Biomedical subjects

C S Williams

Publications and source records attributed to C S Williams.

At least 19 recordsLinked to original sources

PubMed2005

Estrogen-induced abnormal accumulation of fat cells in the rat penis and associated loss of fertility depends upon estrogen exposure during critical period of penile development.

We previously reported that diethylstilbestrol (DES) or estradiol valerate (EV) exposure at a dose of 0.10-0.12 mg/kg, or higher, per day, on alternate days, from postnatal days 2-12, resulted in abnormal penis development and infertility (H. O. Goyal et al., 2005, J. Androl. 26, 32-43). The objective of this study was to identify a critical developmental period(s) during which EV exposure results in the observed penile abnormalities. Male pups received EV at a dose of 0.10-0.12 mg/kg on postnatal day(s) 1, 1-3, 4-6, 1-6, 7-12, 13-18, 19-24, or 25-30. Fertility was tested at 102-115 days of age and tissues were examined at 117-137 days. Both penile morphology and fertility were unaltered in rats treated with EV after 12 days of age. Conversely, except in rats treated on postnatal day 1 only, none of the males treated prior to 12 days of age sired pups, and all had abnormal penises, including varying degrees of abnormal accumulation of fat cells and loss of cavernous spaces and smooth muscle cells in the corpora cavernosa penis, which were maximal in the 1-6-day group. Also, the preputial sheath was partially released or its release was delayed, and the weight of the bulbospongiosus muscle was significantly reduced. Plasma testosterone (T) in the 1-6- and 4-6-day groups and intratesticular T in the 4-6-day group were significantly lower. The testosterone surge, characteristic of controls in the first week of life, was suppressed in the 1-3-day group. Estrogen receptor alpha mRNA expression was enhanced in the body of the penis in the 1-3-day group, but not in the 13-18-day group. Hence, EV exposure prior to 12 days of age (as short as 1-3 days postnatal), but not after 12 days of age, results in long-term abnormal penile morphology, characterized by abnormal accumulation of fat cells in the corpora cavernosa penis and, consequently, loss of fertility.

Adipocytes↗

PubMed2004

Abnormal morphology of the penis in male rats exposed neonatally to diethylstilbestrol is associated with altered profile of estrogen receptor-alpha protein, but not of androgen receptor protein: a developmental and immunocytochemical study.

Objectives of the study were to determine developmental changes in morphology and expression of androgen receptor (AR) and estrogen receptor (ER)alpha in the body of the rat penis exposed neonatally to diethylstilbestrol (DES). Male pups received DES at a dose of 10 microg per rat on alternate days from Postnatal Day 2 to Postnatal Day 12. Controls received olive oil vehicle only. Tissue samples were collected on Days 18 (prepuberty), 41 (puberty), and 120 (adult) of age. DES-induced abnormalities were evident at 18 days of age and included smaller, lighter, and thinner penis, loss of cavernous spaces and associated smooth muscle cells, and increased deposition of fat cells in the corpora cavernosa penis. Fat cells virtually filled the entire area of the corpora cavernosa at puberty and adulthood. Plasma testosterone (T) was reduced to an undetectable level, while LH was unaltered in all treated groups. AR-positive cells were ubiquitous and their profile (incidence and staining intensity) did not differ between control and treated rats of the respective age groups. Conversely, ERalpha-positive cells were limited to the stroma of corpus spongiosus in all age groups of both control and treated rats, but the expression in treated rats at 18 days was up-regulated in stromal cells of corpora cavernosa, coincident with the presence of morphological abnormalities. Hence, this study reports for the first time DES-induced developmental, morphological abnormalities in the body of the penis and suggests that these abnormalities may have resulted from decreased T and/or overexpression of ERalpha.

Aging↗

PubMed2003

Neonatal estrogen exposure of male rats alters reproductive functions at adulthood.

