Infertility affects ∼7% of all men. Despite much progress, mainly in genetics, its etiology remains obscure in ∼50% of cases. To fill this gap, imaging of the male genital tract (MGT) has ...progressively expanded, providing useful information in the assessment of MGT abnormalities.
A critical, systematic review of the available literature was performed using Medline, with no restrictions regarding date of publication (i.e. from inception date until March 2014), along with analysis of previous reports in color Doppler ultrasound (CDUS) atlas textbooks. Normal anatomy and sonographic characteristics of the MGT have also been summarized.
Testicular volume (TV) is tightly associated with both sperm and hormonal parameters. Ultrasound (US) offers a greater accuracy in TV measurement than Prader orchidometer (PO). However US- and PO-derived TV are closely related, making PO-derived TV informative enough in the work-up of the infertile man in everyday clinical practice. US-derived TV might play an independent role in specific clinical conditions (i.e. large hydrocele, inguinal testis, enlarged epididymis). Scrotal US may detect signs of testicular dysgenesis, often related to an impaired spermatogenesis and to a higher risk of malignancy, or testicular lesions suggestive of malignancy. A decreased testis vascularization is characteristic of testicular torsion, whereas hyperemia is often observed in epididymo-orchitis or in some malignant conditions (i.e. lymphoma, leukemia). The impact of varicocele detection and surgical correction on sperm parameters/fatherhood is debated. At present, the clinical management of varicocele is mainly based on physical examination. However, CDUS is useful in assessing venous reflux, when palpation is unreliable and/or in detecting recurrence/persistence after surgery. Epididymis head and/or tail dilation is suggestive of MGT obstruction or inflammation and both are related, along with echo-texture abnormalities, to impaired sperm parameters. Scrotal and transrectal US (TRUS) are useful in detecting congenital uni- or bilateral absence of vas deferens (CBAVD), which may be associated with epididymis, seminal vesicles (SV) or kidney abnormalities/agenesis. TRUS plays a key role in assessing obstructive azoospermia and detecting distal CBAVD or anomalies related to ejaculatory ducts obstruction, such as ejaculatory duct abnormalities, prostate median cysts or SV enlargement/emptying impairment. TRUS findings lead to operational decision-making, such as testicular sperm extraction in the case of CBAVD, cyst aspiration in the case of a large prostatic median cyst, and surgical treatment if ejaculatory duct abnormalities are observed. TRUS may reveal prostate volume reduction (suggestive of hypogonadism) or enlargement, which can be related to aging or even metabolic abnormalities. Finally, TRUS may reveal prostate and SV echo-texture abnormalities suggestive of inflammation or SV stasis.
MGT-CDUS is a useful tool in detecting abnormalities related to impaired male reproductive health. However, it suffers from a lack of standardization and often produces subjective/vague diagnoses. To fill this gap, the European Academy of Andrology has promoted an ongoing multicenter study aimed at defining the MGT-CDUS characteristics of healthy, fertile men.
Lung carcinoma is often incurable and remains the leading cancer killer in both men and women. Recent evidence indicates that tumors contain a small population of cancer stem cells that are ...responsible for tumor maintenance and spreading. The identification of the tumorigenic population that sustains lung cancer may contribute significantly to the development of effective therapies. Here, we found that the tumorigenic cells in small cell and non-small cell lung cancer are a rare population of undifferentiated cells expressing CD133, an antigen present in the cell membrane of normal and cancer-primitive cells of the hematopoietic, neural, endothelial and epithelial lineages. Lung cancer CD133(+) cells were able to grow indefinitely as tumor spheres in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. The injection of 10(4) lung cancer CD133(+) cells in immunocompromised mice readily generated tumor xenografts phenotypically identical to the original tumor. Upon differentiation, lung cancer CD133(+) cells acquired the specific lineage markers, while loosing the tumorigenic potential together with CD133 expression. Thus, lung cancer contains a rare population of CD133(+) cancer stem-like cells able to self-renew and generates an unlimited progeny of non-tumorigenic cells. Molecular and functional characterization of such a tumorigenic population may provide valuable information to be exploited in the clinical setting.
