Nanocrystal segmentation in scanning precession electron diffraction data.

Scanning precession electron diffraction (SPED) enables the local crystallography of materials to be probed on the nanoscale by recording a two-dimensional precession electron diffraction (PED) pattern at every probe position as a dynamically rocking electron beam is scanned across the specimen. SPED data from nanocrystalline materials commonly contain some PED patterns in which diffraction is measured from multiple crystals. To analyse such data, it is important to perform nanocrystal segmentation to isolate both the location of each crystal and a corresponding representative diffraction signal. This also reduces data dimensionality significantly. Here, two approaches to nanocrystal segmentation are presented, the first based on virtual dark-field imaging and the second on non-negative matrix factorization. Relative merits and limitations are compared in application to SPED data obtained from partly overlapping nanoparticles, and particular challenges are highlighted associated with crystals exciting the same diffraction conditions. It is demonstrated that both strategies can be used for nanocrystal segmentation without prior knowledge of the crystal structures present, but also that segmentation artefacts can arise and must be considered carefully. The analysis workflows associated with this work are provided open-source. LAY DESCRIPTION: Scanning precession electron diffraction is an electron microscopy technique that enables studies of the local crystallography of a broad selection of materials on the nanoscale. The technique involves the acquisition of a two-dimensional diffraction pattern for every probe position in an area of the sample. The four-dimensional dataset collected by this technique can typically comprise up to 500 000 diffraction patterns. For nanocrystalline materials, it is common that single diffraction patterns contain signals from overlapping crystals. To process such data, we use nanocrystal segmentation, where a representative diffraction pattern is constructed for each individual crystal, together with a real space image showing its morphology and location in the data. This reduces the dimensionality of the data and allows unmixing of signals from overlapping crystals. In this work, we demonstrate two methods for nanocrystal segmentation, one based on creating virtual dark-field images, and one based on unsupervised machine learning. A model system of partly overlapping nanoparticles is used to demonstrate the segmentation, and a demanding case for segmentation is highlighted, where some crystals are not discernible based on their diffraction patterns. To obtain a more complete nanocrystal segmentation, we add an image segmentation routine to both methods, and we discuss benefits and limitations of the two methods. The demonstration data and the used code are provided open-source, so that it can be used by everyone for analysis of nanocrystalline materials or as a starting point for further development of nanocrystal segmentation in scanning precession electron diffraction data.

Attitudes towards embryo donation among infertile couples with frozen embryos.

STUDY QUESTION: What are the attitudes towards different aspects of embryo donation among Swedish infertile couples who have surplus cryopreserved embryos? SUMMARY ANSWER: Nearly three-quarters of infertile couples with surplus embryos were in favour of embryo donation. A majority of respondents were also in favour of embryos being donated for research. WHAT IS KNOWN ALREADY: Currently, embryo donation to other infertile couples is prohibited by law in Sweden. Encouraging results have been published from countries allowing embryo donation, although it is a complex procedure associated with many emotional, ethical, legal and psychosocial aspects. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included 471 infertile couples (942 patients) treated during the period March 2006 to March 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: Infertile couples who had been treated at a Swedish university-based hospital and private IVF clinic and who had cryopreserved embryos were sent questionnaires with questions regarding socio-demographic data and their attitudes towards embryo donation. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate to the questionnaire was 58%. Of the respondents, 76% supported the donation of surplus embryos to other infertile couples, but there were divided opinions regarding the disclosure of the genetic parents' identities. Close to 60% of the participants indicated that donations of embryos should be allowed for research and about 45% of the participants approved donations of embryos to single women. LIMITATIONS, REASONS FOR CAUTION: The relatively low response rate and the hypothetical nature of the questions may limit the validity of the results. WIDER IMPLICATIONS OF THE FINDINGS: The results from the study indicate that cryopreserved embryos may be available for donation to other infertile couples, particularly where restrictions can be set on recipient characteristics.

Drug design for ever, from hype to hope.

In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data.

Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome.

