Lack of evidence that progesterone in ovulatory cycles causes breast cancer.

A recent Perspective article asserted that progesterone secretion during ovulatory cycles is the cause of breast cancer. However, we challenge most of the evidence developed in this publication. First, there is a lack of evidence that progesterone is mutagenic for breast cells. Cause of a cancer should mean initiation by mutation, as opposed to promotion. Second, subclinical ovulatory disturbances occur rather frequently in normal-length menstrual cycles. Third, the authors attribute a potential carcinogenic effect to progesterone secreted during menstrual cycles but not to progesterone during pregnancy. They did not discuss breast cancer evidence from progesterone/progestin therapeutics. They argue that in genetic primary amenorrhea, a hypothetic lower risk of breast cancer could be due to the lack of progesterone, despite the progesterone/progestin in hormone replacements these women receive. Fourth, they advocate a regulatory effect of progesterone on several genes potentially involved in cancer genesis. In particular, they attribute a lower risk of breast cancer in women with Mayer-Rokitansky-Küster-Hauser syndrome to a defect in the progesterone-stimulated Wnt4 gene. However, this defect is only present in a small subset. Thus, the postulated progesterone breast cancer risk is unconvincing, which we discuss point by point in this commentary.

Integrated morphologic and molecular analysis of Trichomonas vaginalis, Mycoplasma hominis, and human papillomavirus using cytologic smear preparations.

Pathogenic microbes may colonize the female genital tract via sexual transmission and cause health issues like inflammation or malignancy, summarized as sexually transmitted disease (STD). A major representative of such pathogens is Trichomonas vaginalis (T.v.), whose role in the etiology of cervical cancer remains elusive. Traditional morphologic screening of cervical smears is able to detect T.v., although its identification may be complicated by look-alikes such as degenerated granulocytes and basal cells. In addition, the parasite's endosymbiont Mycoplasma hominis (M.h.) cannot be detected in the Pap test. This investigation was aimed at designing a PCR-based method to detect specific pathogenic germs by using cervical cytology slides to overcome morphologic uncertainty and increase diagnostic accuracy. To test our molecular screening method on T.v., M.h., and HPV in archival smears, we elaborated a multiplex PCR approach based on microdissection. This assay was applied to a minute quantity of starting material which harbored or was suspected to harbor T.v.; the resulting isolated DNA was used for subsequent molecular analyses of T.v., M.h., and HPV. We clarified the diagnosis of genital T.v. infection in 88 and 1.8% of morphologically suspicious and T.v.-negative cases, respectively. We also revealed a tendency of M.h. co-infection in high-risk HPV cases. In conclusion, a microdissection-based approach to detect pathogenic microbes such as T.v., HPV, and M.h. is a molecular tool easy to implement and may help to better understand the interactivity of these germs with respect to pathogenesis.

Estrogen-progestin therapy causes a greater increase in spinal bone mineral density than estrogen therapy - a systematic review and meta-analysis of controlled trials with direct randomization.

OBJECTIVE: To assess whether progesterone (P4) or osteoblast P4 receptor-acting progestin (P) contributed to estrogen (E) therapy-related increased areal bone mineral density (BMD) in randomized controlled trials (RCT) with direct randomization to estrogen (ET) or estrogen-progestin (EPT) therapy. METHODS: Systematic literature searches in biomedical databases identified RCT with direct randomization and parallel estrogen doses that measured spinal BMD change/year. Cyclic P4/P was included in this random effects meta-analysis only if for ≥ half the number of E-days. RESULTS: Searches yielded 155 publications; five met inclusion criteria providing eight dose-parallel ET-EPT comparisons in 1058 women. Women averaged mid-50 years, ⟨five years into menopause and took conjugated equine E daily at 0.625 mg with/without 2.5 mg medroxyprogesterone acetate (MPA). The weighted mean EPT minus ET percentage difference in spinal BMD change was +0.68%/year (95% CI 0.38, 0.97%) (P=0.00001). This result was highly heterogeneous (I²=81%) but this may reflect the small number of studies. CONCLUSION: Estrogen with an osteoblast P4R-acting progestin (EPT) in these five published RCT provides Level 1 evidence that MPA caused significantly greater annual percent spinal BMD gains than the same dose of ET. These data have implications for management of vasomotor symptoms and potentially for osteoporosis treatment in menopausal women.

