Rose Medical Center

PURPOSE: The primary aim of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 was to determine whether four cycles of adjuvant paclitaxel (PTX) after four cycles of adjuvant doxorubicin/cyclophosphamide (AC) will prolong disease-free survival (DFS) and overall survival (OS) compared with four cycles of AC alone in patients with resected operable breast cancer and histologically positive axillary nodes. PATIENTS AND METHODS: Between August 1995 and May 1998, 3,060 patients were randomly assigned (AC, 1,529; AC followed by PTX [AC --> PTX], 1,531). Patients > or = 50 years and those younger than 50 years with estrogen receptor (ER) or progesterone receptor (PR) -positive tumors also received tamoxifen for 5 years, starting with the first dose of AC. Postlumpectomy radiotherapy was mandated. Postmastectomy or regional radiotherapy was prohibited. Median follow-up is 64.6 months. RESULTS: The addition of PTX to AC significantly reduced the hazard for DFS event by 17% (relative risk [RR], 0.83; 95% CI, 0.72 to 0.95; P = .006). Five-year DFS was 76% +/- 2% for patients randomly assigned to AC --> PTX compared with 72% +/- 2% for those randomly assigned to AC. Improvement in OS was small and not statistically significant (RR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Five-year OS was 85% +/- 2% for both groups. Subset analysis of the effect of paclitaxel according to hormone receptors or tamoxifen administration did not reveal statistically significant interaction (for DFS, P = .30 and P = .44, respectively). Toxicity with the AC --> PTX regimen was acceptable for the adjuvant setting. CONCLUSION: The addition of PTX to AC resulted in significant improvement in DFS but no significant improvement in OS with acceptable toxicity. No significant interaction between treatment effect and receptor status or tamoxifen administration was observed.

Objective To identify clinical factors associated with prevalence of fat atrophy (lipoatrophy) and fat accumulation (lipoaccumulation) in HIV-1 infected patients. Design Evaluation of HIV-1 infected patients seen for routine care between 1 October and 31 December 1998 in the eight HIV Outpatient Study (HOPS) clinics. Setting Eight clinics specializing in the care of HIV-1 infected patients. Patients A total of 1077 patients were evaluated for signs of fat maldistribution. Interventions A standardized set of questions and specific clinical signs were assessed. Demographic, clinical and pharmacological data for each patient were also included in the analysis. Main outcome measures Demographic, immunologic, virologic, clinical, laboratory, and drug treatment factors were assessed in stratified and multivariate analyses for their relationship to the presence and severity of fat accumulation and atrophy. Results Independent factors for moderate/severe lipoatrophy for 171 patients were increasing age, any use of stavudine, use of indinavir for longer than 2 years, body mass index (BMI) loss, and measures of duration and severity of HIV disease. Independent risk factors for moderate/severe fat accumulation for 104 patients were increasing age, BMI gain, measures of amount and duration of immune recovery, and duration of antiretroviral therapy (ART). The number of non-drug risk factors substantially increased the likelihood of lipoatrophy. If non-drug risk factors were absent, lipoatrophy was unusual regardless of the duration of drug use. Conclusions HIV-associated lipodystrophy is associated with several host, disease, and drug factors. While prevalence of lipoatrophy increased with the use of stavudine and indinavir, and lipoaccumulation was associated with duration of ART, other non-drug factors were strongly associated with both fat atrophy and accumulation.

Numerous methods for reading abnormalities of rheumatoid arthritis in hand and wrist radiographs have been proposed over the past several decades. There are many differences among these methods, one of the more striking of which is the variation in the number of joints that are scored. In this study, we tested the number of joints that need to be read in order to represent abnormalities accurately and reproducibly, using the scores of multiple observers. Thirteen rheumatologists and radiologists each read a set of 41 hand and wrist films from patients with rheumatoid arthritis. Ten of 13 readers scored 27 joints in each hand and wrist; the other 3 readers scored fewer areas. Fourteen combinations of joints were selected based on the frequency of involvement and the technical adequacy of routine films in assessing a given area. After testing these 14 different combinations, 1 scheme, which included 17 areas read for erosions and 18 areas read for joint space narrowing, was tested further. The correlation coefficients for 10 intraobserver scores derived from this modified scheme compared with the original scores were between 0.981 and 0.997. Seventy-one of 78 interobserver comparisons were better using the new scheme than using the original scheme. These data indicate that the simplified scheme, using a combination of 17 joints to score erosions and 18 to score joint space narrowing, more accurately reflects the extent of abnormalities perceived by a panel of experts than does the original scheme. This abbreviated number of joints shortens the amount of time required to read a set of films and simplifies the scoring of films, since a number of areas that are difficult to read are eliminated from radiographic assessment.