The effects of neonatal exposure to different doses of diethylstilbestrol (DES) on the reproductive functions of male rats at adulthood were evaluated. Sprague-Dawley rats (5-8/group) received sc injections of 25 microl olive oil containing DES (Sigma Chemical Co., St. Louis, MO) at a dose of 10 microg, 1 microg, 100 ng, 10 ng, or 1 ng per rat on alternate days from Postnatal Days 2-12. Control animals received olive oil only. All animals were allowed to develop until 83-91 days of age; however, when they were 70 to 80 days old, four male rats each from the 10 microg, 1 microg, 100 ng, and control groups were cohabited with untreated 60- to 70-day-old females (1:1) for 12 days. At the end of cohabitation, both mated and unmated male rats were weighed, and blood and tissue samples were collected and processed. Results revealed that although sperm motility patterns and sperm morphology were adversely affected in the 10- microg group, other reproductive parameters, including 1). daily sperm production (DSP)/testis; 2). absolute and relative weights of the testis, epididymis, and seminal vesicle; and 3). sperm numbers in both regions of the epididymis declined significantly in a dose-dependent manner in the 10- and 1- microg groups. Conversely, in the <1- microg groups, none of these parameters (except DSP/testis and weight of the epididymis in the 100-ng group, and sperm numbers in the epididymis of the 100- and 10-ng groups) was different from controls. Generally, plasma testosterone levels decreased in the 10- and 1- microg groups, FSH level increased in the 10-microg group, and prolactin and LH levels were unaltered. In the fertility study, although each male in the 1-microg, 100-ng, and control groups produced a copulatory plug and impregnated a female, none could do so in the 10-microg group. The mean number of pups per litter was reduced to eight in the 1-microg group, in contrast to 15 each in the 100-ng and control groups. In conclusion, exposure of neonatal male rats to DES altered sperm motility patterns, sperm fertility (as evident from the reduced number of pups in the 1-microg group), and sexual behavior (as evident from the absence of copulatory plugs in the 10-microg group) and reduced weights of reproductive organs, DSP/testis, and sperm numbers in the epididymis. Whether these alterations/reductions persist in older rats (6-8 mo of age) is under investigation.

Animals↗

PubMed2001

Functional disability and health care expenditures for older persons.

BACKGROUND: The rapidly expanding proportion of the US population 65 years and older is anticipated to have a profound effect on health care expenditures. Whether the changing health status of older Americans will modulate this effect is not well understood. This study sought to determine the relationship between functional status and government-reimbursed health care services in older persons. METHODS: Longitudinal cohort study of a representative sample of community-dwelling persons 72 years or older. Clinical data were linked with data on 2-year expenditures for Medicare-reimbursed hospital, outpatient, and home care services and Medicare- and Medicaid-reimbursed nursing home services. Per capita expenditures associated with different functional status transitions were calculated, as were excess expenditures associated with functional disability adjusted for demographic, health, and psychosocial variables. RESULTS: The 19.6% of older persons who had stable functional dependence or who declined to dependence accounted for almost half (46.3%) of total expenditures. Persons in these groups had an excess of approximately $10 000 in expenditures in 2 years compared with those who remained independent. The 9.6% of patients who were dependent at baseline accounted for more than 40.0% of home health and nursing home expenditures; the 10.0% who declined accounted for more than 20.0% of hospital, outpatient, and nursing home expenditures. CONCLUSIONS: Functional dependence places a large burden on government-funded health care services. Whereas functional decline places this burden on short- and long-term care services, stable functional dependence places the burden predominantly on long-term care services. Declining rates of functional disability and interventions to prevent disability hold promise for ameliorating this burden.

Aged↗

PubMed2001

Restricted activity among community-living older persons: incidence, precipitants, and health care utilization.

