Effects of tamoxifen on normal breast tissue histological composition: Results from a randomised six-arm placebo-controlled trial in healthy women

Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen.     

Diagnostic challenges for a novel SH2D1A mutation associated with X‐linked lymphoproliferative disease

Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X‐linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21‐year‐old patient with fatal Epstein‐Barr virus infection–associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.     

Cognitive function after on or off pump coronary artery bypass grafting.

OBJECTIVE: To investigate cognitive outcome after on and off pump coronary artery bypass grafting. METHODS: Seventy patients between 50 and 80 years with stable angina pectoris, ejection fraction >30%, serum creatinine <150 micromol/l, and lack of tight main stem stenosis were randomized to on or off pump coronary artery bypass grafting. Standardized neuropsychological tests evaluated attention, verbal and visuo-spatial short-term and working memory, verbal learning, delayed recall, visuo-motor speed, and aspects of executive functions. Levels of anxiety and depression were also investigated. Testing was performed before and at 1 week, 1 and 6 months after surgery. RESULTS: There was no difference in cognitive impairment (defined as a 20% reduction in at least 20% of the tests) between groups. The incidence at 1 week post-operatively was 57% in the on pump group and 58% in the off pump group, after 1 month 30% and 12% and after 6 months 19% and 15%, respectively (p for interaction=0.19). There was no difference between groups in anxiety (p=0.18) or depression (p=0.48). CONCLUSIONS: This prospective, randomized study showed no differences in post-operative cognitive function after on pump compared to off pump coronary artery bypass grafting in low risk patients.     

A role for decorin in cutaneous wound healing and angiogenesis

Decorin is known to influence tissue tensile strength and cellular phenotype. Therefore, decorin is likely to have an impact on tissue repair, including cutaneous wound healing. In this study, cutaneous healing of both excisional and incisional full‐thickness dermal wounds was studied in decorin‐deficient (Dcn^?/?) animals. A statistically significant delay in excisional wound healing in the Dcn^?/? mice occurred at 4 and 10 days postwounding and, in incisional wounds at 4, 10, and 18 days when compared with wild‐type (Dcn^?/?) controls. Fibrovascular invasion into polyvinylalcohol sponges was significantly increased by day 18 in Dcn^?/? mice relative to Dcn^+/+ mice. The 18‐day sponge implants in the Dcn^?/? mice showed a marked accumulation of biglycan when compared with the corresponding implants in Dcn^+/+ mice. Thus, regulated production of decorin may serve as an excellent therapeutic approach for modifying impaired wound healing and harmful foreign body reactions.     

Nonoperatively treated burst fractures of the thoracic and lumbar spine in adults: a 23- to 41-year follow-up

