Reference standards for follicular density in ovarian cortex from birth to sexual maturity.

RESEARCH QUESTION: Are age-normalized reference values for human ovarian cortical follicular density adequate for tissue quality control in fertility preservation? DESIGN: Published quantitative data on the number of follicles in samples without known ovarian pathology were converted into cortical densities to create reference values. Next, a sample cohort of 126 girls (age 1-24 years, mean ± SD 11 ± 6) with cancer, severe haematological disease or Turner syndrome were used to calculate Z-scores for cortical follicular density based on the reference values. RESULTS: No difference was observed between Z-scores in samples from untreated patients (0.3 ± 3.5, n = 30) and patients treated with (0.5 ± 2.9, n = 48) and without (0.1 ± 1.3, n = 6) alkylating chemotherapy. Z-scores were not correlated with increasing cumulative exposure to cytostatics. Nevertheless, Z-scores in young treated patients (0-2 years -2.1 ± 3.1, n = 10, P = 0.04) were significantly lower than Z-scores in older treated patients (11-19 years, 2 ± 1.9, n = 15). Samples from patients with Turner syndrome differed significantly from samples from untreated patients (-5.2 ± 5.1, n = 24, P = 0.003), and a Z-score of -1.7 was identified as a cut-off showing good diagnostic value for identification of patients with Turner syndrome with reduced ovarian reserve. When this cut-off was applied to other patients, analysis showed that those with indications for reduced ovarian reserve (n = 15) were significantly younger (5.9 ± 4.2 versus 10.7 ± 5.9 years, P = 0.004) and, when untreated, more often had non-malignant haematologic diseases compared with those with normal ovarian reserve (n = 24, 100% versus 19%, P = 0.009). CONCLUSION: Z-scores allow the estimation of genetic- and treatment-related effects on follicular density in cortical tissue from young patients stored for fertility preservation. Understanding the quality of cryopreserved tissue facilitates its use during patient counselling. More research is needed regarding the cytostatic effects found in this study.

Skeletal adverse events in childhood cancer survivors: An Adult Life after Childhood Cancer in Scandinavia cohort study.

The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population-based cohort of childhood cancer survivors. A cohort of 26 334 1-year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127 531 age- and sex-matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first-time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared to the expected numbers derived from the comparison cohort. In total, 1987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% confidence interval, 1.29-1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0-44.5), osteoporosis, RR 4.53 (3.28-6.27), fractures, RR 1.27 (1.20-1.34), osteochondropathies, RR 1.57 (1.28-1.92) and osteoarthrosis, RR 1.48 (1.28-1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high-risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors.

Toward a transdiagnostic neurocircuitry-based biomarker model for pro-cognitive effects: challenges, opportunities, and next steps.

Cognitive impairment has emerged as a key treatment priority in neuropsychiatric disorders. However, there is a lack of treatments with solid and lasting efficacy on cognition. A neurocircuitry-based biomarker model of pro-cognitive effects is critically needed to select among new candidate treatments. In a recent review of functional magnetic resonance imaging (fMRI) studies in mood disorders, we found that cognitive impairments are consistently accompanied by aberrant (hypo- and hyper-) activity in the dorsal prefrontal cortex (PFC) and the default mode network (DMN), and that activity change in these regions commonly occurs with cognitive improvements. Here, we (i) review the putative model from our recent review article, which explains the discrepant findings regarding the direction of aberrant dorsal PFC activity and treatment-related activity change in mood disorders. Inspired by the Research Domain Criteria project, we do this in order to (ii) examine whether a similar pattern of activity change occurs across distinct neuropsychiatric disorders and thereby provides a common biomarker for pro-cognitive effects. Lastly, we (iii) discuss whether dorsal PFC and DMN target engagement is a putative transdiagnostic neurocircuitry-based biomarker model for pro-cognitive effects, and (iv) outline the necessary next steps to address this question.