We used fluoroscopy to study the kinematics of the knee in 47 patients with total knee arthroplasty (TKA) and four control subjects with normal knees while performing a single-leg deep-knee bend. The videos were analysed using still photographs taken at 5 degrees increments of flexion. Femorotibial contact points, patellar ligament rotation, and patellar rotation were calculated from each image. Maximum weight-bearing flexion was determined for each knee. Compared with the control group, posterior-cruciate-retaining TKA did not reproduce normal knee kinematics in any case, but showed a starting point posterior to the tibial midline which translated anteriorly with flexion. The curves from successive knee bends could not be consistently reproduced. Under weight-bearing conditions, the maximum flexion for any PCR TKA was 98 degrees and several patients could not flex beyond 70 degrees.

Sixty-four subjects having implanted and nonimplanted knees were studied using fluoroscopic videos. Each subject, flexing in the sagittal plane, performed successive deep knee bends under fluoroscopic surveillance. Femorotibial contact in the sagittal plane was then determined using image matching and discrete digitization. At full extension, the mean contact point of the normal and posterior stabilized implanted femurs was anterior to the tibial midpoint in the sagittal plane. The average position was 6.49 mm (+3 - +13 mm) for the normal knees and 0.30 mm (0 - +4 mm) for the posterior stabilized knees. The implanted posterior cruciate retaining and anterior cruciate ligament deficient knees differed from the other knee types. Their average initial contact was posterior. The average contact at full extension for the posterior cruciate retaining and anterior cruciate ligament deficient knees was -5.13 mm (-2 - -8 mm) and -5.45 mm (-2 - -14 mm), respectively. The femur of the normal knee contacts the tibia anterior to the midpoint in the sagittal plane in full extension and translates posteriorly during flexion. The femur of the posterior stabilized knee contacts the tibia anteriorly, slightly less than the normal knee, and rolls back posteriorly during flexion similar to normal knees. The femurs of the posterior cruciate retaining and anterior cruciate ligament deficient knees contact the tibia posterior in extension, but translate anteriorly during midflexion in a substantial number of cases, which is kinematically opposite of the normal knees. The abnormal anterior femoral translation observed in the posterior cruciate retaining knees may be a factor in the premature polyethylene wear seen in retrieval studies.

It has been suggested that mitochondrial DNA defects that effect metabolic capacity may be a proximal cause of failures in oocyte maturation, fertilization, or early embryonic development. Here, the distribution of mitochondria was examined by scanning laser confocal microscopy in living human pronuclear oocytes and cleavage stage embryos, followed either by measurements of the net ATP content of individual blastomeres or anti-tubulin immunofluorescence to determine the relationship between mitochondrial distribution and microtubular organization. The results indicate that specific patterns of perinuclear mitochondrial aggregation and microtubular organization are related, and that asymmetrical mitochondrial distributions at the pronuclear stage can result in some proportion of blastomeres with reduced mitochondrial inheritance and diminished ATP generating capacity. While the inability to divide appears to be a development consequence for an affected blastomere, for the embryo, reduced competence may occur during cleavage if several blastomeres inherit a mitochondrial complement inadequate to support normal cellular functions. The findings provide a possible epigenetic explanation for the variable developmental ability expressed within cohorts of morphologically normal early cleavage stage human embryos obtained by in-vitro fertilization.

