The importance of local control in the conservative treatment of breast cancer

The purpose of this study was to examine the meaning of local control, especially on survival, in breast cancer patients treated by lumpectomy with or without radiotherapy. We analyzed the survival results of four major published randomized trials that compare conservation surgery with or without radiation using three different statistical approaches: p-values, confidence intervals, and Bayesian techniques. All four trials report statistically significant increased local control and improved survival for the irradiated patients. Survival based on p-values and confidence intervals shows statistical significance for long-term follow-up of the NSABP-B06 trial, but not for the other trials, probably because of small sample sizes and short follow-up. At 10 years, the overall survival rates for the NSABP-B06 were 65% and 71% for lumpectomy alone or with radiation respectively. Interpreted in a Bayesian framework, the expected advantage in 10-year survival was 6% (the mean of NSABP-B06 10-year survival) with an 83% probability that the 10-year survival difference may lie between 2% and 10%. An 85% probability that 3% of patients will survive at 10 years because of irradiation translates into a 30% reduction in annual odds of death several years after treatment in stage I good prognosis patients and 15% in stage I poor prognosis patients. Analysis of the randomized trials comparing lumpectomy with or without radiation indicate a clear improvement in survival for the irradiated patients associated with increased local control. Combination of improved survival with the reduced psychological and economic costs associated with local recurrence argues well for the inclusion of radiation for many breast cancer patients.     

A multicenter clinical trial of PerioGard in distinguishing between diseased and healthy periodontal sites. (I). Study design, methodology and therapeutic outcome

We designed and performed a multicenter clinical trial to determine the relationship between measurements of the level of the enzyme aspartate aminotransferase (AST) in gingival crevicular fluid (GCF) to other measures used to detect periodontal disease and monitor outcome of treatment, including pocket depth and gingival inflammation. 32 periodontitis patients were enrolled at the University of Washington, Seattle, 30 at the University of Florida, Gainesville, and 34 at the University of Illinois, Chicago. 10 periodontally normal control subjects were enrolled at each location. 8 diseased and 4 healthy sites were designated for study in each patient and 8 healthy sites designated in each control subject. Measures of disease included pocket depth, severity of gingival inflammation, and GCF volume. AST levels were measured using the PerioGard test kit. Clinical measurements were made and GCF samples harvested and tested 2x before and 2x after therapy consisting of scaling and root planing under local anesthetic. Specific design and other issues are discussed, including selection of patients and control subjects, sample size, selection of experimental test sites, methods for assessment of diseased and therapeutic improvement, harvesting of GCF and selection of appropriate biostatistical methods for data analysis. Demographics of the patient populations at the 3 locations are reported. As expected, therapy induced only negligible changes in the measures of disease at healthy sites in control subjects, and relatively minor improvement in healthy sites in patients. In contrast, statistically significant improvement relative to pretreatment baseline status in all 3 measures of disease was observed for diseased sites at all 3 study locations with all p-values less than 0.0002. The magnitude of improvement was comparable to that reported previously by others. The % of PerioGard-positive sites decreased significantly between the screening baseline and both post-treatment visits for patients at all 3 locations, with p values of 0.0001 to <0.0008.     

A technique revisited: hemodynamic comparison of closed- and open-chest cardiac massage during human cardiopulmonary resuscitation

OBJECTIVE: To compare the hemodynamics of closed-chest cardiac massage vs. open-chest cardiac massage in patients resuscitated from cardiac arrest that occurred outside of the hospital. DESIGN: Prospective, non-outcome, case series. SETTING: Large urban emergency department. PATIENTS: Ten adult, normothermic, nontraumatic, out-of-hospital, cardiac arrest patients who failed advanced cardiac life support (ACLS) therapy. INTERVENTIONS: Patients presenting to the hospital in cardiac arrest were managed according to the ACLS protocol at the clinician's discretion. Proximal aortic and central venous pressure catheters were placed to measure arteriovenous compression- and relaxation-phase pressure gradients. After 5 mins of baseline measurements during closed-chest cardiac massage, patients underwent a left lateral thoracotomy, and open-chest cardiac massage was performed for 5 mins. MEASUREMENTS AND MAIN RESULTS: The mean coronary perfusion pressure and compression-phase pressure gradients were 7.3 +/- 5.7 and 6.2 +/- 5.4 mm Hg, respectively, during closed-chest cardiac massage, while increasing to 32.6 +/- 17.8 and 32.6 +/- 29.9 mm Hg, respectively, during open-chest cardiac massage. The differences between both measurements were statistically significant (p < .05). CONCLUSIONS: Open-chest cardiac massage is superior to closed-chest cardiac massage in providing relaxation-phase and compression-phase pressure gradients during cardiac arrest in patients failing current ACLS protocols. During open-chest cardiac massage, all patients exceeded the minimum coronary perfusion pressure of 15 mm Hg, which is recommended to obtain a return of spontaneous circulation. Further outcome studies are needed to determine the timeliness and appropriate indications for open-chest cardiac massage.     