The impact of weight reduction on metabolic, endocrine, and anthropometric variables was studied in 13 obese, insulin-resistant women with the polycystic ovary syndrome (PCOS). Insulin sensitivity (euglycemic insulin clamp), insulin secretion and glucose tolerance (iv glucose tolerance test), basal sex steroid hormones, gonadotropins and free fatty acids (FFA), skin folds and waist hip ratio (WHR) were evaluated before (PCO-BD) and after (PCO-AD) diet-induced weight reduction to a weight stable level [mean (SD) diet duration 14.9 (6.2) months]. Mean weight loss was 12.4 kg (4.7; P < 0.0001), equalling a reduction from a body mass index (BMI) of 32.2 (3.7) kg/m2 to 27.6 (3.7; P < 0.0001) kg/m2. The results were compared with those of two groups of weight stable (no diet) women, 21 with PCOS (PCO-ND) and 23 normal control subjects (C), who were matched to the BMI the diet group reached after weight loss. Insulin sensitivity index (M/I) improved on average 132% (P < 0.001) and plasma FFA by 32% (P < 0.01), serum sex hormone binding globulin levels increased by 35% (P < 0.01), and the sum of truncal-abdominal skin-folds (subscapular, umbilical, and suprailiacal) were reduced by 28% (P < 0.0001), whereas the early insulin response to iv glucose, the levels of gonadotropins and androstenedione, and the femoral sc fat did not change significantly with weight loss. M/I, levels of SHBG and FFA and truncal-abdominal fat reached levels similar to the controls, whereas PCO-ND had lower M/I (P < 0.01) and SHBG levels (P < 0.0001), greater concentrations of FFA (P < 0.01) and truncal-abdominal fat (P < 0.05) than C. Among women with normal glucose tolerance, the insulin increment was higher in both PCO-AD (P < 0.05) and PCO-ND (P < 0.01) than in C. There was a strong correlation between M/I and sum of truncal-abdominal skinfolds in all groups (PCO-BD: r = 0.82; P < 0.001, PCO-AD: r = 0.68; P < 0.05, PCO-ND: r = 0.81; P < 0.0001, C: r = 0.44; P < 0.05). The variation in M/I in PCO-AD and PCO-ND (pooled) was best explained by FFA and truncal-adbominal fat (model R2 = 0.67). In conclusion, insulin resistance in obese women with PCOS was reduced by weight loss to similar levels as BMI-matched control subjects, suggesting that insulin resistance in PCOS is not a feature of PCOS per se.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhanced early insulin response to glucose in relation to insulin resistance in women with polycystic ovary syndrome and normal glucose tolerance.

Insulin secretion in response to iv glucose and insulin sensitivity (euglycemic hyperinsulinemic clamp) were evaluated in 49 women with polycystic ovary syndrome (PCOS) [body mass index (BMI), 17.6-37.2 kg/m2] and 42 control subjects (BMI, 18.8-38.1 kg/m2). Seven women with PCOS exhibited glucose intolerance with subnormal insulin secretion. Compared with control subjects, women with PCOS and normal glucose tolerance had an increased (36-56%) insulin increment, not explained by insulin resistance, and over the whole range of BMI. In contrast, insulin sensitivity was similar in women with PCOS and control subjects at BMI 21 kg/m2, but showed a more pronounced decline with increasing BMI in women with PCOS, who had 35% and 70% lower insulin sensitivities at BMI 28 and 35 kg/m2, respectively. After adjusting for truncal-abdominal sc fat distribution, which was more pronounced in the women with PCOS, the two groups had similar insulin sensitivity over the entire range of BMI (P = 0.9), whereas the difference in insulin increment was insignificant after adjusting for the free androgen index (testosterone x 100/sex hormone binding globulin; P = 0.16). Hemoglobin A1C levels were lower in women with PCOS than in the control subjects. It is concluded that the early insulin response to glucose was increased in women with PCOS, not accounted for by insulin resistance, closely associated to the increased androgenicity, and present also at low-normal BMI. In contrast, insulin resistance was seen only at higher BMI levels and was largely determined by the increased truncal-abdominal fat mass in PCOS.

Prolactin secretion and menstrual function after long-term bromocriptine treatment.