BACKGROUND The global obesity epidemic has paralleled a decrease in semen quality. Yet, the association between obesity and sperm parameters remains controversial. The purpose of this report was to ...update the evidence on the association between BMI and sperm count through a systematic review with meta-analysis. METHODS A systematic review of available literature (with no language restriction) was performed to investigate the impact of BMI on sperm count. Relevant studies published until June 2012 were identified from a Pubmed and EMBASE search. We also included unpublished data (n = 717 men) obtained from the Infertility Center of Bondy, France. Abstracts of relevant articles were examined and studies that could be included in this review were retrieved. Authors of relevant studies for the meta-analysis were contacted by email and asked to provide standardized data. RESULTS A total of 21 studies were included in the meta-analysis, resulting in a sample of 13 077 men from the general population and attending fertility clinics. Data were stratified according to the total sperm count as normozoospermia, oligozoospermia and azoospermia. Standardized weighted mean differences in sperm concentration did not differ significantly across BMI categories. There was a J-shaped relationship between BMI categories and risk of oligozoospermia or azoospermia. Compared with men of normal weight, the odds ratio (95% confidence interval) for oligozoospermia or azoospermia was 1.15 (0.93-1.43) for underweight, 1.11 (1.01-1.21) for overweight, 1.28 (1.06-1.55) for obese and 2.04 (1.59-2.62) for morbidly obese men. CONCLUSIONS Overweight and obesity were associated with an increased prevalence of azoospermia or oligozoospermia. The main limitation of this report is that studied populations varied, with men recruited from both the general population and infertile couples. Whether weight normalization could improve sperm parameters should be evaluated further.
Multiresolution analysis (MRA) and component substitution (CS) are the two basic frameworks to which image fusion algorithms can be reported when merging multispectral (MS) and panchromatic (Pan) ...images (pansharpening), acquired with different spatial and spectral resolutions. State-of-the-art algorithms add the spatial details extracted from the Pan into the MS data set by considering different injection strategies. The capability of efficiently modeling the relationships between MS and Pan is crucial for the quality of fusion results and particularly for a correct recovery of local features with a consequent reduction of spectral distortions. Although context-adaptive (CA) injection models have been proposed in the MRA framework, their adoption in CS schemes has been scarcely investigated so far. In this letter, CA strategies are compared with global models by considering a general protocol in which both MRA- and CS-based schemes can be described. Qualitative and quantitative results are reported for three high-resolution data sets from two different sensors, namely, IKONOS and simulated Pleiades. The score gains of well-known and novel quality figures show that CA models are more efficient than global ones.
Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, ...therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ in in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions. CBZ is able to decrease proliferation and migration of OS cells, inhibiting ERK and AKT signaling pathways. Furthermore, CBZ leads to the inhibition of the proliferation of OS cells expressing receptor activator of nuclear factor κB (RANK), due to its effect on bone microenvironment, where it causes an overproduction of osteoprotegerin and a decrease of production of RANK ligand by osteoblasts. Overall, our data demonstrate that CBZ might represent a new potential treatment against OS, affecting both OS cells and their microenvironment. In this scenario, RANK expression in OS cells could represent a predictive factor of better response to CBZ treatment.
STUDY QUESTION
Is sexual dysfunction associated with severity of semen quality impairment in men with couple infertility?
SUMMARY ANSWER
In males of infertile couples the prevalence of erectile ...dysfunction (ED) increases as a function of semen quality impairment severity.
WHAT IS KNOWN ALREADY
Infertile men are at a higher risk for sexual dysfunction, psychopathological and general health disorders. However, it has never been systematically investigated if these problems are associated with severity of semen quality impairment.