To identify clinical factors associated with the incidence of HIV-1-associated lipoatrophy, HIV-1-infected patients in the HIV Outpatient Study (HOPS) were prospectively evaluated for clinical signs of lipoatrophy at two visits about 21 months apart. Development of lipoatrophy was analyzed in stratified and multivariate analyses for its relationship to immunologic, virologic, clinical, and drug treatment information for each patient. Of 337 patients with no lipoatrophy at Survey 1, 44 (13.1%) developed moderate or severe lipoatrophy between the two surveys. In multivariate analyses, significant risk factors for incident lipoatrophy were white race (OR = 5.2; 95% CI: 1.9-17.1; =.003), CD4 T-lymphocyte count at Survey 2 less than 100 cells/mm3 (OR = 4.2; 95% CI: 1.3-13.1; =.013), and body mass index (BMI) less than 24 kg/m2 (OR = 2.4; 95% CI: 1.1-5.4; =.024). Analyses that controlled for the severity of HIV illness demonstrated no significant association with use of or time on any antiretroviral agent or class of agents and the development of lipoatrophy. Some host factors and factors associated with previous or current severity of HIV infection, especially CD4 T-lymphocyte cell count, appeared to have the strongest association with incidence of lipoatrophy.

Erosions and cartilage destruction are nearly universal features in peripheral joints that have been chronically affected by rheumatoid arthritis. Scoring methods to measure the extent of these abnormalities in hands and wrists have been developed and have been thoroughly tested in several studies to establish their reproducibility. In this study, we utilized one of these scoring methods to examine the progression of radiologic damage as related to duration of disease. Two hundred ninety-two patients from 3 different participating centers in the Arthritis, Rheumatism, and Aging Medical Information System were included. Six hundred fifty films of the hands and wrists, obtained from 210 patients, were scored for erosions and joint space narrowing. The average annual rate of progression of the total radiologic score, which sums erosion and joint space abnormalities and has a maximum possible score of 314, was approximately 4 units per year over the first 25 years after onset; this progression was more rapid in the earlier years of disease and slightly slower in the later years. Data were insufficient to accurately determine the progression rate in disease of more than 25 years duration.

Ten normal subjects and 10 patients with a posterior cruciate retaining mobile bearing total knee replacement performed successive deep knee bends under fluoroscopy to determine tibiofemoral contact positions. At full extension the average initial contact position for the normal and mobile total knee replacement was 6.2 mm (range, 4.8 to 12 mm) anterior, and -4.4 mm (range, 3.9 to 11 mm) posterior to the sagittal tibial midplane, respectively. At 60 degrees flexion, the normal knee rolled back to -5.8 mm (range, -2.5 to -13.2 mm), whereas the mobile bearing total knee replacement rolled back to -9.2 mm (range, -4 to -17 mm). From 60 degrees to 90 degrees, normal knees rolled back to -7.8 mm (range, -5.8 to -13.8 mm), but the mobile bearing total knee replacement slid anteriorly to -5 mm (range, 2 to -12 mm). All mobile bearing total knee replacements had some form of roll back, but some slid anterior more than others. Five of 10 mobile bearing total knee replacements had some movement of the bearings while the others remained fixed. Patellar kinematics was similar to normal but reflected tibiofemoral abnormalities.

The occurrence of a pleiomorphic population of cytoplasmic fragments is a common characteristic of early human embryos fertilized in vitro. Here, temporal, spatial, fine structural, and biochemical aspects of fragmentation were examined in fragmented monospermic and dispermic pronuclear to early cleavage stages human embryos classified as stage-appropriate during the first 3.5 days of culture. The morphodynamics of certain common patterns of fragmentation and the movement and composition of fragments were analysed by time-lapse video, mitochondrial fluorescent probes, and transmission electron microscopy. Plasma membrane and nuclear DNA integrity were assessed by annexin V staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) and single-cell alkaline gel electrophoresis ('comet') assays respectively. Developmental competence for affected embryos was related to outcome after embryo transfer. The results demonstrate that certain common forms of spontaneous fragmentation affecting early human embryos are not lethal, and that clusters of apparent fragments are often transient structures, which disappear by resorption or lysis. The findings suggest that the occurrence and fate of fragments characteristic of these phenotypes may be related to oncosis-like processes associated with transient and focal ATP deficiencies in blastomeres and mitochondrial deficiencies or absence in extracellular fragments.

The results of treatment of desmoid tumor patients with nonsteroid antiinflammatory drugs alone or in combination with tamoxifen are described. Tumor growth was inhibited in six of seven patients. Nonsteroid antiinflammatory drugs administered along with 5-fluorouracil and cyclophosphamide and other inhibitors of T-suppressor cells were used to treat nine patients with metastatic carcinoma of the stomach. Survival of these patients was extended so that after 12 months minimal follow-up the majority are well. A prospective controlled clinical trial is indicated.