BACKGROUND: Restricted activity is a potentially important indicator of health and functional status. Yet, relatively little is known about the incidence, precipitants, or health care utilization associated with restricted activity among older persons. OBJECTIVE: To more accurately estimate the rate of restricted activity among community-living older persons, to identify the health-related and non-health-related problems that lead to restricted activity, and to determine whether restricted activity is associated with increased health care utilization. DESIGN: Prospective cohort study. SETTING: New Haven, Connecticut. PARTICIPANTS: 754 nondisabled members of a large health plan, 70 years of age or older, who were categorized according to their risk for disability (low, intermediate, or high). MEASUREMENTS: Occurrence of restricted activity (defined as having stayed in bed for at least half a day or having cut down on one's usual activities because of an illness, injury, or another problem), problems leading to restricted activity, and health care utilization were ascertained during monthly telephone interviews for up to 2 years. RESULTS: In median follow-up of 15 months, 76.6% of participants reported restricted activity during at least 1 month and 39.3% reported restricted activity during 2 consecutive months. The rates of restricted activity per 100 person-months were 19.0 episodes for all participants and 16.9, 27.3, and 22.7 episodes for participants at low, intermediate, and high risk for disability, respectively. Of the 24 prespecified health-related and non-health-related problems, the rates per 100 person-months of restricted activity ranged from 0.1 episode for "problem with alcohol" to 65.5 episodes for "been fatigued." On average, participants identified 4.5 different problems as a cause for their restricted activity. Health care utilization was substantially greater during months with restricted activity than months without restricted activity. The corresponding rates per 100 person-months were 63.8 and 45.1 for physician office visits, 12.5 and 1.0 for emergency department visits, 14.1 and 0.3 for hospital admissions, and 67.6 and 45.1 for any health care utilization (P < 0.001 for each pairwise comparison). CONCLUSIONS: Restricted activity is common among community-living older persons, regardless of risk for disability, and it is usually attributable to several concurrent health-related problems. Although restricted activity is associated with a substantial increase in health care utilization, older persons with restricted activity often do not seek medical attention.

Activities of Daily Living↗

PubMed2001

Goals for the care of frail older adults: do caregivers and clinicians agree?

PURPOSE: Establishing shared treatment goals for patients may improve the quality of care by facilitating achievement of appropriate and desired outcomes. The purpose of this study was to describe types of family caregiver and physician treatment goals for frail elderly patients who had a high prevalence of cognitive impairment, and to ascertain the level of agreement between family caregivers and physicians on principal treatment goals. SUBJECTS AND METHODS: We surveyed family caregivers and physicians for 200 consecutive older adults who were initially evaluated at the outpatient geriatric assessment center of a major teaching hospital. Treatment goals for patients were measured after a comprehensive geriatric assessment. RESULTS: Goals commonly chosen as most important by family caregivers and physicians pertained to day-to-day functioning (61 [31%] family caregivers, 81 [41%] physicians), behavior and emotional health (56 [28%] family caregivers, 50 [25%] physicians), and safety (40 [20%] family caregivers, 29 [15%] physicians). Although a substantial proportion of family caregiver and physician pairs shared at least one goal (157 [79%] of 200), agreement on presence or absence of individual categories of goals was poor (kappas from -0.19 to 0.28), and agreement on the most important goal was also poor (kappa 0.20). CONCLUSIONS: Agreement on treatment goals between family caregivers and physicians for patients at the study site was low. These results suggest that encounters between family caregiver and physician may need improvement. Further research is needed to assess whether lack of agreement is found in other settings, persists over time, and affects achievement of goals and optimal health outcomes.

Activities of Daily Living↗

PubMed2001

Treatment of myelopathy in Sjögren syndrome with a combination of prednisone and cyclophosphamide.

BACKGROUND: Peripheral neuropathy is a common complication of primary Sjögren syndrome, but central nervous system involvement also occurs and may be the only extraglandular manifestation. Sicca symptoms may also be minimal. Combinations of lesions along with relapses and remissions can suggest multiple sclerosis in the proper clinical setting, making the correct diagnosis elusive. OBJECTIVES: To report a case of progressive transverse myelopathy with previous optic neuropathy in primary central nervous system Sjögren syndrome (CNS-SS), and to review 17 previously reported cases and the patient's responses to various therapies. DESIGN: Case report and literature review. SETTING: University hospital. PATIENT: A 63-year-old Hispanic woman with a 10-month history of progressive spastic paraparesis associated with optic neuropathy and a T10 sensory level. Magnetic resonance imaging demonstrated multifocal, contrast-enhancing lesions in the spinal cord. The patient was diagnosed as having CNS-SS because of the presence of sicca symptoms, abnormal serological test results, and salivary gland biopsy results, which fulfilled San Diego criteria for "definite" Sjögren syndrome. She responded to treatment with a combination of prednisone and cyclophosphamide. CONCLUSIONS: Diagnosis of primary CNS-SS requires a high index of suspicion and specialized clinical testing. Treatment with pulse doses of corticosteroids alone may be suboptimal, but results of treatment with a combination of corticosteroids and either cyclophosphamide or chlorambucil have been encouraging.