Neuronal underpinnings of cognitive impairment and - improvement in mood disorders.

Neuropsychiatric illnesses including mood disorders are accompanied by cognitive impairment, which impairs work capacity and quality of life. However, there is a lack of treatment options that would lead to solid and lasting improvement of cognition. This is partially due to the absence of valid and reliable neurocircuitry-based biomarkers for pro-cognitive effects. This systematic review therefore examined the most consistent neural underpinnings of cognitive impairment and cognitive improvement in unipolar and bipolar disorders. We identified 100 studies of the neuronal underpinnings of working memory and executive skills, learning and memory, attention, and implicit learning and 9 studies of the neuronal basis for cognitive improvements. Impairments across several cognitive domains were consistently accompanied by abnormal activity in dorsal prefrontal (PFC) cognitive control regions-with the direction of this activity depending on patients' performance levels-and failure to suppress default mode network (DMN) activity. Candidate cognition treatments seemed to enhance task-related dorsal PFC and temporo-parietal activity when performance increases were observed, and to reduce their activity when performance levels were unchanged. These treatments also attenuated DMN hyper-activity. In contrast, nonspecific cognitive improvement following symptom reduction was typically accompanied by decreased limbic reactivity and reversal of pre-treatment fronto-parietal hyper-activity. Together, the findings highlight some common neural correlates of cognitive impairments and cognitive improvements. Based on this evidence, studies are warranted to examine the reliability and predictive validity of target engagement in the identified neurocircuitries as a biomarker model of pro-cognitive effects.

Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium.

Treatment with chemotherapy, radiotherapy, or surgery that involves reproductive organs can cause impaired spermatogenesis, testosterone deficiency, and physical sexual dysfunction in male pubertal, adolescent, and young adult cancer survivors. Guidelines for surveillance and management of potential adverse effects could improve cancer survivors' health and quality of life. Surveillance recommendations vary considerably, causing uncertainty about optimum screening practices. This clinical practice guideline recommended by the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consortium, developed using evidence-based methodology, critically synthesises surveillance recommendations for gonadotoxicity in male childhood, adolescent, and young adult (CAYA) cancer survivors. The recommendations were developed by an international multidisciplinary panel including 25 experts in relevant medical specialties, using a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. The aim of the recommendations is to enhance evidence-based care for male CAYA cancer survivors. The guidelines reveal the paucity of high-quality evidence, highlighting the need for further targeted research.

Hybrid iterative reconstruction algorithm in brain CT: a radiation dose reduction and image quality assessment study.

BACKGROUND: Iterative reconstruction (IR) algorithms improve image quality and allow for radiation dose reduction in CT. Dose reduction is particularly challenging in brain CT where good low-contrast resolution is essential. Ideally, evaluation of image quality combines objective measurements and subjective assessment of clinically relevant quality criteria. Subjective assessment is associated with various pitfalls and biases. PURPOSE: To evaluate the potential of the hybrid IR algorithm iDOSE(4) to preserve image quality in phantom and clinical brain CT acquired with 30% reduced radiation dose, and to discuss the image quality assessment methods. MATERIAL AND METHODS: Forty patients underwent two consecutive brain CTs with normal radiation dose (ND) and 30% reduced dose (RD). Both ND and RD were reconstructed with FBP. In addition the reduced dose CTs were reconstructed with two levels of IR (ID2, ID4). Three image quality criteria (grey-white-matter discrimination, basal ganglia delineation, general image quality) were graded and ranked by six neuroradiologists. Noise levels and contrast-to-noise ratios (CNR) were measured in clinical data. Noise, signal-to-noise ratio (SNR), spatial resolution, and noise-power spectrum (NPS) were also assessed in a phantom. RESULTS: Subjective image quality was considered adequate for clinical use for all reconstructions, graded good or excellent in 93% of cases for ND, 83% for ID4, 79% for ID2, and 67% for RD. For all quality parameters, ID4 and ID2 were graded better than RD (P < 0.0055 and P < 0.035), but worse than ND (P < 0.001). In clinical images, objective measurements showed lower noise and significantly higher CNR in ID4 compared with ND and RD (P < 0.001). CNR was similar for ID2 and ND. In the phantom, IR reduced noise while maintaining spatial resolution and NPS. CONCLUSION: The IR algorithm improves image quality of reduced dose CTs and consistently delivers sufficient image quality for clinical purposes. Pitfalls related to subjective assessment can be addressed with careful study design.