STUDY DESIGN, SIZE, DURATION
Cross-sectional analysis of a first-time evaluation of 448 males of infertile couples attending an outpatient clinic from September 2010 to November 2015. In addition, 74 age-matched healthy, fertile men from an ultrasound study on male fertility were studied for comparison.
PARTICIPANTS/MATERIALS, SETTING, METHODS
All subjects underwent a complete physical, biochemical, scrotal and flaccid penile colour-Doppler ultrasound evaluation and semen analysis. Patients had already undergone at least one semen analysis; therefore, the majority were aware of their sperm quality before taking part in the study. Validated tools, such as the International Index of Sexual Function-15 (IIEF-15), Premature Ejaculation Diagnostic Tool (PEDT), Middlesex Hospital Questionnaire (MHQ), National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score and Chronic Disease Score (CDS), were used to evaluate, respectively, sexual dysfunction, premature ejaculation (PE), psychopathological traits, prostatitis-like symptoms, lower urinary tract symptoms and general health status.
MAIN RESULTS AND THE ROLE OF CHANCE
Among men with couple infertility, 96 showed azoospermia (Group #1), 245 at least one sperm abnormality (Group #2) and 107 normozoospermia (Group #3). Fertile men were considered as a control group (Group #4). After adjusting for age, we observed a higher prevalence of ED (IIEF-15-erectile function domain score <26) (18.3% versus 0%; P = 0.006) and PE (PEDT score >8) (12.9% versus 4.1%; P = 0.036) in males of infertile couples compared with fertile men. The ED prevalence increases as a function of semen quality impairment severity (P < 0.0001), even after adjusting for confounders (age, CDS, MHQ and NIH-CPSI total score), despite similar hormonal, glyco-metabolic and penile vascular status. Compared to fertile men, all three groups of males with couple infertility showed a poorer erectile function, associated with an overall psychopathological burden (MHQ total score), particularly with somatized anxiety (MHQ-S). Azoospermic men showed the worst erectile function and general health: in this group, erectile function was negatively associated not only with psychopathological disturbances (MHQ total and MHQ-S scores; P < 0.0001) but also with a less healthy phenotype (higher CDS; P = 0.015). In addition, azoospermic men reported higher PE prevalence and lower sexual desire and orgasmic function when compared to fertile men (all P < 0.05), all of which were related to psychopathological symptoms.
LIMITATIONS, REASONS FOR CAUTION
The cross-sectional nature of the study represents its main limitation. A possible selection bias concerning the control group of healthy, fertile men recruited into an ultrasound study might have occurred. Finally, causality cannot be inferred in this type of study design and hence there should be some caution in interpreting the results.
WIDER IMPLICATIONS OF THE FINDINGS
Investigation of male sexual function, general health and psychological status in infertile couples, especially if azoospermic, is advisable, in order to improve not only reproductive but also general and sexual health.
STUDY FUNDING/COMPETING INTEREST(S)
Grants were received from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). There are no conflicts of interest.
TRIAL REGISTRATION NUMBER
None.
Cancer stem cell (SC) chemoresistance may be responsible for the poor clinical outcome of non-small-cell lung cancer (NSCLC) patients. In order to identify the molecular events that contribute to ...NSCLC chemoresistance, we investigated the DNA damage response in SCs derived from NSCLC patients. We found that after exposure to chemotherapeutic drugs NSCLC-SCs undergo cell cycle arrest, thus allowing DNA damage repair and subsequent cell survival. Activation of the DNA damage checkpoint protein kinase (Chk) 1 was the earliest and most significant event detected in NSCLC-SCs treated with chemotherapy, independently of their p53 status. In contrast, a weak Chk1 activation was found in differentiated NSCLC cells, corresponding to an increased sensitivity to chemotherapeutic drugs as compared with their undifferentiated counterparts. The use of Chk1 inhibitors in combination with chemotherapy dramatically reduced NSCLC-SC survival in vitro by inducing premature cell cycle progression and mitotic catastrophe. Consistently, the co-administration of the Chk1 inhibitor AZD7762 and chemotherapy abrogated tumor growth in vivo, whereas chemotherapy alone was scarcely effective. Such increased efficacy in the combined use of Chk1 inhibitors and chemotherapy was associated with a significant reduction of NSCLC-SCs in mouse xenografts. Taken together, these observations support the clinical evaluation of Chk1 inhibitors in combination with chemotherapy for a more effective treatment of NSCLC.