Anti-Inflammatory Agents↗

PubMed2001

Risk adjustment for older hospitalized persons: a comparison of two methods of data collection for the Charlson index.

To compare Charlson indices based on chart data and ICD-9 data for agreement overall and on rating specific comorbid conditions, and to compare mortality risks associated with these indices. Prospective cohort study. Six general medicine wards at Yale-New Haven Hospital. 524 consecutive patients who had no clinical evidence of delirium at enrollment, admitted between November 6, 1989 and July 31, 1991, aged 70 years or older. Death within 1 year of the index hospital admission date. Scores using the chart-based data were significantly higher than those using ICD-9 data. About half of the individual conditions showed fair-to-good agreement between the two scores, whereas the other half showed poor agreement. A comparison of mortality prediction indicated that the weightings assigned to individual comorbidities differed substantially from those used in Charlson's original index. While mortality prediction of each individual index was comparable, the ICD-9 and chart indices contributed independently to mortality prediction in the presence of the other. Low agreement between Charlson scores based on the two methods of data collection and their cumulative contribution to mortality prediction suggest that these indices may include different information. Our results suggest that the original Charlson index may not provide optimal risk adjustment for elderly general medicine samples. We suggest development of an empirically-derived index of comorbid conditions and weights may be warranted for older general medical patients.

Aged↗

PubMed2001

Ultrastructural response of pulmonary intravascular macrophages to exogenous oestrogen in the bovine lung: translocation of the surface-coat and enhanced cell membrane plasticity and angiogenesis.

The pulmonary intravascular macrophages (PIMs) of domestic ungulates are recognised by their specific surface coat, consisting of linearly arranged globules along the external leaf of the plasma membrane. The coat is sensitive to in vitro digestion with lipolytic lipase (LPL), intravenous heparin and clinical exposure to halothane anaesthesia. The sensitivity to these experimental manipulations suggests that the globules of the coat are predominantly composed of lipoproteins (LDL). The present administration of oestradiol proprionate in castrated male calves potentiated the translocation of the surface coat into the endocytotic pathway of the PIMs. Concurrently with mobilisation of the coat, the plasma membrane was thrown into prominent arrays of lamellipodial extensions. The sprawling macrophages made extensive adhesive contacts with the lining endothelium of the capillaries. Consequently, the endothelial cells were highly attenuated and precariously maintained the integrity of the vascular wall. At some focal points, the vascular wall was penetrated by the filopodial processes of PIMs, which protruded into the perivascular space. Furthermore, there were signs of neovascularisation in the form of overt mitotic changes, sprouting and precursor capillary formation. It is conceivable that the evolving profile of angiogenesis is due to the vascular endothelial growth factor (VEGF) paracrine function of PIMs. Endothelial cell specificity has been considered an important advantage of VEGF for neovascularisation. It allows pleotrophic response of endothelial cells to proliferate and to assemble into endothelial tubes.

Animals↗

PubMed2001

Validation of dizziness as a possible geriatric syndrome.

OBJECTIVE: While dizziness has traditionally been considered solely as a symptom of discrete diseases, recent findings from population-based studies of older persons suggest that it may often be a geriatric syndrome with multiple predisposing risk factors, representing impairments in diverse systems. To validate these findings, we identified predisposing risk factors for dizziness in a clinic-based population. DESIGN: Cross-sectional study. SETTING: Geriatric assessment center. PARTICIPANTS: 262 consecutive, eligible patients. MEASUREMENTS: Medical history and physical examination data were ascertained and characteristics of patients with and without a report of dizziness were compared. RESULTS: Seven factors were independently associated with a report of dizziness, namely depressive symptoms, cataracts, abnormal balance or gait, postural hypotension, diabetes, past myocardial infarction, and the use of three or more medications. Of patients with none of these risk factors, none reported dizziness. This proportion rose from 6% among patients with one factor, to 12%, 26%, and 51% among patients with two, three, and four or more factors, respectively. CONCLUSIONS: The finding of similar factors associated with dizziness in previous community-based cohorts and the present clinic-based cohort supports the possibility of a multifactorial etiology of dizziness in many older persons. A multifactorial intervention targeting the factors identified in these studies may be effective at reducing the frequency or severity of dizziness in older patients.

Aged↗

PubMed2001

Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth.

