A new selective estrogen receptor modulator with potent uterine antagonist activity, agonist activity in bone, and minimal ovarian stimulation

The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective estrogen receptor modulator compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors and has potent estrogen antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluation showed granulosa cell hyperplasia in few of the rats. Bone studies demonstrated that LY2066948 prevented ovariectomy-induced bone loss and treatment of ovary-intact rats caused no bone loss, confirming estrogen receptor agonist skeletal effects. Collectively, these data show that LY2066948 exhibits a tissue-specific profile consistent with strong antagonist activity in the uterus, agonist activity in bone, and minimal effects in the ovaries.     

Interpretation of Dual-Energy X-Ray Absorptiometry-Derived Body Composition Change in Athletes: A Review and Recommendations for Best Practice

Dual-energy X-ray absorptiometry (DXA) is a medical imaging device which has become the method of choice for the measurement of body composition in athletes. The objectives of this review were to evaluate published longitudinal DXA body composition studies in athletic populations for interpretation of “meaningful” change, and to propose a best practice measurement protocol. An online search of PubMed and CINAHL via EBSCO Host and Web of Science enabled the identification of studies published until November 2016. Those that met the inclusion criteria were reviewed independently by 2 authors according to their methodological quality and interpretation of body composition change. Twenty-five studies published between 1996 and November 2016 were reviewed (male athletes: 13, female athletes: 3, mixed: 9) and sample sizes ranged from n?=?1 to 212. The same number of eligible studies was published between 2013 and 2016, as over the 16?yr prior (between 1996 and 2012). Seven did not include precision error, and fewer than half provided athlete-specific precision error. There were shortfalls in the sample sizes on which precision estimates were based and inconsistencies in the level of pre-scan standardization, with some reporting full standardization protocols and others reporting only single (e.g., overnight fast) or no control measures. There is a need for standardized practice and reporting in athletic populations for the longitudinal measurement of body composition using DXA. Based on this review and those of others, plus the official position of the International Society for Clinical Densitometry, our recommendations and protocol are proposed as a guide to support best practice.     

AN ATYPICAL CASE OF ATYPICAL PNEUMONIA

SUMMARY A 23-year-old man, previously fit and well, presented with an atypical pneumonia, associated with microangiopathic anaemia, thrombocytopenia, rhabdomyolysis and renal impairment. Despite administration of intravenous fluids and antibiotics, his condition rapidly deteriorated, and the possibility of an aggressive connective tissue disorder was raised. Thus he was treated with high-dose oral steroids and plasma exchange until autoantibodies were shown to be negative. At this stage it transpired that the patient had swallowed water from a stream three weeks earlier, and leptospira antibody titres were subsequently found to be elevated. Antibiotics were continued, and after a protracted course he made a full recovery. Leptospirosis should be remembered as a rare cause of atypical pneumonia, particularly if there is associated hepatic or renal impairment.     

Human papillomavirus antigens and T-cell recognition

This review will summarize what is known about natural T-cell responses to human papillomavirus infections, including potential mechanisms for their dysregulation which may lead to the development of disease. We will also describe new strategies to enhance human papillomavirus specific T-cell responses following vaccination that are currently in development and recent reports on human vaccine trials with particular regard to the generation of appropriate T-cell responses.     

Postal consent for upper gastrointestinal endoscopy

BACKGROUND: Standards for good practice in clinical risk management issued by the Clinical Negligence Scheme for Trusts indicate that "appropriate information is provided to patients on the risks and benefits of proposed treatment, and of the alternatives available before a signature on a consent form is sought". AIMS: To investigate the practicability and patient acceptability of a postal information and consent booklet for patients undergoing outpatient gastroscopy. METHODS: Information about gastroscopy procedure, personalised appointment details, and a carbonised consent form were compiled into a single booklet. This was mailed to patients well in advance of their endoscopic procedure. Patient satisfaction for this new process was assessed by questionnaire. RESULTS: 275 patients received a patient information booklet. Of these, 150 (54.5%) returned the consent form by post when they confirmed their attendance; 141 (94%) had signed the form, and the other nine requested further information. Of the remaining 125 booklets sent out, 115 (92%) forms were brought back on the day of the investigation having been previously signed. The remaining 10 (8%) required further information before signing the form. An audit of 168 patients was used to test reaction to the booklet and the idea of filling in the form before coming to hospital; 155 patients (92. 2%) reported the information given in the booklet to be "very useful", and all reported it to be "clear and understandable". CONCLUSION: A specifically designed patient information booklet with integral consent form is accepted by patients, and improves the level of understanding prior to the investigation being carried out.     