The elderly patient with multiple complaints

"Thick chart" patients often have both a stated and an unstated agenda. Failure to recognize the latter can create a crisis of confidence that may prompt the patient to search for a more empathetic physician. So in addition to making a diagnosis in the face of confusing data, the physician must establish confidence by listening carefully and involving the patient in treatment decisions.     

Monoaminergic influences on temporal patterning of sexual behavior in male rats

We evaluated the effects of the serotonin (5-HT) presynaptic uptake blocker fluoxetine (FLX) and the dopamine (DA)/noradrenaline (NE) releaser amantadine (AMA), separately and in combination, on the temporal patterning of male rat sexual behavior. FLX alone increased intermount-bout intervals, time-outs, grooming time, ejaculation latency, number of mounts per mount bout, and number of mount bouts per ejaculation. AMA alone had the opposite effect on these measures. Additionally, AMA, when given in combination with FLX, completely reversed the FLX-induced deficits in copulatory behavior. We interpret our results as suggesting an interaction between 5-HT and catecholamines in the temporal patterning of male rat copulatory behavior.     

Nicotinic receptor binding site probed with unnatural amino acid incorporation in intact cells

The nonsense codon suppression method for unnatural amino acid incorporation has been applied to intact cells and combined with electrophysiological analysis to probe structure-function relations in the nicotinic acetylcholine receptor. Functional receptors were expressed in Xenopus oocytes when tyrosine and phenylalanine derivatives were incorporated at positions 93, 190, and 198 in the binding site of the alpha subunit. Subtle changes in the structure of an individual side chain produced readily detectable changes in the function of this large channel protein. At each position, distinct features of side chain structure dominated the dose-response relation, probably by governing the agonist-receptor binding.     

Pneumatic retinopexy failures. Cause, prevention, timing, and management

BACKGROUND: Pneumatic retinopexy is a procedure for reattaching the retina by injecting an expanding gas bubble and using either laser or cryopexy. The procedure is controversial because there may be a lower initial success rate, and intraocular gas may increase the risk of proliferative vitreoretinopathy. METHODS: The authors performed a retrospective review of 107 unpublished consecutive cases of pneumatic retinopexy together with a literature review of 25 statistical series with primary attention to failures. Univariate and multivariate analyses were carried out on the data set, and adjusted odds ratios for risk factors associated with failure were calculated using logistic regression. RESULTS: Initially, 74 (69%) of 107 patients had successful results, and with re-operations the success rate increased to 98%. Failure of the procedure to achieve retinal reattachment occurred soon after the initial procedure, with 86% of recorded failures occurring within the first month. The initial cause of failure was new or missed breaks in 14.9%, reopened initial breaks in 11.2%, and breaks never closed in 4.6%. Risk factors that showed a correlation with failure were patients being male (adjusted odds ratio = 2.65), eyes with preoperative visual acuity worse than 20/50 (adjusted odds ratio = 1.21), eyes with four quadrants of retinal detachment or total detachment (adjusted odds ratio = 2.03), aphakic or pseudophakic eyes (adjusted odds ratio = 1.91), and eyes with additional pathologic findings (adjusted odds ratio = 3.14). Poor visual outcome was associated with initial visual acuity less than 20/50 (adjusted odds ratio = 15.7) and eyes with four quadrants of retinal detachment or total detachment (adjusted odds ratio = 5.01). CONCLUSIONS: Failures of pneumatic retinopexy occur early in the postoperative course. Factors known to be associated with failure of retinal reattachment using scleral buckling also were associated with failure in pneumatic retinopexy. A higher success rate in females was noted, suggesting that educational efforts may need to be greater in males. Poorer visual results occurred in patients with poor initial vision and in eyes with four quadrants of retinal detachment or total detachments.     

