHEA with transferring and a summary ADL index (r=0.2-0.3, P=0.0001-0.01). Trends existed between estrone and eating, and DHEA and toileting (r=0.1-0.2, P=0.04). CONCLUSION: In male residents, higher sex hormone levels are associated with better ADL performance. Among females the opposite is true. While further studies are needed to elucidate these relationships, our results and recent findings of others suggest sex hormone actions in older women differ from those in younger populations. A possible stress-related mechanism is also presented.

Elevated serum total and LDL cholesterol in very old patients with Alzheimer's disease.

The relationships of serum lipids with Alzheimer's disease (AD) and other dementias in very old patients are not clear. All residents of an academic nursing home were studied clinically for dementia and for serum lipids. All those autopsied over a 7.7-year period had apolipoprotein E (apoE) genotyping and detailed neuropathological examination. Those with pathologically defined criteria for AD (n = 84) were compared to all others who also had clinical dementia but did not show AD changes (n = 22). In contrast to most other reports of serum lipids in very old patients with AD, total cholesterol (TC) and low density lipoprotein cholesterol levels were each significantly higher for those with AD. The lipid-AD associations were progressively stronger with increasing pathological certainty of AD diagnosis. These relationships remained significant after adjustment for apoE genotype and for other known risk factors. The lipid-AD associations in a very old cohort, and prior evidence that elevated TC in middle life is a risk factor for later dementia, prompt consideration of factors associated with lipid metabolism in the development of Alzheimer's dementia.

[Sense of coherence and commitment to a cardiac rehabilitation program after a myocardial infarction: preliminary results]. / Le sens de la cohérence et l'engagement dans un programme de revalidation cardiaque suite à un infarctus du myocarde: résultats préliminaires.

This study investigate the impact of the sense of coherence or SOC (1) on the commitment to health behaviors, as the participation in a revalidation program (physical training) after a first myocardial infarction. Fifteen subjects have been assessed three times after their myocardial infarction. The data indicate a possible effect of the sense of coherence which is higher among participants in comparison with subjects who refused to be involved in the program.

The relationship of tamoxifen with dementia, depression, and dependence in activities of daily living in elderly nursing home residents.

OBJECTIVES: To evaluate the association between tamoxifen treatment and the prevalence of Alzheimer's disease, other dementias, depression, and the levels of dependence in activities of daily living (ADL) in elderly, nursing home residents. PARTICIPANTS: 93,031 women, at least 65 years old, whose data were part of the 1993 New York State MDS, and for whom there was documentation of treatment with at least one medication. SETTING: New York State long-term care facilities. DESIGN: Cross-sectional study via secondary analysis of 1,385 matched sets of residents. Each set included one resident who received tamoxifen treatment and up to four residents who did not. MEASUREMENTS: Included age, ethnicity, tamoxifen treatment, hormone replacement therapy, depression, levels of dependence in ADL and in cognitive skills for daily decision-making, and documentation of Alzheimer's disease and other dementias. RESULTS: Women receiving tamoxifen were less likely to have a diagnosis of Alzheimer's disease documented on the MDS (odds ratio: 0.674; 95% confidence interval: 0.551-0.823), were significantly more independent in bed mobility, eating, toileting (in each case P < 0.0001), personal hygiene (P = 0.0155), dressing (P = 0.0015), transferring (P = 0.0006), locomotion (P = 0.0016), and they had better cognitive skills for daily decision-making (P < 0.0001). They were, however, 42% more likely to have a MDS diagnosis of depression (P < 0.0001). All tests of statistical significance are two-sided. CONCLUSION: In this population, tamoxifen was associated with a higher level of independence in ADL and decision-making. While the MDS also suggested a relationship of tamoxifen with a lower prevalence of Alzheimer's disease, there seemed to be an increased prevalence of depression among treated women. The findings of this cross-sectional study could be evaluated in the randomized clinical trial that has just begun, and that will compare tamoxifen and raloxifene treatments.