BACKGROUND & AIMS: The cyclooxygenase 2 (COX-2) and ErbB/HER pathways are important modulators of cancer cell growth. We sought to determine the effects of treatment with a specific COX-2 inhibitor and/or a monoclonal antibody against the ErbB receptor subtype HER-2/neu on carcinoma cell growth. METHODS: A cell-proliferation assay was used to determine the response of HCA-7 cells to the HER-3/HER-4 ligand heregulin beta-1 (HRGbeta-1). Both in vitro and in vivo assays were used to determine the effects of the selective COX-2 inhibitor, celecoxib, and/or an anti-HER-2/neu monoclonal antibody (either Herceptin [Genetech Inc., S. San Francisco, CA] or 2C4) on cell growth. RESULTS: HCA-7 cells express HER-2/neu messenger RNA and protein, and exposure of these cells to HRGbeta-1 results in a significant stimulation of cell growth. Celecoxib or Herceptin inhibits HCA-7 cell growth in vitro and in vivo. Combination therapy with celecoxib plus Herceptin or celecoxib plus 2C4 resulted in additive effects that resulted in almost complete inhibition of tumor growth. CONCLUSIONS: Combined treatment with COX-2 and HER-2/neu inhibitors more effectively reduces colorectal carcinoma growth than either agent alone. Therefore, targeting of both the COX-2 and ErbB signaling pathways may represent a novel approach for the treatment and/or prevention of colorectal cancer in humans.

Animals↗

PubMed2001

Diethylstilbestrol-treated adult rats with altered epididymal sperm numbers and sperm motility parameters, but without alterations in sperm production and sperm morphology.

In this study, we characterized estrogenic effects of diethylstilbestrol (DES) on reproductive parameters in male rats to identify a minimal dose level that alters epididymal and sperm functions but has little or no effect on sperm production and/or spermatogenesis. Adult rats (five animals/group) received s.c. injections of 0.2 ml of corn oil containing DES at a rate of 1.0 mg, 200 microg, 40 microg, 8 microg, 1.6 microg, or 320 ng x rat(-1) x day(-1) for 12 days. The control group received corn oil only. DES effects were similar in the 8-microg group and higher dose groups and included significant (P < or = 0.05) reductions in 1) absolute and relative weights of the head and body of the epididymis (EP), tail of the EP, and seminal vesicle, 2) numbers of sperm in both regions of the EP, and 3) motility characteristics in sperm collected from the tail of the EP. Conversely, no significant changes were observed in relative testis weight, daily sperm production, spermatogenesis, seminiferous epithelial height in stage VII, and sperm morphology. All of the above parameters in the 1.6-microg group (except seminal vesicle weight) and 320-ng group were comparable to those of controls. Plasma testosterone (T) level was reduced to an almost undetectable level in the > or = 8-microg groups and to a very low level in the 1.6-microg group (0.35 vs. 2.36 ng/ml in controls or 320-ng group), but LH level was unaltered. In a parallel fertility study, males received DES at a rate of 40, 8, or 1.6 microg x rat(-1) x day(-1) for 12 days prior to and 12 days during cohabitation (1:1) with untreated females. Of the 15 females cohabited with treated males (5 females/dose), none in the 40-microg and 8-microg groups and 1 in the 1.6-microg group formed a copulatory plug and delivered 8 pups, in contrast to 5/5 copulatory plugs and 13-15 pups/litter in the controls. DES at a rate of 8 microg x rat(-1) x day(-1) for 12 days reduced EP weights, sperm numbers in the EP, and sperm motility patterns but caused minimal to no alterations in daily sperm production, spermatogenesis, or sperm morphology. Factors other than T, or in addition to lower T, may be responsible for DES-induced reproductive disorders (despite lower T, sperm contents and sperm motility patterns in the EP were normal in the 1.6-microg group). Deficits in EP sperm functions and/or sexual behavior (as evident from absence of copulatory plugs) probably accounted for reduced fertility in treated males.

Animals↗

PubMed2001

Multicomponent targeted intervention to prevent delirium in hospitalized older patients: what is the economic value?