[German ophthalmology in developing countries : Partnerships with eye clinics in developing countries - an initiative of the German Ophthalmological Society]. / Deutsche Augenheilkunde in Entwicklungsländern : Partnerschaften mit Augenkliniken in Entwicklungsländern ­ eine Initiative der Deutschen Ophthalmologischen Gesellschaft.

In 1999 the global initiative "Vision 2020 - The Right to Sight" was established by the World Health Organization (WHO), the International Agency for the Prevention of Blindness (IAPB) and several non-governmental organizations (NGOs) with the goal of reducing avoidable blindness. Based on this initiative, the working group "International Ophthalmology" of the German Ophthalmological Society (DOG), which was established in 1994, was converted into a DOG section with the same name in 2004 and represents one of the core components of the DOG; however, even before there were a number of established partnerships of German and African eye hospitals. The first cooperation of this kind was the partnership between the Department of Ophthalmology, Ludwig-Maximilians University Munich and the University of Nairobi, Kenya, which was founded in 1978. As a result of this cooperation, the Department of Ophthalmology in Nairobi has evolved into one of the major centers of ophthalmological training and ophthalmic care in East Africa. Since then a number of similar cooperation projects between several hospitals and numerous further projects (e. g. in Myanmar) have been implemented and some of these are presented in this manuscript.

Vitamin D and Mammographic Findings.

Introduction: Pleiotropic immune-modulatory and anti-proliferative effects of vitamin D and hopes to stop cancerogenesis have led to an increased interest in possible reduction of breast cancer with higher vitamin D levels. Mammographic density is an established risk factor for breast cancer risk, and its association with serum vitamin D is complex, as recent studies have shown. Patients and Methods: In this cross-sectional study, 1103 participants were recruited in the breast diagnostic unit of the Klinikum rechts der Isar, TU Munich. A standardised questionnaire and blood samples for 25-OH-vitamin D were taken on the day of mammography. Histologic results of biopsies in suspicious mammographies were documented. Results: In the 1090 data-sets analysed, vitamin D-deficiency was common among women under 40. Highest vitamin D values were observed in participants aged 60-69 years, but average values for all age cohorts were below 20 ng/ml of vitamin D. 15.6 % of all participants had very low vitamin D values (< 10 ng/ml), 51.3 % were vitamin D-deficient (10-19 ng/ml) and only 5.7 % were above 30 ng/ml, i.e. showed sufficient vitamin D. Patients with malignant results had vitamin D < 10 ng/ml more often (16.9 %; p = 0.61), and only 3.4 % in this group had sufficient vitamin D supply (> 30 ng/ml). There were no significant differences in vitamin D-levels between density groups according to the American College of Radiology (ACR) criteria. Conclusion: Vitamin D values were lower than in comparable US women. Up to now, there is no direct clinical evidence for a relationship between the risk for breast cancer and a specific vitamin D value.

[International ophthalmology and travel medicine]. / Internationale Ophthalmologie und Reisemedizin.

Medical eye care in developing countries is very different from the situation in industrialized nations. In order to prevent rising numbers of blind people worldwide due to increased life expectancy and population growth, the global initiative Vision 2020 "The Right to Sight" was established in 1999. Coordinated initiatives are important as most causes of blindness are either preventable or curable (e.g. cataract surgery); however, due to a lack of resources eye care in developing countries cannot implement all necessary preventive and therapeutic measures at present. The epidemiology of causes of blindness and the situation of ophthalmic care are discussed. Because of increased mobility of people and goods (e.g. air travel and trucking), imported eye diseases are of increasing importance. The difference between travel medicine, which deals with the medical situation of travelers and international ophthalmology (i.e. diseases in tropical countries) is discussed and illustrated on the basis of several important disease patterns.