[Long-term follow up after childhood cancer - during childhood and adult life]. / Behandling för barncancer ger risk för sena komplikationer.

In Sweden, approximately 350 children and teenagers up to 18 years of age are diagnosed with cancer each year. The survival rate is high, above 80%, but the majority of those who survive will experience at least one late complication. The risk of late complications after treatment are mainly related to cumulative dose exposure of specific chemotherapeutic agents as well as radiation doses to certain organs at risk. A Swedish national working group has developed a national care program with recommendations for follow-up during childhood and adult life after childhood cancer treatment. Besides specific follow-up recommendations, the long-term follow-up care program describes both the organization needed to ensure adequate information to patients during their teenage years as well as the basic resources needed to provide a proper follow-up service for adults who survived childhood cancer.

Spermatogonia Loss Correlates with LAMA 1 Expression in Human Prepubertal Testes Stored for Fertility Preservation.

Fertility preservation for male childhood cancer survivors not yet capable of producing mature spermatozoa, relies on experimental approaches such as testicular explant culture. Although the first steps in somatic maturation can be observed in human testicular explant cultures, germ cell depletion is a common obstacle. Hence, understanding the spermatogonial stem cell (SSC) niche environment and in particular, specific components such as the seminiferous basement membrane (BM) will allow progression of testicular explant cultures. Here, we revealed that the seminiferous BM is established from 6 weeks post conception with the expression of laminin alpha 1 (LAMA 1) and type IV collagen, which persist as key components throughout development. With prepubertal testicular explant culture we found that seminiferous LAMA 1 expression is disrupted and depleted with culture time correlating with germ cell loss. These findings highlight the importance of LAMA 1 for the human SSC niche and its sensitivity to culture conditions.

Coxsackievirus and adenovirus receptor is up-regulated in migratory germ cells during passage of the blood-testis barrier.

The coxsackievirus and adenovirus receptor (CAR) is a cell adhesion molecule expressed in epithelial tight junctions and other cell-cell contacts. Using indirect immunofluorescence, quantitative RT-PCR, and Western blots, the expression and distribution of CAR in developing and adult testis are examined. CAR is highly expressed in both Sertoli and germ cells during perinatal and postnatal development, followed by a rapid down-regulation of both mRNA and protein levels. Interestingly, we find that CAR is a previously unknown downstream target for FSH because CAR mRNA levels were induced in primary cultures of FSH-stimulated Sertoli cells. In contrast to other epithelia, CAR is not a general component of tight junctions in the seminiferous epithelium, and Sertoli cells in the adult testis do not express CAR. Instead, CAR expression is stage dependent and specifically found in migratory germ cells. RT-PCR also demonstrated the presence of junctional adhesion molecule-like (JAML) in the testis. JAML was previously reported by others to form a functional complex with CAR regulating transepithelial migration of leukocytes. The expression of JAML in the testis suggests that a similar functional complex might be present during germ cell migration across the blood-testis barrier. Finally, an intermediate compartment occupied by CAR-positive, migrating germ cells and flanked by two occludin-containing junctions is identified. Together, these results implicate a function for CAR in testis morphogenesis and in migration of germ cells across the blood-testis barrier during spermatogenesis.

Water hyacinths as a resource in agriculture and energy production: a literature review.