Summary
Background
Autoantibodies against thyroid hormones (THAbs) directed towards triiodothyronine (T3‐Ab) and/or thyroxine (T4‐Ab) are very rare in the general population. They are increased in ...some nonthyroidal autoimmune diseases, where they seem to predict autoimmune thyroid disorders (ATDs). So far, their presence in patients with vitiligo has not been evaluated, but it might have a possible predictive role.
Objectives
To assess the prevalence of THAbs in a group of vitiligo patients and to correlate their presence with clinical and historical parameters.
Methods
In total 79 patients with nonsegmental vitiligo and 100 controls were examined. Clinical characteristics of vitiligo and family and personal medical history were evaluated. Antinuclear autoantibodies, thyroid hormones and thyroid autoantibodies were measured. IgM T3‐Ab, IgG T3‐Ab, IgM T4‐Ab and IgG T4‐Ab were assayed by a radioimmunoprecipitation technique. Fisher's test, Student's t‐test and χ2‐test were used for statistical analysis.
Results
Overall 77 of 79 patients (97%) had at least one type of THAb (11 T3‐Ab, 10 T4‐Ab, 56 both). In the control group, only one person (1%) had THAbs. In patients with vitiligo, T3‐Abs were significantly associated with leucotrichia (IgM+IgG, P = 0·033; IgG, P = 0·039; IgM, P = 0·005) and thyroglobulin autoantibodies (IgM+IgG, P = 0·031; IgG, P = 0·058), while the absence of T3‐Ab was related to personal history of cancer (IgM+IgG, P = 0·021; IgG, P = 0·039). T4‐Abs were significantly associated with vitiligo activity (IgM+IgG, P < 0·001; IgM, P = 0·037) and duration (IgG, P = 0·013).
Conclusions
The surprisingly high prevalence of THAb in patients with vitiligo and their associations suggest a possible pathogenetic role in the disease and stress the tight link between vitiligo and ATDs. Further evaluation in a larger group of patients and an adequate follow‐up are needed to define their potential predictive role.
What's already known about this topic?
Vitiligo is strongly associated with autoimmune thyroid disorders.
Autoantibodies against thyroid hormones (THAbs) have a very low prevalence in the general population and are increased in thyroid and extrathyroid autoimmune diseases.
What does this study add?
For the first time, THAbs against triiodothyronine (T3‐Ab) and thyroxine (T4‐Ab) have been detected in a group of patients with vitiligo.
T3‐Ab and T4‐Ab were associated with some clinical and historical parameters of vitiligo.
Italian manufacturing firms have been losing ground with respect to many of their European competitors. This article presents some empirical evidence on the effects of innovation on employment growth ...and therefore on firms’ productivity with the goal of understanding the roots of such poor performance. We use firm level data from the last three surveys on Italian manufacturing firms conducted by Mediocredito-Capitalia, which cover the period 1995–2003. Using a slightly modified version of the model proposed by Harrison, Jaumandreu, Mairesse and Peters (Harrison et al., 2005), which separates employment growth rates into those associated with old and new products, we find no evidence of significant employment displacement effects stemming from process innovation. The sources of employment growth during the period are split equally between the net contribution of product innovation and the net contribution from sales growth of old products. However, the contribution of product innovation to employment growth is somewhat lower than in the four European countries considered in Harrison et al. (2005), and the contribution of innovation in general to productivity growth is almost nil in Italy during this period.