BACKGROUND: Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. METHODS: This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log(10) copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of > or =1.0 log(10) copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. RESULTS: We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log(10) copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from > or =8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P<.001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. CONCLUSION: The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.

BACKGROUND: We sought to identify factors associated with the clinical diagnosis of symmetrical peripheral neuropathy (SPN) during the era of highly active antiretroviral therapy (HAART) in a retrospective, longitudinal cohort analysis. METHODS: Patients infected with human immunodeficiency virus type 1 were evaluated for clinical signs of SPN and its association with immunologic, virologic, clinical, and drug treatment factors by means of univariate and multivariate logistic regression analyses. RESULTS: Of 2515 patients, 329 (13.1%) received a diagnosis of SPN. In the logistic regression analysis, statistically significant non-drug-based risk factors for SPN were age >40 years (adjusted odds ratio [aOR], 1.17), diabetes mellitus (aOR, 1.79), white race (aOR, 1.33), nadir CD4(+) T lymphocyte count <50 cells/mm(3) (aOR, 1.64), CD4(+) T lymphocyte count 50-199 cells/mm(3) (aOR, 1.40), and viral load >10,000 copies/mL at first measurement (aOR, 1.44). Although initial use of didanosine, stavudine (40 mg b.i.d.), nevirapine, or 4 protease inhibitors was associated with SPN (ORs for all 4 treatments, >1.41), the strength of association decreased with continued use of all medications studied. CONCLUSION: Since HAART was introduced, the incidence of SPN has decreased. Host factors and signs of increased disease severity were associated with an increased risk of developing SPN during the initial period of exposure to drug therapy. Immunity improved and the risk of SPN decreased with continued use of HAART. Delaying the initiation of therapy may select those individuals who will be more likely to develop SPN, and earlier initiation of HAART may decrease the risk of developing this common problem, as well as increase the therapeutic effects and decrease the toxic effects of the drugs.

In areas bordering wildlife reserves in Zimbabwe, agro‐pastoralists suffer livestock depredation by wild carnivores. However, the economic value of these losses, and therefore the levels of compensation required has never been calculated. Between January 1993 and June 1996 in a 33‐km 2 area of Gokwe communal land bordering the Sengwa Wildlife Research Area, 241 livestock were killed by wild carnivores. Baboons ( Papio ursinus Kerr), lions ( Panthera leo Linnaeus) and leopards ( P. pardus Linnaeus) were the most serious predators, contributing 52%, 34% and 12% of kills, respectively. Baboons only killed young goats ( Capra hircus Linnaeus) and sheep ( Ovis aries Linnaeus) by day, while lions and leopards jumped into fortified kraals at night and killed cattle ( Bos indicus Linnaeus), donkeys ( Equus asinus Linnaeus) and smallstock. In 1995, predators killed 5% of livestock holdings, double that recorded by other African studies. The annual total value of losses depended upon the degree of lion predation on the most valuable species, cattle and donkeys. The average annual loss per livestock‐owning household was US$13, or 12% of each household's net annual income. Losses could be reduced by improving kraal defences against lion and leopard predation in the dry season, when attacks were most common.

Five patients with laparoscopic trocar site incisional hernias are presented. These occurred following laparoscopic cholecystectomy (4) and pelvic laparoscopy (1). The hernias appeared from 1 week to 4 months postoperatively. Both 5-mm and 10-mm fascial defects were involved. Hernias occurred only in the abdominal midline. The brief literature on this complication is reviewed, and recommendations for hernia prevention are suggested. The use of laparoscopy for more complex procedures will result in an increased incidence of trocar site hernias. Suture closure of the larger fascia defects will minimize this complication. Other techniques for hernia prevention have been described but never have been rigorously tested.

Forty-one coded radiographic films from 16 patients with rheumatoid arthritis were read by 13 observers, using 4 different methods for scoring abnormalities. Although absolute scores differed widely among individual observers, correlation coefficients were greater than 0.850 for approximately 2 of 3 comparisons. When films were ranked, using the median rank of all readers, 72% of individual ranks were within 10% of the median ranks. Among serial films on individual patients, 92% of comparisons between early and late films were interpreted as demonstrating progression of abnormalities when mean standardized scores showed an increase in scores of 15 units or greater. Films with lesser changes were interpreted inconsistently. This study shows good general agreement among readers in scoring radiologic abnormalities of hands and wrists, when applied to a film set showing a broad spectrum of severity, and defines the sensitivity of radiologic detection of disease progression.

