Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins

BACKGROUND. Postmenopausal estrogen-replacement therapy may reduce the risk of cardiovascular disease, and this beneficial effect may be mediated in part by favorable changes in plasma lipid levels. However, the effects on plasma lipoprotein levels of postmenopausal estrogens in the low doses currently used have not been precisely quantified, and the mechanism of these effects is unknown. METHODS. We conducted two randomized, double-blind crossover studies in healthy postmenopausal women who had normal lipid values at base line. In study 1, 31 women received placebo and conjugated estrogens at two doses (0.625 mg and 1.25 mg per day), each treatment for three months. In study 2, nine women received placebo, oral micronized estradiol (2 mg per day), and transdermal estradiol (0.1 mg twice a week), each treatment for six weeks. The metabolism of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) was measured by endogenously labeling their protein component, apolipoprotein B. RESULTS. In study 1, the conjugated estrogens at doses of 0.625 mg per day and 1.25 mg per day decreased the mean LDL cholesterol level by 15 percent (95 percent confidence interval, 11 to 19 percent; P less than 0.0001) and 19 percent (95 percent confidence interval, 15 to 23 percent; P less than 0.0001), respectively; increased the HDL cholesterol level by 16 percent (95 percent confidence interval, 12 to 20 percent; P less than 0.0001) and 18 percent (95 percent confidence interval, 14 to 22 percent; P less than 0.0001), respectively; and increased VLDL triglyceride levels by 24 percent (95 percent confidence interval, 8 to 40 percent; P less than 0.003) and 42 percent (95 percent confidence interval, 26 to 58 percent; P less than 0.0001), respectively. In study 2, oral estradiol increased the mean concentration of large VLDL apolipoprotein B by 30 +/- 10 percent (P = 0.05) by increasing its production rate by 82 +/- 18 percent (P less than 0.01). Most of this additional large VLDL was cleared directly from the circulation and was not converted to small VLDL or LDL. Oral estradiol reduced LDL cholesterol concentrations by 14 +/- 3 percent (P less than 0.005), because LDL catabolism increased by 36 +/- 7 percent (P less than 0.005). The oral estradiol increased the HDL cholesterol level by 15 +/- 2 percent (P less than 0.0001). Transdermal estradiol had no effect. CONCLUSIONS. The postmenopausal use of oral estrogens in low doses favorably alters LDL and HDL levels that may protect women against atherosclerosis, while minimizing potentially adverse effects on triglyceride levels. The decrease in LDL levels results from accelerated LDL catabolism; the increase in triglyceride levels results from increased production of large, triglyceride-rich VLDL.     

Isolation and characterization of cell surface mutants of Candida albicans.

Mutant strains of Candida albicans were obtained by selecting for cells that escaped agglutination by a polyclonal antiserum raised against standard C. albicans serotype A isolate B311. Mutants were obtained from strains B311 and B792 and from four strains isolated from patients with acquired immunodeficiency syndrome. All 15 tested mutants retained characteristic sugar assimilation patterns. All but one of the mutants retained the ability to form germ tubes and chlamydospores. Two mutants from an acquired immunodeficiency syndrome-derived isolate were deficient in binding complement ligands iC3b and C3d, whereas another mutant was deficient in binding ligand iC3b but not C3d. The hyphae of these three mutants lacked antigens when examined by Western immunoblotting with monoclonal antibody Ca-A, which detects several glycoproteins, including C3d-binding proteins. One of the complement-binding-deficient mutants was tested for its ability to colonize the gastrointestinal tract of rabbits but did not differ from the wild-type parent in site or degree of colonization. The proton magnetic resonance spectra of bulk mannan carbohydrate extracted from tested mutants showed the loss of a signal characteristic of the mannosyl alpha-PO4 linkage; each mutant also had a distinct pattern of other changes.     

Techniques of exposure for the stiff total knee

Primary and revision total knee arthroplasty have become common orthopaedic procedures. The operating surgeon, at times, may be faced with a difficult surgical case due to soft tissue contractures or bone deformities. A review of multiple surgical techniques using soft tissue releases and osteotomies are presented including their potential complications. Although these techniques are aimed at the atypical operative case, the operating surgeon may utilize them for ‘routine’ exposures as well. Importance is focused on the functional integrity of the knee extensor mechanism.     

Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers–Danlos syndrome clinic: A retrospective review

The new 2017 diagnostic criteria for hypermobile Ehlers–Danlos Syndrome (hEDS) provide a framework for diagnosing hEDS but are more stringent than the previous Villefranche criteria. Our clinical experience at the GoodHope EDS clinic was that the 2017 criteria left many highly symptomatic patients without a diagnosis of hEDS. We conducted a retrospective cohort study to confirm our clinic experience and assess the accuracy of the 2017 diagnostic criteria for hEDS in patients who had a previous hEDS diagnosis based on the Villefranche criteria. Our study found that 15% (n = 20 of 131) of patients with a prior diagnosis of hEDS met the 2017 diagnostic criteria, and many of the traits used to distinguish hEDS were not significantly more frequent in patients who met 2017 criteria versus those who did not. In both groups objective systemic manifestations were found less frequently than subjective systemic manifestations. Beighton score (BS) as assessed by primary care practitioner was found to be higher than assessment by EDS practitioner in 81% (n = 74 of 91) of cases. Generalized joint hypermobility was confirmed in only 46% (n = 51 of 111) of patients who had a previous diagnosis of hEDS. Higher BS did not correlate with increased number of systemic manifestations in our cohort. Common comorbidities of hEDS were found with similar frequency in those who met 2017 criteria and those who did not. Based on our cohort, the 2017 hEDS diagnostic criteria require refinement to improve its diagnostic accuracy.     

Comparison of magnetic resonance imaging and ultrasonography in staging early prostate cancer. Results of a multi-institutional cooperative trial

BACKGROUND. In 1987, a cooperative study group consisting of five institutions was formed to determine the relative benefits of magnetic resonance imaging (MRI) and endorectal (transrectal) ultrasonography in evaluating patients with clinically localized prostate cancer (stage Ta or Tb). METHODS. Over a period of 15 months, 230 patients were entered into the study and evaluated with identical imaging techniques. We compared imaging results with information obtained at the time of surgery and on pathological analysis. RESULTS. MRI correctly staged 77 percent of cases of advanced disease and 57 percent of cases of localized disease; the corresponding figures for ultrasonography were 66 and 46 percent (P not significant). These figures did not vary significantly between readers; moreover, simultaneous interpretation of MRI and ultrasound scans did not improve accuracy. In terms of detecting and localizing lesions, MRI identified only 60 percent of all malignant tumors measuring more than 5 mm on pathological analysis and ultrasonography identified only 59 percent. CONCLUSIONS. The MRI and ultrasonography equipment that is currently available is not highly accurate in staging early prostate cancer, mainly because neither technique has the ability to identify microscopic spread of disease. Further evaluation with improved equipment may improve the accuracy of these techniques.     

Surgery in the treatment of varicose veins

To identify variables which might influence the results of varicose vein surgery, a ten-year retrospective study was carried out on 612 patients undergoing varicose vein surgery. Patient symptomatology, type of venous insufficiency and operator experience were examined and correlated with the results of surgery. The female-to-male ratio was 2:1. The mean age was 47 years for women, 45 years for men. A family history of varicose veins was recorded in 74% of patients. A history of previous deep venous thrombosis was reported in 5% of cases, but in the sub-group of patients with stasis ulceration, the incidence was 9%. Cosmetic appearance was the commonest presenting complaint (54%), while ulceration was relatively infrequent (14%). There was moderate-to-marked improvement in 86% of cases at one year. This was sustained in 79% at three years, in 75% at five years and in 74% at ten years. There was no correlation between the type of venous insufficiency or the presenting complaint, and the result of surgery. Operator experience had the most significant effect on the outcome of surgery (P less than 0.001). Our findings indicate that varicose vein surgery offers most patients a satisfactory result. The only significant variable was operator experience. We strongly recommend closer supervision of junior staff performing this type of surgery, particularly as a large proportion of these patients (25% in this study) are operated on by the more junior staff.     

The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

We have recently reported isolation of the gene responsible for X- linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X- specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.      

Routes to transplant tolerance versus rejection; the role of cytokines

The alloimmune response can be divided into specific junctures where critical decisions between tolerance and immunity are made which define the outcome of the transplant. At these "decision nodes" various cytokines direct alloresponsive T cells to develop either a proinflammatory response aimed at graft destruction or an immunoregulatory response facilitating graft acceptance. This review will focus on the role of these cytokines in influencing the progression of an alloimmune response leading ultimately to either allograft survival or rejection.     

Suppression of charge movement by calcium antagonists is not related to calcium channel block

The calcium channel-inhibiting drugs nitrendipine and diltiazem represent two important classes of organic calcium antagonists. In the present study, the effect of these drugs on calcium currents and charge displacement currents in bullfrog semitendinosus muscle fibers was examined using a vaseline gap voltage clamp. Nitrendipine (10 M) reduced the quantity of charge that moved both during the ON phase (Q_ON) and the OFF phase (Q_OFF) of charge movement. This action appeared to be most selective for Q_ON. However, at this same concentration, nitrendipine had no blocking action on inward calcium currents. In contrast to these findings, diltiazem blocked calcium currents in a concentration-dependent manner, while slightly increasing the quantity of charge moved during Q_ON and Q_OFF. The enhancement of charge movement by diltiazem resulted from two actions. First, diltiazem shifted the voltage-dependence of charge movement to more negative potentials. Second, diltiazem increased the maximum amount of charge moved. (Supported by NIH NS 03178 and HL 07382.)