Alterations in exon 4 of the p53 gene in gastric carcinoma

BACKGROUND & AIMS: Our long-term goal was to evaluate the role of p53 in the prognosis of gastric cancer. We previously showed a discrepancy between p53 expression and the presence of mutations when only exons 5-9 were examined. We then evaluated exon 4. METHODS: DNA was sequenced from 217 gastric cancers to detect exon 4 alterations. Codon 72 was examined by restriction enzyme digestion. RESULTS: Mutations were present in 3.2% of tumors. In addition, 2 polymorphic sites were found at codons 36 and 72. Polymorphisms at codon 36 were only found in 2 patients. In contrast, the codon 72 polymorphism was very frequent. The genotype frequency was arg/arg (54%), arg/pro (33%), and pro/pro (14%). The genotype of the polymorphic site varied with race (P = 0.001): 64% of whites had the arg/arg genotype, compared with 24% of blacks. The difference in genotype by site, sex, or histological tumor type was not statistically significant (P = 0.067). CONCLUSIONS: There are several exon 4 alterations in gastric cancers. These include the rare mutations and the very rare codon 36 polymorphism. The most common change is the codon 72 polymorphism, the genotype of which differs significantly with race. The more common arg/arg genotype in whites may explain why whites are more prone to develop cardiac cancer, whereas the more common proline allele in blacks may explain why they are more prone to develop antral cancers. Further studies are required to determine whether the codon 72 polymorphism affects patient predisposition to gastric cancer.     

Human papillomavirus type 16 DNA in anal cancers from six different countries.

An association between anal squamous cell carcinoma and human papillomavirus (HPV) type 16 DNA has been documented in the UK. If HPV type 16 is an important aetiological factor in the development of this tumour it would be expected to occur in anal cancer tissues from other parts of the world. In this study a series of 173 anal squamous cell carcinoma tissue samples from five centres around the world have been examined by DNA hybridisation for HPV type 16 DNA sequences. HPV type 16 DNA was found in 50 of 173 (29%) of these. The prevalence of HPV associated anal squamous cell carcinoma was significantly lower in tissue from India and South Africa than in the Swiss, Polish, or Brazilian samples. HPV associated anal squamous cell carcinoma does occur in other countries and further investigations of the prevalence of these tumours in association with other HPV types are required.     

Long-term modifications of synaptic efficacy in the human inferior and middle temporal cortex.

The primate temporal cortex has been demonstrated to play an important role in visual memory and pattern recognition. It is of particular interest to investigate whether activity-dependent modification of synaptic efficacy, a presumptive mechanism for learning and memory, is present in this cortical region. Here we address this issue by examining the induction of synaptic plasticity in surgically resected human inferior and middle temporal cortex. The results show that synaptic strength in the human temporal cortex could undergo bidirectional modifications, depending on the pattern of conditioning stimulation. High frequency stimulation (100 or 40 Hz) in layer IV induced long-term potentiation (LTP) of both intracellular excitatory postsynaptic potentials and evoked field potentials in layers II/III. The LTP induced by 100 Hz tetanus was blocked by 50-100 microM DL-2-amino-5-phosphonovaleric acid, suggesting that N-methyl-D-aspartate receptors were responsible for its induction. Long-term depression (LTD) was elicited by prolonged low frequency stimulation (1 Hz, 15 min). It was reduced, but not completely blocked, by DL-2-amino-5-phosphonovaleric acid, implying that some other mechanisms in addition to N-methyl-DL-aspartate receptors were involved in LTD induction. LTD was input-specific, i.e., low frequency stimulation of one pathway produced LTD of synaptic transmission in that pathway only. Finally, the LTP and LTD could reverse each other, suggesting that they can act cooperatively to modify the functional state of cortical network. These results suggest that LTP and LTD are possible mechanisms for the visual memory and pattern recognition functions performed in the human temporal cortex.