Expression of matrix metalloproteinase-2 in glial and neuronal tumor cell lines: inverse correlation with proliferation rate.

The expression of matrix metalloproteinases (MMPs) has been found to be positively correlated to the degree of malignancy in gliomas, indicating that poorly differentiated brain tumor cells produce more MMPs than differentiated ones. We determined the production of active MMP-2 in five glial (U138MG, U373MG, A172, C6, GOS-3), two neuronal (SK-N-SH, SK-N-MC), and two pluripotent cell lines with facultative neuronal and glial differentiation (P19 and NT2) by gelatin zymography. The MMP-2 activity profiles were compared to the proliferative activities of the cell lines. MMP-2 expression varied from barely existent (P19 cells) to strong (U138MG and SK-N-SH). Interestingly, for the cell lines with high MMP-2 expression levels, low proliferative activities were recorded, and vice versa. Retinoic acid induced neuronal differentiation and a reduction of proliferation of P19 cells; the differentiated cells produced significantly more MMP-2 than untreated cells. Upon confluency, GOS-3 cells showed reduced proliferation, but increased MMP expression. Thus, proliferative activity was inversely correlated to MMP-2 expression in the tumor cell lines analyzed.

Changes in bedrail prevalence during a bedrails-reduction initiative.

OBJECTIVE: To examine the prevalence of bedrails and observe whether use of bedrails can be decreased during a bedrails-reduction initiative. DESIGN: A serial, cross-sectional, observational study of bedrail use. PATIENTS AND SETTING: An 816-bed not-for-profit nursing facility with academic affiliation and closed medical staff. Median age of residents was 88.1 (range 62-108); 74% were women and 26% were men. MEASUREMENTS: Observed use of bedrails with classification of bedrail configurations into Enclosure Levels based on percentage of bedsides enclosed; serial census of bedrail use during a restraint-reduction effort. RESULTS: Bedrail configurations fell into five Enclosure Levels based on percentage of the bed enclosed. Over 9 months, total bedrail prevalence increased from 50 to 56%; however, the highest Enclosure Levels decreased from 7.7 to 3.9%. CONCLUSIONS: Bedrail configurations can be placed on a continuum of enclosure, and highest Enclosure Levels can be decreased during a bedrails-reduction program.

Restraint reduction reduces serious injuries among nursing home residents.

OBJECTIVES: To describe how removing physical restraints affected injuries in nursing home settings. DESIGN: A 2-year prospective study of an educational intervention for physical restraint reduction. SETTING: Sixteen diverse nursing homes with 2075 beds in California, Michigan, New York, and North Carolina. PARTICIPANTS: Study A: 859 residents who were physically restrained at the onset of the intervention on October 1, 1991. Study B: all residents who occupied the 2075 beds in the 16 facilities 3 months before the intervention and 3 months after its completion. INTERVENTION: Educational program for nursing home staff followed by quarterly site consultations to participating nursing homes. MAIN OUTCOME MEASURES: Rate of physical restraint use and injuries. RESULTS: Study A: Serious injuries declined significantly among the 859 residents restrained initially when restraint orders were discontinued (X2 = 6.2, P = .013). Study B: During the intervention period, physical restraint use among the 2075 residents decreased from 41% to 4%, a 90% reduction. The decrease in the percentage of injuries of moderate to serious severity was significant (i.e., 7.5% vs 4.4%, P2-tail = .0004) as was the rate of moderate and serious injuries combined (Rate Ratio = 1.580, P2-tail = .0033). CONCLUSIONS: A substantial decrease in restraint use occurred without an increase in serious injuries. Although minor injuries and falls increased, restraint-free care is safe when a comprehensive assessment is done and restraint alternatives are used.

Increased TIMP-1 activity results in increased expression of gelatinases and altered cell motility.