Long-term bromocriptine treatment was discontinued in 75 hyperprolactinemic women. Bromocriptine had been given for up to 65 months (median, 24 months). Treatment was reinstituted in 42 women (56%) after 1 to 3 months, mainly because of increasing prolactin levels. Thirty-three women (44%) were followed up for 6 months or more without treatment. Menstrual bleeding occurred in 19 of the 33 women (58%) after 6 months without treatment. The mean prolactin concentration in this group had decreased more than 60% compared with pretherapy concentrations. In 18 of the 42 women who had bromocriptine therapy again, treatment was discontinued a second time. Six of these patients have regular menstrual bleeding. Long-term bromocriptine treatment seems to induce long-standing normalization of prolactin secretion in patients with hyperprolactinemia.

A prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate.

OBJECTIVE: To determine the relative efficacy of intrauterine insemination (IUI), direct intraperitoneal insemination, and intercourse in cycles stimulated with clomiphene citrate (CC) or human menopausal gonadotropins (hMG). DESIGN: A prospective randomized trial with a 2(3) factorial design with eight different treatment alternatives. Only one cycle per couple was performed. SETTINGS: The Departments of Obstetrics and Gynecology, Central Hospital, Västerås and Akademiska Hospital, Uppsala University, Uppsala, Sweden. PATIENTS: Of 157 randomized couples with unexplained infertility including 51 cases with minimal or mild endometriosis, 148 were selected for comparison. MAIN OUTCOME MEASURE: Pregnancy rate (PR). RESULTS: Follicular stimulation with hMG gave a higher PR than with CC in the insemination cycles, 19% (10/52) and 4% (2/49), respectively, but the PRs in intercourse cycles were not significantly different for hMG and CC, 13% (3/24) and 17% (4/23), respectively. Insemination cycles and intercourse cycles had a similar overall PR, 12% (12/101) and 13% (7/47), respectively. Furthermore, IUI and direct intraperitoneal insemination did not differ in efficacy. CONCLUSION: Follicular stimulation with hMG is more effective than CC in insemination cycles, but insemination as such seems to have no beneficial effect on the PR in stimulated cycles for treatment of unexplained infertility.

The importance of human chorionic gonadotropin support of the corpus luteum during human gonadotropin therapy in women with anovulatory infertility.

One hundred ten women with anovulatory infertility (World Health Organization [WHO] group I n = 50, WHO group II n = 60) were given 341 treatment courses with human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). Additional hCG was given as single or repeated injections during the luteal phase in 205 ovulatory cycles. In WHO group I, the incidence of luteal phase defects was lower and the pregnancy rate higher in cycles with extra hCG administration during the luteal phase than in cycles with no extra hCG. In WHO group II, there was no such difference after supplemental hCG. The abortion rate was the same after cycles with or without extra hCG administration. It is suggested that during ovulation induction with hMG/hCG in anovulatory women with no evidence of endogenous estrogen activity, the luteal phase should be supplemented with additional hCG.

Direct intraperitoneal insemination--clinical results and comparison between two methods of sperm preparation.

OBJECTIVE: To compare sperm preparation with a new self-migration method in sodium hyaluronate and a centrifugation/swim-up method and to study the efficiency of direct intraperitoneal (IP) insemination. STUDY DESIGN: Sodium hyaluronate and centrifugation/swim-up were used randomly for direct IP insemination in alternating cycles. Treatments were given with an interval of at least one untreated cycle. When ovulation occurred on weekends, the patients received only controlled ovarian hyperstimulation. SETTINGS: Department of Obstetrics and Gynecology University Hospital, Uppsala, Sweden. PATIENTS: Seventy-nine couples with unexplained infertility (n = 53), endometriosis (n = 17), and cervical factor (n = 9). INTERVENTIONS: Controlled ovarian hyperstimulation was accomplished by clomiphene citrate and gonadotropins. MAIN OUTCOME MEASURES: Sperm parameters and pregnancy rates. RESULTS: Sodium hyaluronate and centrifugation/swim-up resulted in similar conception rates, but sodium hyaluronate recovered more motile spermatozoa than centrifugation/swim-up (P less than 0.0001). The number of patients who became pregnant after direct IP insemination or controlled ovarian hyperstimulation only was significantly higher than that observed after untreated cycles (P = 0.00001 and P = 0.008, respectively). CONCLUSIONS: Sperm preparation with sodium hyaluronate can be used as an alternative to centrifugation/swim-up. Direct IP insemination appears to increase the cycle fecundity, but whether direct IP insemination/controlled ovarian hyperstimulation is more effective than controlled ovarian hyperstimulation alone has yet to be proven.