Computer-generated profiles of the anal canal in patients with anal fissure

PURPOSE: The pathophysiology of anal fissure remains poorly understood. This study examines manometric findings in patients with anal fissure with use of a computer-assisted system, which helps to standardize manometric performance as well as generating longitudinal and cross-sectional profiles of the anal canal. METHODS: Water-perfused, eight-channel, computer-assisted manometry was performed on 12 patients with chronic anal fissure and compared with 12 age-matched and sex-matched controls. RESULTS: Mean maximum average resting pressure (MARP) was 120.5 mmHg in patients and 82.6 mmHg in controls (P = 0.0005). Pain was felt during manometry in six patients. In these patients, MARP was 123.2 mmHg, and, in the other six patients, MARP was 117.8 mmHg. Sphincter length was 4.72 cm, and the high pressure zone or that part of the sphincter with pressure more than 50 percent of MARP) was 2.78 cm in length. The high pressure zone/sphincter length ratio was 58 percent compared with 48 percent in controls. Longitudinal profile was bell shaped. Elevated pressures were not confined to the site of the fissure. Cross-sectional analysis showed higher anterior pressures in the distal sphincter. Ultraslow waves were seen in as many as 91 percent of patients and 73 percent of controls. However, ultraslow wave amplitude was 31 mmHg in patients and 15 mmHg in controls (P = 0.03). The rectoanal reflex was normal; overshoot was not seen. CONCLUSIONS: The primary abnormality in fissure is persistent hypertonia affecting the entire internal sphincter, unrelated to pain. Cross-sectional pressure profiles may explain the predilection of fissures to occur in the posterior midline; other factors must prevent chronic fissures from healing.     

Femoral abnormalities and vitamin D metabolism in X-linked hypophosphatemic (Hyp and Gy) mice

X-linked hypophosphatemia is a genetic bone disease in humans and mice. Two closely linked mutations in mice, Hyp and Gy, cause low plasma phosphate and a rachitic and osteomalacic bone disease. Because of the controversy as to whether Gy is a good model for X-linked hypophosphatemia, the phenotypic severity of these two mutations was compared in both sexes and on two genetic backgrounds. The depression in plasma levels of phosphate was similar in all 10-week-old mutant mice. Male Hyp mice and heterozygous female Hyp mice were affected with similar severity in terms of reduced tail growth, shortened femora, reduced femoral mineral content, and abnormal mineral composition of the femoral matrix. In contrast, male Gy mice did not survive on the C57BL/6J background and were more severely affected than female Gy mice on the B6C3H background. The hybrid B6C3H background ameliorated the bone disease compared with the inbred C57BL/6J background for both mutant strains. There was no evidence of change in the plasma levels of 1,25-dihydroxyvitamin D, duodenal level of vitamin D-dependent calcium-binding protein, or urinary level of calcium in these adult mutant mice. In summary, Gy mice have a sexual dimorphism not present in Hyp mice. These two genes may indicate the presence of multiple gene loci in the human disease, with multiple proteins involved in the pathophysiology of the bone disease.     

Protection of C3H/He mice from experimental Borrelia burgdorferi infection by immunization with a 110-kilodalton fusion protein

A 110-kDa Borrelia burgdorferi fusion protein, Escherichia coli expressing the fusion protein, transformed E. coli lacking the fusion protein insert, and lyophilized whole B. burgdorferi bacteria were compared for immunogenicity in C3H/He mice. Immunized mice were challenged with a variety of isolates from the United States or the European isolate P/Gau 3 weeks following the last inoculation. An average of 76.7% of the mice immunized with 25 micrograms of lyophilized whole B. burgdorferi cells were protected from infection, while 60% of the mice immunized with the 110-kDa fusion protein were protected. Whole E. coli bacteria expressing the fusion protein protected 57.7% of immunized mice against experimental challenge. Lower levels of protection occurred in mice challenged with the European isolate than in those challenged with isolates originating from the United States. These results demonstrate the potential of the 110-kDa fusion protein for use as a component of a subunit vaccine for prevention of Lyme borreliosis.