Matrix metalloproteinases are proteolytic enzymes which play a major role in resorption of collagen and other components of the extracellular matrix. They are controlled by specific inhibitors, so-called tissue inhibitors of metalloproteinases (TIMPs). The balance between matrix metalloproteinases and TIMPs seems to play a major role in controlling extracellular matrix homeostasis and cell migration. The influence of TIMP-1 on migration behaviour was explored in human hepatoma cells transiently and stably transfected with mouse TIMP-1, and incubated with biologically active TIMP-1. Transfection and biosynthesis were verified by Northern blotting, Western blotting, metabolic labeling, and reverse zymography. Overexpression of and incubation with TIMP-1 resulted in suppressed migration and seemed to enhance cell-cell contact. Using gelatin zymography and Western blotting we measured a significant increase of matrix metalloproteinases-2 and matrix metalloproteinases-9 in cells transfected with TIMP-1. This new phenomenon may be of important physiological significance in modulating TIMP and MMP expression. Our results indicate a functional involvement of TIMP-1 in matrix homeostasis and some automatic control in matrix turnover.

Migratory potential of transplantable neural tumor cell lines.

Experimentally induced primitive neuroectodermal tumor (PNET) cell lines were transplanted into neonatal and adult rat brain and examined neuropathologically for their tumorigenic potential. Both cell lines showed a striking migratory behavior in both neonatal and adult brain. Migration of tumor cells was found in host brain parenchyma, along white matter tracts and associated with CSF pathways. These neural tumor cell lines provide a valuable tool for the development of strategies against strongly migrating neural tumors.

[Institutional handling of sexual abuse: experiences, evaluations, and desires of nonabusing parents of sexually abused children]. / Institutioneller Umgang mit sexuellem Missbrauch: Erfahrungen, Bewertungen und Wünsche nichtmissbrauchender Eltern sexuell missbrauchter Kinder.

This article describes experiences of parents of sexual abused children and their evaluations of institutional interventions on sexual child abuse. Results are presented of a study investigating 'individual and institutional reactions on sexual child abuse'. The number of contacted institutions, personnel experiences with these institutions and resulting requirements are described. The results are based on a sample of 47 (82.5%) girls and 10 (17.5%) boys (range 6-18 years) and interviews with their 'non-abusing' parents. 28 (49.1%) of these children were abused by a member of the family, 29 (50.9%) children by non-familiar persons. It could be shown that 70.2% of the children had contacted four or more different institutions soon after the sexual abuse had been revealed. In cases of sexual abuse by a family member the first contacted institution was the Youth-and-Health-Care-System whereas in cases of sexual abuse by non-familiar persons mostly the police was contacted. Nevertheless in most cases both judicial and supporting approach were chosen. Additionally to concrete advices and professional competences the interviewed parents reported that emotional warmth was a very helpful aspect of the professional intervention. Generally the perspective of the parents seems to give some interesting informations about 'consumer satisfaction'.

ErbB-2 protein in sera and tumors of breast cancer patients.

We compared levels of erbB-2 oncoprotein among three groups: Group I included 60 asymptomatic women; Group II had 51 women with benign breast biopsies; and Group III had 67 women with node-negative breast cancer. Serological levels of erbB-2 protein were measured in all participants; tumor levels were measured for Groups II and III. Forty-three percent of usable tumors (25/58), including three of seven lobular tumors, were erbB-2 positive. Tumor and blood oncoprotein levels were unrelated. Blood levels, however, were positively related to tumor volume, but only when the tumor had both a ductal carcinoma in situ (DCIS) component and an invasive component, suggesting a role for erbB-2 protein in progression of DCIS to invasive carcinoma. In Groups I and II serological levels of erbB-2 protein were directly related to age, and inversely related to having had a live birth. Therefore, a model that determined the threshold levels of serological erbB-2 positivity in Group III included age and nulliparity as independent variables. Only three of the 67 women (4.5%) in Group III were positive for serological erbB-2. In a multivariate model, with serological erbB-2 as the dependent variable, and in which the independent variables included Study Group, there was a statistical trend for younger women, in which Group III had the highest serological levels of erbB-2, followed by Group II, and then Group I. In women who were over the age of 50 years the trend was reversed; i.e., levels of erbB-2 tended to be lowest in Group III, followed by Group II, and finally Group I.