INTRODUCTION: Delirium, or acute confusional state, is a common and serious occurrence among hospitalized older persons. Current estimates suggest that delirium complicates hospital stays for more than 2.3 million older persons each year, involving more than 17.5 million hospital days and accounting for more than $4 billion (1994 dollars) of Medicare expenditures. A 40% reduction was recently reported in the risk for delirium among hospitalized older persons receiving a multicomponent targeted risk factor intervention (MTI) strategy to prevent delirium, compared with subjects receiving usual hospital care.1 Before recommending that this preventive strategy be implemented in clinical practice, however, the cost implications must be thoroughly examined as well. METHODS: The present analysis performs net cost evaluations of the MTI for the prevention of delirium among hospitalized patients. Hospital charge and cost-to-charge ratio data are linked to a database of 852 subjects, who were treated with MTI or usual care. Multivariable regression methods were used to help isolate the impact of MTI on hospital costs. These results were then combined with our earlier work on the impact of the MTI on delirium prevention to assess the cost effectiveness of this intervention. RESULTS: The MTI significantly reduced nonintervention costs among subjects at intermediate risk for developing delirium, but not among subjects at high risk. When MTI intervention costs were included, MTI had no significant effect on overall health care costs in the intermediate risk cohort, but raised overall costs in the high risk group. CONCLUSIONS: Because the MTI prevented delirium in the intermediate risk group without raising costs, the conclusion reached is that it is a cost effective treatment option for patients at intermediate risk for developing delirium. In contrast, the results suggest that the MTI is not cost effective for subjects at high risk.

Aged↗

PubMed2001

What does the medical record reveal about functional status? A comparison of medical record and interview data.

OBJECTIVE: Functional status measures are potent independent predictors of hospital outcomes and mortality. The study objective was to compare medical record with interview data for functional status. SUBJECTS AND METHODS: Subjects were 525 medical patients, aged 70 years or older, hospitalized at an academic medical center. Patient interviews determined status for 7 basic activities of daily living (BADLs) and 7 instrumental activities of daily living (IADLs). Medical records were reviewed to assess documentation of BADLs and IADLs. RESULTS: Most medical records contained no documentation of individual BADLs and IADLs (61% to 98% of records lacking documentation), with the exception of walking (24% of medical records lacking documentation). Impairment prevalence was lower in medical records than at interview for all BADLs and IADLs, and agreement between interview and medical record was poor (kappa < 0.40 for individual BADLs and IADLs). Sensitivity of the medical record for BADL and IADL impairment was poor (range 95% to 44%), using the interview as a reference standard. Sensitivity and specificity of the medical record for detection of BADL and IADL impairment changed substantially when records with nondocumentation of functional status were excluded or were assumed to be equivalent to independence. CONCLUSIONS: The results suggest that the medical record is a poor source of data on many functional status measures, and that assuming that nondocumentation of functional status is equivalent to independence may be unwarranted. Given the prognostic importance of functional status measures, the results highlight the importance of developing reliable and efficient means of obtaining functional status information on hospitalized older patients.

Academic Medical Centers↗

PubMed2001

Enteral absorption of erythropoietin in the suckling rat.

Milk contains biologically relevant concentrations of erythropoietin (Epo), the primary hormone responsible for erythrocyte production. In animals, milk-borne Epo stimulates erythropoiesis. Epo receptors have been found in nonerythropoietic tissues including gastrointestinal tract. We hypothesized that milk-borne Epo is distributed to local gastrointestinal tissues, absorbed intact, and then distributed peripherally via the systemic circulation. Rat milk protected recombinant human Epo (rhEpo) from degradation in the suckling rat gastrointestinal tract. Simulated digestion of (125)I-rhEpo in suckling rat gastrointestinal juices was performed. When measured by acid precipitation and immunoassay, rat milk protected rhEpo from gastrointestinal juices better than saline (p < 0.0001). The fate of enterally administered milk-borne (125)I-rhEpo was examined in 10-d-old rats. RhEpo fed in rat milk was better protected from in vivo proteolytic degradation than rhEpo in saline (p < 0.05). After enteral (125)I-rhEpo dosing, radiolabeled protein from gastric tissue comigrated on SDS-PAGE with intact rhEpo at 36.5 kD. To determine the local and systemic distribution of physiologic intakes of rhEpo, suckling rats were fed (125)I-rhEpo in rat milk, and tissues were harvested 1, 2, and 4 h later. Intact (125)I-rhEpo was found in gastric and small intestinal walls and lumens. Five percent of total administered dose was found intact in the plasma, whereas another 8 to 10% of total administered dose was localized to bone marrow, percentages comparable to those seen after parenteral administration. Radiolabel was also localized to liver and peripheral solid tissues. These patterns of localization and degradation of rhEpo after acute administration support both systemic absorption and gastrointestinal cellular processing.