[Tropical ophthalmology : Intraocular inflammation caused by "new" infectious pathogens and travel-related infections]. / Tropenophthalmologie : Intraokulare Entzündungen bei "neuen" Infektionserregern und Reiseinfektionen.

A number of "new" (emerging) infections that can also cause inflammatory eye changes are appearing and becoming increasingly important. In the past, diseases such as chikungunya, dengue fever or West Nile virus infections were endemic in tropical regions, but are now expanding worldwide and causing significant morbidity and even mortality. "Globalization" and human migration are important factors leading to the import of these infections. Climate changes are probably even more important. Increasing temperatures provide suitable conditions for new vectors, and may lead to autochthonous transmission of infectious pathogens. Diagnosis of these diseases requires not only careful assessment of medical and travel history, but also the application of specific laboratory diagnostic tests. A broad spectrum of ocular involvement has been reported, with frequent posterior segment involvement. Emerging infections should therefore be considered in the differential diagnosis of retinitis, chorioretinitis, retinal vasculitis and optic neuropathy in a patient living in or traveling back from an endemic area. Since these infections are often vector (insect) borne and effective treatments are almost uniformly lacking, prevention is at least as important as prompt diagnosis and initiation of supportive care. Here, we focus on Chikungunya, Dengue fever, Ebola fever, the West Nile virus and Rickettsioses, which frequently demonstrate ocular involvement.

Non-reproductive Effects of Anovulation: Bone Metabolism in the Luteal Phase of Premenopausal Women Differs between Ovulatory and Anovulatory Cycles.

Introduction: Several authors have linked subclinical ovulatory disturbances in normal length menstrual cycles to premenopausal fracture risk and bone changes. This study systematically examined the influence of ovulation and anovulation on the bone metabolism of premenopausal women. Participants and Methods: In 176 cycles in healthy premenopausal women, FSH, 17ß-estradiol (E2) and progesterone (P4) as well as bone alkalic phosphatase (BAP), pyridinoline (PYD) and C-terminal crosslinks (CTX) were measured during the follicular and during the luteal phase. The probability and timing of ovulation was self-assessed by a monitoring device. In addition, bone density of the lumbar spine was measured by quantitative computed tomography (QCT) at baseline and at the end of the study. Analysis was restricted to blood samples taken more than three days before the following menstruation. Results: 118 cycles out of the 176 collected cycles were complete with blood samples taken within the correct time interval. Of these, 56.8 % were ovulatory by two criteria (ovulation symbol shown on the monitor display and LP progesterone > 6 ng/ml), 33.1 % were possibly ovulatory by one criterion (ovulation symbol shown on the monitor display or LP progesterone > 6 ng/ml), and 10.2 % were anovulatory by both criteria). Ovulation in the previous cycle and in the same cycle did not significantly influence the mean absolute concentrations of the bone markers. However, bone formation (BAP) was higher in the luteal phase of ovulatory cycles than in anovulatory cycles (n. s.) and the relative changes within one cycle were significantly different for bone resorption (CTX) during ovulatory vs. anovulatory cycles (p < 0.01). In 68 pairs of cycles following each other directly, both ovulation in the previous cycle and ovulation in the present cycle influenced CTX, but not the differences of other bone markers. Conclusion: Ovulatory cycles reduce bone resorption in their luteal phase and that of the following cycle. The interaction between ovulation and bone metabolism is complex. Since anovulation may occur in low estrogen states such as pre-anorexic dietary restraint, as well as with high estrogenic circumstances e.g. from functional perimenopausal ovarian cysts, the association with bone changes has been variable in the literature. Accumulating physiological and clinical evidence however point towards a role for ovulation in enhancing bone formation and limiting bone resorption.

[Staying and working at home or considering migrating: Survey-based study of African ophthalmologists]. / Arbeiten im Heimatland oder an Auswandern Denken: Fragebogenbasierte Studie mit afrikanischen Augenärzten.