The relationship between apolipoprotein E, dementia, and vascular illness.

The purpose of this study was to concurrently assess the relationship of Apolipoprotein E (APOE) with both dementias and vascular illnesses in the very old. Nine hundred and fifty nine subjects (mean age 85 years) in a long-term care facility were genotyped and cognitively tested with the Mini Mental State Exam. All subjects were studied for the relationship of APOE with atherosclerotic heart disease, hypertension, or stroke without concomitant dementia. Four hundred fifty individuals met criteria for inclusion into one of the following groups: Alzheimer's disease (n = 318), vascular dementia (n = 49), or not demented controls (n = 83) and were investigated for the relationship between APOE and these diagnostic categories. APOE epsilon4 was not associated with atherosclerotic heart disease, hypertension, or stroke without concomitant dementia. The APOE epsilon3 allele was more common in men with atherosclerotic heart disease. In contrast, the APOE epsilon4 allele was more common in patients with Alzheimer's disease (22%) and vascular dementia (26%) than in not demented controls (7%). APOE epsilon4 is associated with dementias in the very old, whereas its relationship with either peripheral or central nervous system vascular disease without dementia is not as robust.

Assessing life expectancies of older nursing home residents.

OBJECTIVE: Care of nursing home (NH) residents is often based on the usual survival of the home's residents. In order to improve our understanding of this population, and, thus, ultimately facilitate individualization of their care, we developed a mathematical model that predicts their survival. SETTING: The Jewish Home and Hospital (JHH), a nursing home. PARTICIPANTS: 1145 older residents who were at the JHH from January 1, 1986, through July 1, 1986. MEASUREMENTS: Information abstracted from medical records and JHH computerized data: clinical, demographic, and dependencies in activities of daily living (ADLs). MAIN OUTCOME MEASURE: survival from July 1, 1986. DESIGN: Retrospective cohort study via medical chart review. The study period covered admission to JHH through January 17, 1996. Accelerated failure time (AFT) models generated the life expectancy model derived from 50% of the study group and were validated on the remaining sample. We computed predicted AFT and proportional hazards (PH) life expectancies. RESULTS: Significant, independent predictors of decreased survival were male gender, increased age, increase in summary ADL index, and impairment of cardiac, respiratory, neurological, and endocrine/metabolic systems. The interaction between gender and respiratory system impairment was significant. The Spearman correlation coefficients between the observed survivals and those predicted by the Phase I model are 0.49 for Phase I residents and 0.42 for Phase II residents. Our sample life table includes NH residents with different risk profiles and their associated survival estimates as well as interquartile ranges. AFT and PH survivals were similar. CONCLUSION: This first comprehensive model that predicts survival of NH residents can help formulate public health policies and identify appropriate NH residents for clinical trials. The model is a promising step toward improving the health care of NH residents.

Effect of tamoxifen on bone fractures in older nursing home residents.