Animals↗

PubMed2001

Transforming growth factor-alpha delays gastric emptying and small intestinal transit in suckling rats.

Transforming growth factor-alpha (TGF-alpha) is a biologically potent polypeptide detected in the gastrointestinal tract in suckling rats. The major goal of the present study was to test the hypothesis that the administration of TGF-alpha affects gastric emptying and small intestinal transit in suckling rats. Suckling (12-day-old) rats fasted 16 h received rat TGF-alpha subcutaneously (s.c.) or orogastrically in varying doses (0, 0.5, 1.0 microg/rat in 0.1% BSA). Control animals received 0.1% BSA only. Poly R-478 dye was used as a motility marker. Rats were decapitated 45 min after marker administration and the amount of dye in the stomach and the small intestine was measured by spectrophotometry. Subcutaneous administration of TGF-alpha significantly delayed stomach evacuation. In controls, the stomach contained 21.4 +/- 1.4% (mean +/- s(x)) of the Poly R-478 marker, whereas in TGF-alpha treated rats the stomach contained 37.2 +/- 2.8% of the total Poly R-478 dye given to animals. The delaying effect of TGF-alpha was time- and dose-dependent. Small intestinal transit was also significantly delayed. The proximal jejunum of TGF-alpha treated rats contained a 1.4-fold higher amount of marker in comparison with control rats. Orogastrically administered rTGF-alpha did not affect gastric emptying or intestinal transit. In conclusion, s.c. administration of rat TGF-alpha significantly delayed the gastrointestinal motility in vivo in suckling rats.

Analysis of Variance↗

PubMed2001

Proximal row carpectomy for the treatment of scaphoid nonunion.

Nonunion of the scaphoid bone may occur even with early diagnosis of fracture and modern internal fixation techniques. A pattern of degenerative instability termed scaphoid nonunion advanced collapse may lead to collapse of the carpus with irreversible articular damage initially isolated to the radiostyloid joint. Proximal row carpectomy (PRC), which removes the intercalary proximal row and creates a radiocapitate articulation, is a motion preserving salvage procedure which unloads the areas of articular pathology, and creates a new articulation that allows motion and is able to bear compressive forces over time. Although results of PRC specifically for scaphoid nonunion are clearly not reported in the article, several studies demonstrate that PRC provides a pain relieving and motion-sparing salvage option particularly suited for this condition.

Carpal Bones↗

PubMed2000

Celecoxib prevents tumor growth in vivo without toxicity to normal gut: lack of correlation between in vitro and in vivo models.

Nonsteroidal anti-inflammatory drugs have potential for use in the prevention and/or treatment of colorectal cancer. We have studied the cytotoxic effect of a specific COX-2 inhibitor, celecoxib, against LLC, HCA-7, and HCT-15 cells grown in cell culture and have compared these results with its effect on HCA-7 cells grown as xenografts in nude mice. "High-dose" celecoxib (>20 microM) reduced the viability of all three cell lines in vitro as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Flow cytometric analysis demonstrated that this loss of viability was attributable to the induction of apoptosis. Significantly, concentrations of the drug <10 microM had no effect on cell viability in vitro. The cytotoxic effects of high-dose celecoxib were independent of COX-2 inhibition because similar effects were observed in cox-2 (+/+), cox-2 (+/-) and cox-2 (-/-) fibroblasts. A plasma concentration of 2.3+/-0.7 microM was achieved when celecoxib (1250 mg/kg of chow) was fed to animals ad libitum. Despite a lack of toxicity at 2-3 microM celecoxib in vitro, there was attenuation of HCA-7 xenograft growth in vivo. Celecoxib had no effect on apoptosis, cell division, or the epithelial architecture of the normal gut in treated mice. These results support the need for additional clinical evaluation of celecoxib for treatment and/or prevention of colorectal cancer in humans.

Animals↗