BACKGROUND: The shortage of ophthalmologists is a major obstacle in the struggle of fighting preventable blindness in sub-Saharan Africa. However, to date reasons affecting migration of ophthalmologists have not been completely understood. OBJECTIVES: Evaluation of reasons reported by ophthalmologists for staying in their current work setting/country, of potential reasons for migration as well as of effects of German-African partnerships. MATERIAL AND METHODS: In the years 2009-2011 and 2013 participants of continuous medical education courses in Ethiopia, Cameroon and Kenya were interviewed using a standardized questionnaire. RESULTS: A total of 106 ophthalmologists participated in this survey. In the years 2009/2010 participants were mainly board certified ophthalmologists, while the 2011/2013 surveys were answered mainly by residents. The main reasons for staying in their current region/country were good working conditions, commitment to help/patriotism, possibility of further training, good income and familial ties. Professional development elsewhere and better income abroad were named as the main reasons for considering migration followed by better technical equipment elsewhere and insecurity in the home country. CONCLUSION: Good working conditions and the possibility of further training were named as the top reasons for staying in the current region/country apart from commitment to help and familial ties. Therefore, international cooperation programs aiming at improving training of ophthalmologists and establishing an ophthalmic infrastructure may have a role in promoting ophthalmic care in Africa.

Progesterone and bone: a closer link than previously realized.

Decreasing rates of ovulation, hormonal changes, and increasing bone loss pre-date menopause by several years. Data suggest that, in addition to estradiol, progesterone may play a significant role in the interrelationship between the ovaries and the skeleton in women. Indeed, the differentiation of human osteoblasts from perimenopausal women has been shown to be dose-dependent on progesterone at physiological concentrations. Data from a pilot study in perimenopasual women also suggested that higher progesterone levels, as seen in the luteal phase of ovulatory cycles, may be associated with more bone formation and with slightly less bone resorption than anovulatory cycles in which progesterone levels are low (< 5.8 ng/ml). These data led to the initiation of a large, prospective, 2-year observational study in perimenopausal women (the PEKNO study). Interim data from the PEKNO study indicate that a decrease in ovulation correlated with an increase in the loss of bone mineral density (BMD). A meta-analysis estimated a BMD increase of 0.5% per year in women with normal ovulation, and a BMD decrease of 0.7% per year in young women with ovulatory disturbances (anovulation or short luteal phase). A meta-analysis in postmenopausal women demonstrated a 1.3% increase per year in BMD when receiving hormone replacement therapy with unopposed estrogens, and a further 0.4% increase in BMD in women receiving estrogens plus progestogens. The role of progesterone in bone metabolism in perimenopausal women who are estrogen-replete requires further study.

Breast cancer after hormone replacement therapy--does prognosis differ in perimenopausal and postmenopausal women?

Hormone replacement therapy (HRT) has been associated with higher incidence of breast cancer in postmenopausal women, but it is unclear if breast cancers developing after HRT use have different prognosis. 1053 women with hormone receptor positive non-metastasized breast cancer were analyzed in a retrospective trial, stratifying by HRT use before diagnosis. Postmenopausal HRT users had significantly more early tumor stages (p<0.001). HRT in postmenopausal patients was associated with longer time to progression (TTP) (HR 0.81, 95%CI 0.55-1.19, p=0.28) and overall survival (OS) (HR 0.68, 95%CI 0.45-1.02, p=0.059). Perimenopausal HRT users showed shorter TTP and OS (HR 1.99, 95%CI 0.57-6.91, p=0.28 and HR 4.59, 95%CI 0.91-23.25, p=0.06 respectively). Higher BMI was significantly associated with poorer prognosis in perimenopausal women only (TTP: HR=1.16; OS: HR=1.31). In this retrospective analysis postmenopausal HRT users seemed to have a better breast cancer prognosis. For perimenopausal HRT users however, a trend towards worse prognosis was found.

Clinical management of clopidogrel inefficiency by point of care platelet function testing and individual adjustment of anti-platelet therapy--initial experiences.