Return of menstruation and normalization of prolactin in hyperprolactinemic women with bromocriptine-induced pregnancy.

Fifty-eight hyperprolactinemic women were followed up for 13 to 108 months after at least one bromocriptine-induced pregnancy for investigation of whether the pregnancy had any adverse long-term effects on the hyperprolactinemic state. Fifteen women had two term pregnancies. The prolactin (PRL) level decreased greater than 50% in 20 women after the pregnancy. Only two women showed a PRL level increase. Spontaneous uterine bleedings returned in 16 women, whereas 42 remained amenorrheic. Thus, bromocriptine-induced pregnancy in women with hyperprolactinemia has no negative long-term effect on PRL secretion.

Effects of triptorelin versus placebo on the symptoms of endometriosis.

OBJECTIVE: To compare the effect of a GnRH-agonist, triptorelin, versus placebo on the symptoms of endometriosis. DESIGN: A prospective, randomized, double-blind study of 6 months of treatment followed by 12 months of follow-up. SETTING: Departments of Obstetrics and Gynecology at two universities and one general hospital. PATIENT(S): Forty-nine women with symptoms of laparoscopically verified endometriosis. INTERVENTION(S): Triptorelin depot or placebo was given every 4 weeks. Clinical evaluation, including the Duration Intensity Behavior Scale and Visual Analogue Scale for pain, was performed before the injections and up to 12 months after treatment. A control laparoscopy was performed 4-6 weeks after the last injection. MAIN OUTCOME MEASURE(S): Quantitation of pain. RESULT(S): Twenty-four patients had active treatment and 25 received placebo. Pain symptoms according to both scales were significantly more reduced after 2 months of triptorelin treatment compared to placebo. The extent of endometriotic lesions was reduced 50% during triptorelin treatment and increased 17% during placebo. The average area of endometriotic lesions was reduced 45% during triptorelin treatment but was unchanged during placebo. Side effects, mainly hot flushes, were experienced by 80% of the actively treated group but also by 33% of patients in the placebo group. Because of recurrent symptoms, only five patients could be observed for 12 months after completion of treatment. CONCLUSION(S): Triptorelin reduces endometriotic lesions and pain to a significantly higher degree than placebo.

Regression of a prolactin-secreting pituitary tumor during long-term treatment with bromocriptine.

A nulliparous woman with 12 years of amenorrhea, galactorrhea, and hyperprolactinemia and radiologic evidence of a pituitary macroadenoma was treated with large doses of bromocriptine. During treatment the greatly increased prolactin levels normalized and ovulatory menstrual cycles were regained after 48 weeks of treatment. A transsphenoidal surgical exploration of the pituitary fossa was performed after 27 months of treatment. The findings at surgery suggested that regression of the pituitary adenoma had occurred during the prolonged treatment with bromocriptine. After discontinuation of the therapy, the patient continued to ovulate and subsequently conceived.

Photosensitivity in South Africa. IV. Pathological changes in the liver in ovine photosensitivity caused by the plant Asaemia axillaris (Thunb.) Harv. Ex Jackson.

Hepatic lesions in 4 field cases of ovine hepatogenous photosensitization caused by the plant, Asaemia axillaris (Thunb.) Harv. Ex Jackson, are described. The liver was usually swollen, friable and yellowish-brown, with distinct lobulation. Microscopically, the lesions ranged from peripheral coagulative necrosis in 1 animal to others with scattered single cell or small foci of necrosis as well as hepatocellular degeneration and unrest, ductular proliferation, portal fibroplasia and cholestasis. The liver lesions are compared with those of previously reported experimental cases of A. axillaris poisoning in sheep. The significance of zonal necrosis and factors that may have a bearing on their production in different hepatotoxic plant poisoning in sheep and cattle in South Africa are discussed.