BACKGROUND CONTEXT: Several studies report a favorable short-term outcome after nonoperatively treated two-column thoracic or lumbar burst fractures in patients without neurological deficits. Few reports have described the long-term clinical and radiological outcome after these fractures, and none have, to our knowledge, specifically evaluated the long-term outcome of the discs adjacent to the fractured vertebra, often damaged at injury and possibly at an increased risk of height reduction and degeneration with subsequent chronic back pain. PURPOSE: To evaluate the long-term clinical and radiological outcome after nonoperatively treated thoracic or lumbar burst fractures in adults, with special attention to posttraumatic radiological disc height reduction. STUDY DESIGN: Case series. PATIENT SAMPLE: Sixteen men with a mean age of 31 years (range, 19-44) and 11 women with a mean age of 40 years (range, 23-61) had sustained a thoracic or lumbar burst fracture during the years 1965 to 1973. Four had sustained a burst fracture Denis type A, 18 a Denis type B, 1 a Denis type C, and 4 a Denis type E. Seven of these patients had neurological deficits at injury, all retrospectively classified as Frankel D. OUTCOME MEASURES: The clinical outcome was evaluated subjectively with Oswestry score and questions regarding work capacity and objectively with the Frankel scale. The radiological outcome was evaluated with measurements of local kyphosis over the fractured segment, ratios of anterior and posterior vertebral body heights, adjacent disc heights, pedicle widths, sagittal width of the spinal canal, and lateral and anteroposterior displacement. METHODS: From the radiographical archives of an emergency hospital, all patients with a nonoperatively treated thoracic or lumbar burst fracture during the years 1965 to 1973 were registered. The fracture type, localization, primary treatment, and outcome were evaluated from the old radiographs, referrals, and reports. Twenty-seven individuals were clinically and radiologically evaluated a mean of 27 years (range, 23-41) after the injury. RESULTS: At follow-up, 21 former patients reported no or minimal back pain or disability (Oswestry Score mean 4; range, 0-16), whereas 6 former patients (of whom 3 were classified as Frankel D at baseline) reported moderate or severe disability (Oswestry Score mean 39; range, 26-54). Six former patients were classified as Frankel D, and the rest as Frankel E. Local kyphosis had increased by a mean of 3 degrees (p<.05), whereas the discs adjacent to the fractured vertebrae remained unchanged in height during the follow-up. CONCLUSIONS: Nonoperatively treated burst fractures of the thoracic or lumbar spine in adults with or without minor neurological deficits have a predominantly favorable long-term outcome, and there seems to be no increased risk for subsequent disc height reduction in the adjacent discs.     

Andrology: Transrectal electroejaculation in combination with in-vitro fertilization: an effective treatment of anejaculatory infertility after testicular cancer

Treatment of non-seminomatous testicular cancer often leadsto infertility due to anejaculation/retrograde ejaculation andpoor sperm quality. In these men spermatozoa may be obtainedby transrectal electroejaculation (TE), but the optimal strategyfor assisted procreation in these couples is not known. Ouraim was to examine whether TE and conventional in-vitro fertilization(IVF) would be successful. A total of 10 couples, with long-standinginfertility due to anejaculation or retrograde ejaculation aftertreatment for testicular cancer 5–14 years earlier, werereferred to our unit. All men underwent diagnostic TE undergeneral anaesthesia. Spermatozoa were recovered in nine cases.The antegrade fraction was prepared and used for IVF. Spermquality was variable and conventional IVF was considered impossiblein three cases. Altogether six IVF treatment cycles in six couplesresulted in five pregnancies, of which four resulted in a deliveryand one resulted in a spontaneous abortion. One additional pregnancyis ongoing after transfer of cryopreserved embryos. The fertilizationrate was 54% (33/61) and the cleavage rate was 97% (32/33).No complications relating to the procedure have been encountered.     

Prevention of travelers' diarrhea by the tablet formulation of bismuth subsalicylate

Within 48 hours of arrival in Mexico, 182 US students participated in a study to compare the efficacy of two dosages of bismuth subsalicylate (262 mg per tablet) as a prophylactic agent against diarrhea. The students were randomly assigned to receive two tablets (high dose) or one tablet (low dose) of bismuth subsalicylate four times daily or a placebo four times daily during a three-week period. Among these completing the trial, diarrhea (four or more unformed stools in 24 hours or three in eight hours, plus one other symptom) occurred in seven (14%) of 51 receiving the high-dose regimen compared with 15 (24%) of 63 receiving the low-dose regimen and 23 (40%) of 58 in the placebo group. Protection rates were 65% for high-dose and 40% for low-dose bismuth subsalicylate. Diarrhea caused by enterotoxigenic Escherichia coli was found in one student receiving the high-dose regimen, in no students receiving the low-dose regimen, and in seven placebo-treated subjects. Bismuth subsalicylate was well tolerated; the most common side effects were blackening of tongues and stools. Bismuth subsalicylate use in both dosages was associated with tinnitus at a low, clinically insignificant frequency of 1.2 days per 100 days of treatment. The dosage of two tablets of bismuth subsalicylate four times daily (2.1 g/d) appears to be a safe and effective means of reducing the occurrence of travelers' diarrhea among persons at risk for periods up to three weeks.