Water hyacinths are becoming a problem in lakes, ponds and waterways in many parts of the world. This paper contains a literature study of different ways to use water hyacinths, mainly in agricultural or alternative energy systems. The literature review indicated that water hyacinths can be rich in nitrogen, up to 3.2% of DM and have a C/N ratio around 15. The water hyacinth can be used as a substrate for compost or biogas production. The sludge from the biogas process contains almost all of the nutrients of the substrate and can be used as a fertiliser. The use of water hyacinth compost on different crops has resulted in improved yields. The high protein content makes the water hyacinth possible to use as fodder for cows, goats, sheep and chickens. Water hyacinth, due to its abundant growth and high concentrations of nutrients, has a great potential as fertiliser for the nutrient deficient soils of Africa and as feed for livestock. Applying the water hyacinths directly without any other processing than sun drying, seems to be the best alternative in small-scale use due to the relatively small losses of nutrients and workload required. To meet the ever-growing energy demand, biogas production could be one option but it requires investments and technological skills that would impose great problems in developing countries where the water hyacinth is often found. Composting as an alternative treatment has the advantage of a product that is easy to work into the soil compared with dried water hyacinths, because of the decomposed structure. Harvesting and transport of water hyacinths can be conducted manually on a small scale and does not require a new harvesting technique to be introduced. Transporting of fresh water hyacinths means, if used as fertiliser in amounts large enough to enhance or effect crop growth, an unreasonably large labour requirement. Based on the labour need and the limited access to technology, using dried water hyacinths, as green manure is a feasible alternative in many developing countries.

Endotoxin and proinflammatory cytokines modulate Sertoli cell proliferation in vitro.

Sertoli cells play a key role in testicular function and their final number in the adult testis determines the capacity of germ cell production. Sertoli cell proliferation, stimulated by FSH and paracrine factors, occurs only in fetal and prepubertal life and may be an important target of pathogenic influences affecting testis development. We used a Sertoli cell proliferation assay to address the question whether if bacterial endotoxin (lipopolysaccharide; LPS) and proinflammatory cytokines could influence early postnatal Sertoli cell development. LPS and tumor necrosis factor-alpha (TNF-alpha) dose-dependently stimulated proliferation of primary cultures of isolated Sertoli cells from 8- to 9-day-old rats, assessed by (3)H-thymidine and BrdU incorporation. LPS also significantly increased the number of living cells in culture, measured by supravital staining. Interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) had no direct effect on Sertoli cell growth, but were found to modulate FSH action. IL-6 increased, while IFN-gamma inhibited, FSH-induced Sertoli cell DNA-synthesis. We conclude that endotoxin and TNF-alpha are potent direct stimulators of Sertoli cell proliferation in vitro, and that IL-6 and IFN-gamma can modulate the mitogenic action of FSH on immature Sertoli cells. This may contribute to the pathogenesis of testicular damage after infections and inflammatory diseases in fetal and early postnatal life, with subsequent disturbance of adult germ cell production.

Use of recycling stations in Borlänge, Sweden--volume weights and attitudes.

This paper presents a study of recycling stations in the municipality of Borlänge, Sweden. The main objectives were to measure volume weights of recyclables, to facilitate future planning of collection intervals and bin/container volume, and to investigate the general attitudes among the public towards waste management in general and recycling stations in particular. Volume weights measured in bins/containers were: paper/newsprint: 297 kg/m3, glass packaging: 297 kg/m3, metal packaging: 81.7 kg/m3, paper packaging: 27.8 kg/m3, plastic packaging: 28.1 kg/m3. The recycling stations have been in use since 1994. Most visitors (90%) arrived by car but said the visit to the recycling station was not the main purpose of the trip. The results from the interviews indicated that the people who use the recycling stations have found ways to incorporate waste sorting into their everyday lives, with the help of information, design of the collection system and environmental concerns.

The sertoli cell--a hormonal target and 'super' nurse for germ cells that determines testicular size.