Rapid regression of pituitary tumours during bromocriptine treatment of women with hyperprolactinaemia.

Four hyperprolactinaemic women with large pituitary adenomas with suprasellar extension were given primary tumour therapy with bromocriptine. The treatment resulted in rapid tumour regression in all the women, as verified by repeated computerized tomography (CT) scans. Pronounced visual field defects were present in three of the four women before treatment. All of them had marked improvement of vision within a few days after the initiation of bromocriptine therapy and they regained normal or nearly normal visual fields during the treatment. The raised serum prolactin concentrations decreased to normal levels in all the women. Thus, medical treatment with bromocriptine can induce rapid tumour regression in patients with hyperprolactinaemia and large pituitary tumours.

A specific form of abomasal phytobezoar in goats and sheep.

A specific form of phytobezoar in goats and sheep is described with regard to epizootology, symptomatology, gross pathology, and gross morphology of the bezoars. The probable mode of formation and control measures are also discussed.

A new definition of wrist sprain necessary after findings in a prospective MRI study.

INTRODUCTION: Wrist injuries with negative X-rays are diagnosed as acute wrist sprains. The prognosis is usually good, but some patients suffer from long-lasting pain and reduced wrist function, probably due to missed diagnosis followed by inappropriate treatment. The aim of this study was to investigate acute wrist sprains with MRI to detect the pathoanatomy of the injury. PATIENTS AND METHODS: This prospective magnetic resonance imaging (MRI) study included patients between 18 and 49 years, who attended the Accident and Emergency Department (A&E) Bergen, Norway, after sustaining an acute wrist trauma within the previous week. Initial X-rays of the wrist were normal. MRI was done within a median of 1 day (range 0-31 days) after the trauma, 80% within 4 days. The study period lasted from 5 November 2009 to 4 November 2010. RESULTS: A total of 155 acute MRIs were done, out of which 30 were completely normal. Patients with positive MRI had a median of two (range 0-8) pathological findings. We found 54 fractures and 56 bone bruises, mostly located to the radius followed by the scaphoid, the triquetrum, the capitate and the lunate. There were 73 soft-tissue injuries, which included 15 injuries to the triangular fibrocartilage complex (TFCC) and five scapho-lunate (SL) ligament lesions. CONCLUSIONS: Wrist sprain is an inaccurate diagnosis. In four out of five patients with normal X-rays, MRI identified pathological findings and a large variety of injuries in different structures. We suggest that wrist sprain should be defined as "occult partial or complete soft tissue (ligament, tendon, muscle) or bony injury in relation to a trauma with negative X-ray". The MRI findings led to a more differentiated treatment in more than a third of the patients. We recommend that MRI should be considered as a part of an early investigation, especially when the wrist pain does not settle within the first couple of weeks.

Construction of an evidence-based integrated morphology cleavage embryo score for implantation potential of embryos scored and transferred on day 2 after oocyte retrieval.

BACKGROUND: Evidence-based morphological embryo scoring models for ranking of implantation potential are still scarce, and the need for a precise model increases when aiming for singleton pregnancies. METHODS: Prospectively, 2266 IVF/ICSI double-embryo, day 2 transfers were studied. The five variables scored in 3- to 5-step scales for the embryos transferred are blastomere number (BL), fragmentation, blastomere size variation ('equality', EQ), symmetry of the cleavage and mononuclearity in the blastomeres (NU). The scoring results of embryos with an individual traceability from scoring to implantation, i.e. treatments resulting in either no implantation (n=1385) or twin implantation (n=228), were studied for prognostic potential. RESULTS: Although all five variables correlated highly with implantation potential, only BL, NU and EQ remained independently significant after regression analysis. The equation thus derived formed the basis for a 10-point integrated morphology cleavage (IMC) embryo score. A table with the scoring point for each possible combination of the embryo variables is presented. The scoring model was statistically validated on the singleton pregnancy group (n=653). CONCLUSIONS: We suggest that this IMC embryo scoring, incorporating cleavage stage and information on the variation in blastomere size and the number of mononucleated blastomeres, may optimize embryo ranking and selection for day 2 transfers.