Insufficient inhibition of ADP dependent platelet aggregation by clopidogrel is associated with an increased risk for adverse coronary events, such as stent thrombosis, after percutaneous coronary intervention. Here, we describe an approach to the clinical management of patients with insufficient inhibition of ADP dependent platelet aggregation by clopidogrel involving dose adjustment or switching of the thienoyridine. We put special emphasize on a patient who experienced recurrent acute myocardial infarction due to stent thrombosis associated with severe clopidogrel non response following elective coronary drug eluting stent implantation. In this patient, an inadequate clopidogrel effect at maintenance doses was confirmed by repeated platelet function assessment with a multiple electrode impedance point of care platelet function test. Subsequent dose adjustments still did not result in sufficient inhibition of ADP dependent platelet aggregation. Only after switching to the then shortly available new thienopyridine prasugrel could a sufficient platelet inhibition be obtained. However, our data from further patients show that although this may overcome inadequate clopidogrel efficiency in many cases, even under prasugrel suboptimal platelet inhibition may occur.

Prothrombotic effects of diclofenac on arteriolar platelet activation and thrombosis in vivo.

BACKGROUND: Diclofenac, like selective cyclooxygenase-2 inhibitors, which alter vascular levels of platelet active prostaglandins, has been reported to increase rates of acute myocardial infarction. OBJECTIVE: The study was performed to investigate, in an animal model of arterial thrombosis in vivo, whether diclofenac differentially influences platelet activation and thrombosis in vessels under non-stimulated conditions or during acute systemic inflammation, such as induced by tumor necrosis factor-alpha (TNF-alpha). METHODS: Platelet-vessel wall interaction (PVWI), firm platelet adhesion and arterial thrombosis following vessel injury were analyzed by intravital microscopy in arterioles of hamsters in the dorsal skinfold chamber model. Prostacyclin [prostaglandin I(2) (PGI(2))] and thromboxane A(2) (TxA(2)) metabolites were measured. In vitro, endothelial adhesion molecule expression in cultured human microvascular endothelial cells was analyzed. RESULTS: Under non-stimulated conditions, diclofenac (1 mg kg(-1)) enhanced PVWI, which was not mediated by increased adhesion molecule expression, but by decreased systemic PGI(2) levels. Following ferric chloride-induced endothelial injury, diclofenac accelerated thrombotic vessel occlusion time, an effect that was reversed by the stable PGI(2) analog iloprost. TNF-alpha, through induction of endothelial adhesion molecule expression, also enhanced PVWI, firm adhesion, and arterial thrombosis, but simultaneous treatment with TNF-alpha and diclofenac did not have an additive effect. CONCLUSIONS: By decreasing levels of PGI(2) without, at the same time, altering prothrombotic TxA(2) levels, diclofenac can exert prothrombotic effects. However, this is not the case when an inflammatory situation is created by TNF-alpha treatment. These data may explain the enhanced risk of acute myocardial infarction observed in patients taking diclofenac.

[Solitary fibrous tumor in the orbit. Case report and review of the literature]. / Solitärer fibröser Tumor in der Orbita. Fallbericht und Literaturübersicht.

BACKGROUND: Solitary fibrous tumor (SFT) is a mesenchymal neoplasm with a benign growth behavior. It was initially described in the pleura and has since been found in extrathoracic locations. In the orbital cavity, SFT is rare. CASE REPORT: We report on a 94-year-old female patient with a large intraorbital SFT on the left side. Tumor growth over 7 years led to a severe exophthalmos with loss of vision. Imaging studies revealed a clearly delineated mass measuring 3x3.3x2.2 cm. Via an anterior orbitotomy approach, we performed an in toto resection. Histological examination, including immunohistochemical detection of CD34 antigen, confirmed the presence of SFT. CONCLUSION: SFT is a rare differential diagnosis of orbital lesions and can be appropriately treated by surgical resection. When left untreated, complications such as loss of vision can occur.

[Training program for vitreoretinal surgery in Nairobi, Kenya from 2000 - 2006]. / Trainingsprogramm zur vitreoretinalen Chirurgie in Nairobi, Kenia, in den Jahren 2000 - 2006.