Abstract
STUDY QUESTION
Is thyroid hormones (TH) evaluation of clinical value in the work-up of males of infertile couples?
STUDY ANSWER
Our results suggest that TH evaluation is not mandatory in the ...work-up of male infertility.
WHAT IS KNOWN ALREADY
A few previous studies performed on a limited series of subjects reported a negative impact of hyper- and hypo-thyroidism on semen volume, sperm concentration, progressive motility and normal morphology. No previous study has systematically evaluated associations between TH variation, semen parameters and ultrasound characteristics of the male genital tract.
STUDY DESIGN, SIZE AND DURATION
Cross-sectional analysis of a consecutive series of 172 subjects seeking medical care for couple infertility from September 2010 to November 2014.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Of the entire cohort, 163 men (age 38.9 ± 8.0 years) free of genetic abnormalities were studied. All subjects underwent a complete andrological and physical examination, biochemical and hormonal assessment, scrotal and transrectal colour-Doppler ultrasound (CDUS) and semen analysis (including seminal interleukin 8 levels, sIL-8) evaluation within the same day.
MAIN RESULTS AND THE ROLE OF CHANCE
Among the patients studied, 145 (88.9%) showed euthyroidism, 6 (3.7%) subclinical hyper- and 12 (7.4%) subclinical hypo-thyroidism. No subjects showed overt hyper- or hypo-thyroidism. At univariate analysis, no associations among thyroid-stimulating hormone (TSH) or TH levels and sperm parameters were observed. Conversely, we observed positive associations among free triiodothyronine (fT3) and free thyroxine (fT4) levels, ejaculate volume and seminal fructose levels. In a multivariate model, after adjusting for confounders such as age, body mass index, smoking habit, sexual abstinence, calculated free testosterone, prolactin and sIL-8 levels, only the associations found for fT3 levels were confirmed. When CDUS features were investigated, using the same multivariate model, we found positive associations between fT3 levels and seminal vesicles (SV) volume, both before and after ejaculation (adj. r = 0.354 and adj. r = 0.318, both P < 0.0001), as well as with SV emptying (ΔSV volume; adj. r = 0.346, P < 0.0001) and echo-texture inhomogeneity. In addition, after adjusting for confounders, negative associations between fT4 levels and epididymal body and tail diameters were found. No significant associations between TSH or TH levels and CDUS features of other organs of the male genital tract, including testis and prostate, were found. Finally, when the features of subjects with euthyroidism, subclinical hypo- and hyper-thyroidism were compared, no significant differences in seminal or hormonal parameters were found. Conversely, evaluating CDUS parameters, subjects with subclinical hyperthyroidism showed a higher difference between the SV longitudinal diameters measured before and after ejaculation when compared with that of subclinical hypothyroid men, even after adjusting for confounders (P < 0.007). All the other male genital tract CDUS characteristics did not differ among groups.
LIMITATIONS, REASONS FOR CAUTION
First, the number of patients investigated is relatively small and those with (subclinical) thyroid dysfunctions are an even smaller number; hence, it is therefore difficult to draw firm conclusions. Moreover, the present results are derived from patients consulting an Italian Andrology Clinic for couple infertility, and could have different characteristics from the male general population or from those males consulting general practitioners for reasons other than couple infertility. Finally, due to the cross-sectional nature of the study, neither a causality hypothesis nor mechanistic models can be inferred.
WIDER IMPLICATIONS OF THE FINDINGS
Although no associations between TH and sperm parameters were observed, present data support a positive effect of TH on SV size and a permissive role on the ejaculatory machinery, likely through an action on SV and epididymal contractility. This is the first study reporting such evidence. However, in contrast with the view that TH assessment is important for female fertility, our results do not support a systematic evaluation of thyroid function in males of infertile couples. How TH abnormalities impact male fertility needs to be addressed by further studies.
STUDY FUNDING/COMPETING INTEREST(S)
No funding was received for the study. None of the authors have any conflict of interest to declare.
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