The somatic Sertoli cell plays an essential role in embryonic determination of male somatic sex and in spermatogenesis during adult life. One individual Sertoli cell supplies a clone of developing germ cells with nutrients and growth factors and it is well established that the number of Sertoli cells present is closely correlated to both testicular size and sperm output. Sertoli cells continue to proliferate and differentiate until the beginning of puberty, when they cease dividing and start nursing the germ cells. At this point in time, the future capacity of the testis for sperm production has thus been determined. Prior to puberty the Sertoli cells are immature and differ considerably with respect to morphology and biochemical activity from the mature cell. The several investigations that have focused on hormonal and paracrine regulation of the functions of the mature cell are reviewed here, but the mechanisms underlying the maturation and general maintenance of well-functioning Sertoli cells remain obscure. An alarming decline in male reproductive health has been observed in several Western countries during recent decades. Disturbance of Sertoli cell differentiation is thought to be involved in the pathogenesis of both a poor sperm count and testicular cancer. It is speculated that environmental agents that disrupt the estrogenic/androgenic balance in the testis may play a role in this connection.

The p38 MAPK pathway mediates interleukin-1-induced Sertoli cell proliferation.

We have reported earlier that interleukin-1 (IL-1) is a potent growth factor for immature Sertoli cells (somatic cells in the testis required for testicular development and later spermatogenesis) and that this effect is synergistic with the mitogenic effect of follicle-stimulating hormone (FSH). The aim of the present study was to determine whether MAPK pathways are involved in mediating the mitogenic effect of IL-1 on Sertoli cells. Western blotting revealed that IL-1alpha activated p38 MAPK and JNK/SAPK, but not ERK, in Sertoli cells from 8- or 9-day-old rat. The inhibitor of p38 MAPK SB203580 attenuated the IL-1alpha-induced proliferation of Sertoli cells, as assessed by (3)H-thymidine incorporation and supravital staining as well as by direct cell counting. We conclude that the p38 MAPK pathway mediates the proliferative effect of IL-1alpha on immature Sertoli cells in vitro. Since the mitogenic effect of FSH is mediated via ERK, the synergistic action of IL-1alpha and FSH may be explained by their different intracellular signalling pathways. Induction of IL-1 by inflammation, infection or other tissue injuries may result in testicular damage by interfering with normal Sertoli cell development and thus future spermatogenesis.

Quality control of waste to incineration--waste composition analysis in Lidköping, Sweden.

In order to decrease environmental impacts in waste management the choice of treatment method must be based on the characteristics of the waste. Present sampling procedures do not provide statistically representative samples of solid waste and this provides difficulties in characterization. The objective of this study was to develop a procedure for waste component analysis and sampling of waste after collection and at plant level. A further objective was to characterize the waste delivered to an incineration plant for physical and chemical properties and to determine the amounts of delivered waste that could be classified as biofuels and fossil fuels. The proportions of recyclables and hazardous waste were also examined. Samples were taken randomly from waste trucks and divided by square implementation. Statistical analysis of the results showed that the number of sub-samples could be decreased with only a moderate increase in the confidence interval. This means that future waste composition analyses could be made more efficient and thereby less expensive. The analysis of the waste delivered to the Lidköping incineration plant (Central Sweden) showed that 66.4% of the household waste was composed of biofuels and 21.3% of non-renewable combustibles, of which 40.3% were recyclables. In addition, 11.6% of the household waste was non-combustible and 0.6% hazardous waste. The heat value for the biofuels was 18.0-19.7 MJ kg(-1) dry mass (DM) and for the fossil fuels 28.2-33.9 MJ kg(-1) DM. The industrial waste consisted of 35.9% biofuels, 62.0% fossil fuels, 1.6% non-combustible and 0.5% hazardous waste. The heat value was 19.5 MJ kg(-1) DM for the biofuels and 31.4 MJ kg(-1) DM for the fossil fuels.