BACKGROUND: After the U. S. Embassy bombing in 1998 in Nairobi, Kenya, a relief operation was immediately initiated by the Department of Ophthalmology of the Ludwig Maximilians University (LMU) Munich, Germany. Surgical devices and material (such as a vitrectomy unit, silicon oil, perfluorodecalin, intraocular lenses, sutures) were supplied to operate on 42 ocular-injured victims of this bombing attack. Apart from these specific operations in Kenya, there is a big need for vitreoretinal surgery in East Africa, as in all other developing countries. Therefore, a vitreoretinal training program was started in 2000 in Nairobi, Kenya. We report about the first 7 years of collaboration between the Ludwig Maximilians University of Munich, Germany and the University of Nairobi in cooperation with the Kenyatta National Hospital, Kenya. MATERIAL AND METHODS: The training program was based on an annual project week in which the author (CLS) carried out vitreoretinal surgery himself and assisted and supervised surgery done by the local Kenyan colleagues at the Kenyatta National Hospital. Within the observation period of the present work (2000 - 2006) the following data were collected: number and kind of surgery, indications, surgeons, grading of eye pathology and the surgical procedure, time to prepare for surgery and duration of surgery. RESULTS: In total, 293 vitreoretinal surgeries were performed during the observation period. Surgeries carried out by the local Kenyan colleagues independently, without intervention of the author, increased from 29.4 % (2000) to 78.6 % (2006). Due to a constant development in the learning process during the project week more severe cases were treated and preparation time for surgery from the nursing side has shortened. CONCLUSIONS: By initiating a project week with high frequency surgery, supported by a highly experienced visiting surgeon, vitreoretinal surgery can be successfully set up in an ophthalmic clinic of a developing country. This approach has some advantages when compared to long-period projects, especially for the purposes of sustainability. However, to be successful it requires systematic planning which is described in this article.

[International initiatives for the prevention of blindness]. / Internationale Initiativen zur Prävention von Blindheit.

Since 1974, when the International Agency for the Prevention of Blindness (IAPB) was founded, international campaigns for blindness prevention have gained tremendous momentum in collaboration with the WHO's blindness prevention programme. In 1999 WHO and IAPB launched the campaign Vision 2020, The Right to Sight, in which WHO, IAPB, member countries of WHO and nongovernmental organizations (NGOs) that are active in this field are all working together. The major emphasis of the programme is on control of the major disorders leading to blindness and the development of infrastructures, of eye care programmes and of training and continuing education for ophthalmic staff. This campaign is unique in medicine and has the potential for reducing the prevalence of blindness in the world significantly by 2020. Even now, we can assume that 75-80% of cases of blindness can be prevented. The WHO has developed strategies for dealing with individual diseases, such as trachoma, onchocerciasis, childhood blindness and refractive errors. Programmes for glaucoma and diabetic retinopathy will follow. Early successes can already be recognized, especially in the rising numbers of cataract operations.

[The effectiveness of the new fluoroquinolones against the normal bacterial flora of the conjunctiva]. / Wirksamkeit neuer Fluorchinolone gegenüber der bakteriellen Normalflora der Bindehaut.

BACKGROUND: Our aim was to determine the antibiotic susceptibility of the preoperative conjunctival bacterial flora against 25 commonly used antibiotics, especially the new fluoroquinolones levofloxacin, gatifloxacin, and moxifloxacin. PATIENTS AND METHODS: The Kirby-Bauer disk-diffusion technique was used to test for the in vitro antibiotic susceptibility of conjunctival bacterial strains isolated from 160 patients (median=74 years, mean=71 years) undergoing cataract surgery at the Department of Ophthalmology, Stanford University, CA, USA. RESULTS: Among the 256 bacteria isolated, 201 (79%) were coagulase-negative staphylococci (CNS), 26 Staphylococcus aureus, 15 Streptococcus group D and 14 gram-negative rods. A total of 100 of these 256 strains (39%) were classified as multiresitant (resistant to>or=five antibiotics). The resistance rate (RR) of commonly used antibiotics for all CNS was: gatifloxacin=moxifloxacin