The past decade has seen unprecedented growth in the number of hip arthroscopies. Acetabular labral tears are the leading indication for arthroscopy of this joint. However, labral anatomy and function, as well as the effects of labral tears and surgical outcomes, have only recently been studied. Labral tears may cause pain and microinstability of the hip joint. They also may increase friction within the joint, cartilage consolidation, and strain within the articular cartilage, thereby possibly resulting in accelerated degeneration of the joint. Partial labrectomy and labral repair are the current surgical options, and basic science data suggest that labral repairs can heal and subsequently restore function. However, a good, validated outcomes measure to adequately assess active patients with a painful nonarthritic hip is needed to determine the efficacy of such repair and aid in managing patient expectations.

Fourteen subjects having a flat on flat condylar posterior cruciate retaining total knee arthroplasty were evaluated under different in vivo weightbearing conditions, with six performing a deep knee bend and eight walking at normal gait. An interactive model fitting algorithm was used to convert two-dimensional fluoroscopic images into three-dimensional computer aided design solid model images. The femorotibial contact positions for the medial and lateral condyle started posterior at full extension. With a deep knee bend the lateral condyle acted as a pivot, and the medial condyle slid in the anterior direction. Five of six had lateral condyle liftoff (maximum 1.6 mm) and abnormal positive screw home motion was seen from 0 degree to 90 degrees flexion. During gait, all femorotibial contact positions were posterior in extension and throughout the cycle. Six of eight patients experienced lateral condyle liftoff (maximum 3.5 mm), but minimal screw home motion was seen. Abnormal medial condyle posteroanterior sliding, lateral condyle liftoff, and erratic screw home motion may be related to abnormal wear characteristics of this flat on flat condylar design.

As patients infected with human immunodeficiency virus (HIV) live longer while receiving antiretroviral therapy, kidney diseases have emerged as significant causes of morbidity and mortality. Black race, older age, hypertension, diabetes, low CD4(+) cell count, and high viral load remain important risk factors for kidney disease in this population. Chronic kidney disease should be diagnosed in its early stages through routine screening and careful attention to changes in glomerular filtration rate or creatinine clearance. Hypertension and diabetes must be aggressively treated. Antiretroviral regimens themselves have been implicated in acute or chronic kidney disease. The risk of kidney disease associated with the widely used agent tenofovir continues to be studied, although its incidence in reported clinical trials and observational studies remains quite low. Future studies about the relationship between black race and kidney disease, as well as strategies for early detection and intervention of kidney disease, hold promise for meaningful reductions in morbidity and mortality associated with kidney disease.

The magnitude of the potential difference (polarity) across the inner mitochondrial membrane (DeltaPsim) determines levels of several mitochondrial activities, including ATP generation, focal regulate calcium homeostasis and organelle volume homeostasis. We investigated whether a domain of mitochondria in the mouse oocyte, characterized by high DeltaPsim and a unique location in the subplasmalemmal cytoplasm, is involved in the earliest events of fertilization: sperm attachment, penetration and cortical granule exocytosis. Experimental manipulations of the magnitude of DeltaPsim and the distribution of mitochondria in zona-free MII oocytes, followed by insemination and culture, indicate that high-polarized mitochondria (HPM) are required for penetration and cortical granule exocytosis, but not for persistent attachment to the oolemma. The capacity of subplasmalemmal mitochondria to undergo transient reductions (dissipations) of DeltaPsim appears necessary for penetration and cortical granule exocytosis. We suggest that the HPM normally establish a continuous circumferential circuit of 'reactive' organelles capable of responding to and propagating, triggering or activating signals across the subplasmalemmal cytoplasm, such as those initiated by the fertilizing sperm at the site of penetration. The HPM in the oocyte and early embryo may have functions similar to those of their somatic cell counterparts and promote the focal regulation of developmental activities that are themselves spatially localized. The establishment of high DeltaPsim in the subplasmalemmal cytoplasm may be among the first steps in the preovulatory maturation of the oocyte and defects in this domain may result in fertilization failure or abnormality.