OBJECTIVES: To evaluate the association between tamoxifen (TAM) treatment and rate of bone fractures in older, nursing home residents. PARTICIPANTS: A total of 93,031 women, aged 65 years and older, whose data were part of the 1993 New York State MDS and for whom there was documentation of treatment with at least one medication. SETTING: New York State long-term care facilities. DESIGN: Cross-sectional study via secondary analysis of 1385 matched sets of residents. Each set included one resident who was receiving TAM treatment and up to four residents who were not. MEASUREMENTS: Measurements included age, ethnicity, TAM treatment, hormone replacement therapy, vision impairment, any bone fractures, and, specifically, hip fractures. RESULTS: During the 1.5-year period for which bone fractures are documented in the 1993 MDS, the fracture rates were: 7.62% in women not treated with TAM, 3.20% in women receiving 10 mg TAM daily, and 6.73% in women receiving 20 mg TAM daily. The odds ratio (OR) for bone fractures among women receiving 20 mg TAM daily compared with nontreated women was 0.916 (95% confidence interval (CI): 0.720-1.164; P = .472), and was 0.312 (95% CI: 0.112-0.865; P = .025) for those receiving 10 mg daily. The rates of hip fracture were 4.98%, 2.40%, and 4.57% for controls and women receiving 10 mg and 20 mg TAM daily, respectively. Whereas the hip fracture rate for women receiving 20 mg daily was statistically similar to that of the controls (OR = .963; 95% CI: 0.718-1.291; P = .800), the difference between the controls and those receiving 10 mg daily approached significance (OR: 0.313; 95% CI: 0.096-1.018; P = .054). CONCLUSION: Although standard treatment of 20 mg TAM daily offers no apparent protection against bone fracture in older nursing home residents, a daily 10 mg dose seems to be protective.

TIMP expression in toxic and cholestatic liver injury in rat.

BACKGROUND/AIMS: Hepatic fibrosis is a dynamic pathological process with a net accumulation of extracellular matrix proteins. Recent evidence suggests that besides their increased synthesis, inhibition of matrix degradation plays a significant role. ECM degradation occurs via metalloproteinases which are inhibited in situ by specific tissue inhibitors of metalloproteinases (TIMPs). The aim of our studies was to determine the expression of TIMPs during toxic liver injury and cholestatic liver injury leading to fibrosis. METHODS: We examined the expression of TIMP-1, -2 and -3 in two different rat models for liver injury (intraperitoneal CCl4 injection and bile duct ligation) by Northern blot analysis and in situ hybridization. For comparison, the mRNA expression of the acute phase protein haptoglobin was measured. RESULTS: TIMP-1 was increased during the early phase of toxic liver injury and in cholestasis. Its expression occurred predominantly in areas of inflammation, in hepatocytes, and in mesenchymal and endothelial cells. There was a slight upregulation of TIMP-2 expression during cholestasis. TIMP-3 was not detected at all. CONCLUSIONS: Our results emphasize an involvement of TIMP-1 in matrix homeostasis, indicating its possible participation in liver fibrosis.

A study of the effects of tamoxifen in the frail elderly: difficulties encountered in nursing home research.

OBJECTIVE: This study was conducted in order to determine whether the effects of tamoxifen in elderly, frail nursing home residents are similar to those that have been previously reported for younger postmenopausal women. DESIGN: A chart review study. SETTING: The Jewish Home and Hospital for Aged (JHHA), a subacute long-term care facility. PARTICIPANTS: One hundred fifty-eight women who had been at the JHHA at any time since 1986. One hundred ten had a history of breast cancer; 43 of these had been treated with tamoxifen while at the JHHA (Group I), and 66 had not (Group II). The remaining 49 women had no history of breast cancer (Group III). MEASUREMENTS: Data were collected from the time of admission to the JHHA through August, 1994 on: chemistry profiles, bone fractures apparently not a consequence of metastasis, gynecological parameters, and thromboemboli. RESULTS: The lack of pre-admission clinical information presented problems regarding research design and the interpretation of our findings. Nevertheless, compared to women who had not been treated with tamoxifen, treated women had a significantly elevated incidence of vaginal discharge (P = 0.01) and a lower prevalence of elevated total cholesterol (P = 0.04). Although not statistically significant, they also had decreased levels of low density lipoprotein cholesterol and an increased incidence of thromboemboli and bone fractures. CONCLUSIONS: While some of the effects of tamoxifen in elderly, frail women are similar to those observed in younger, postmenopausal women, others may be different. Our results suggest a need for further innovative studies that focus on the consequences of tamoxifen treatment in the elderly, frail population.