Early morphological and neurochemical changes of the bed nucleus of stria terminalis (BNST) in gestational protein-restricted male offspring.

BACKGROUND: The bed nucleus of the stria terminalis (BNST) is a structure with a peculiar neurochemical composition involved in modulating anxietylike behavior and fear. AIM: The present study investigated the effects on the BNST neurochemical composition and neuronal structure in critical moments of the postnatal period in gestational protein-restricted male rats' offspring. METHODS: Dams were maintained during the pregnancy on isocaloric rodent laboratory chow with standard protein content [NP, 17%] or low protein content [LP, 6%]. BNST from male NP and age-matched LP offspring was studied using the isotropic fractionator method, Neuronal 3D reconstruction, dendritic-tree analysis, blotting analysis, and high-performance liquid chromatography. RESULTS: Serum corticosterone levels were higher in male LP offspring than NP rats in 14-day-old offspring, without any difference in 7-day-old progeny. The BNST total cell number and anterodorsal BNST division volume in LP progeny were significantly reduced on the 14th postnatal day compared with NP offspring. The BNST HPLC analysis from 7 days-old LP revealed increased norepinephrine levels compared to NP progeny. The BNST blot analysis from 7-day-old LP revealed reduced levels of GR and BDNF associated with enhanced CRF1 expression compared to NP offspring. 14-day-old LP offspring showed reduced expression of MR and 5HT1A associated with decreased DOPAC and DOPA turnover levels relative to NP rats. In Conclusion, the BNST cellular and neurochemical changes may represent adaptation during development in response to elevated fetal exposure to maternal corticosteroid levels. In this way, gestational malnutrition alters the BNST content and structure and contributes to already-known behavioral changes.

Functional fitness of adults with Down syndrome: a longitudinal study.

BACKGROUND: Individuals with Down syndrome (DS) are born with and develop many health-related complications. The purpose of this study was to determine the longitudinal functional fitness profile of adults with DS. METHODS: The functional fitness of adults with DS was tested twice, 12 years apart. Sixty-six adults with DS were tested for body mass, stature and 10 functional fitness tests. Data were categorised according to gender and age-specific categories. RESULTS: Static balance, shoulder flexibility, trunk strength and aerobic capacity deteriorated significantly with medium to large effect sizes for both DS men and women (most age categories). For women, dynamic balance deteriorated significantly, and for men, leg- and upper body-strength deteriorated significantly. CONCLUSIONS: Practitioners working in the field of adapted physical activity should take cognisance of the functional fitness ageing profile of adults with DS and timeously develop habitual physical activity interventions to reduce the effect of accelerated ageing experienced by this population.

The effect of 8 weeks of freestyle swim training on the functional fitness of adults with Down syndrome.

BACKGROUND: Studies conducted on adults with Down syndrome have demonstrated the improvement of functional fitness (aerobic capacity, muscular strength, balance, flexibility, functional ability, body mass or body mass index) with varying exercise modalities but often with one or two components in isolation. Such modalities included walking, running, cycling, rowing or resistance training. Freestyle swim training has shown significant improvements of all parameters associated with functional fitness in the general population. Swimming is an aerobic activity where many of the large muscle groups are involved and may provide more functional fitness benefits. As a consequence, the purpose of our study was to investigate the effect of freestyle swim training on the functional fitness of adults with Down syndrome. METHODS: Twenty-six adults with Down syndrome (33 ± 6 years; 34 ± 9 kg/m2 ) were randomly allocated to an exercise (n = 13; 81.3 kg) or control group (n = 13; 81.5 kg). The exercise group performed 8 weeks of freestyle swim training, three times a week, 30 min per session (increased to 40 min after 4 weeks). To evaluate differences between groups, a one-way analysis of variance was used, controlling for differences at baseline. RESULTS: After 8 weeks of training, the results showed significant differences between the exercise and control group for body mass, body mass index, aerobic capacity, dynamic balance, muscular strength, 12-m swim time and functional ability (P < 0.05). Effect sizes ranged from small to large. CONCLUSIONS: Various components of functional fitness improved significantly after an intervention period of freestyle swim training. The collective improvement of many functional fitness parameters shown by this study may hold benefits for these often-neglected and in many cases functionally impaired individuals.

Burden of surgical site infections in the Netherlands: cost analyses and disability-adjusted life years.

BACKGROUND: Surgical site infections (SSIs) are associated with morbidity, mortality and costs. AIM: To identify the burden of (deep) SSIs in costs and disability-adjusted life years (DALYs) following colectomy, mastectomy and total hip arthroplasty (THA) in the Netherlands. METHODS: A retrospective cost-analysis was performed using 2011 data from the national SSI surveillance network PREZIES. Sixty-two patients with an SSI (exposed) were matched to 122 patients without an SSI (unexposed, same type of surgery). Patient records were studied until 1 year after SSI diagnosis. Unexposed patients were followed for the same duration. Costs were calculated from the hospital perspective (2016 price level), and cost differences were tested using linear regression analyses. Disease burden was estimated using the Burden of Communicable Disease in Europe Toolkit of the European Centre for Disease Prevention and Control. The SSI model was specified by type of surgery, with country- and surgery-specific parameters where possible. FINDINGS: Attributable costs per SSI were €21,569 (THA), €14,084 (colectomy) and €1881 (mastectomy), mainly caused by prolonged length of hospital stay. National hospital costs were estimated at €10 million, €29 million and €0.6 million, respectively. National disease burden was greatest for SSIs following colectomy (3200 DALYs/year, 150 DALYs/100 SSIs), while individual disease burden was highest following THA (1200 DALYs/year, 250 DALYs/100 SSIs). For mastectomy, these DALYs were <1. The total cost of DALYs for the three types of surgery exceeded €88 million. CONCLUSION: Depending on the type of surgery, SSIs cause a significant burden, both economically and in loss of years in full health. This underlines the importance of appropriate infection prevention and control measures.

Dosimetric comparison of library of plans and online MRI-guided radiotherapy of cervical cancer in the presence of intrafraction anatomical changes.

BACKGROUND: Online magnetic resonance imaging (MRI)-guided radiotherapy of cervical cancer has the potential to further reduce dose to organs at risk (OAR) as compared to a library of plans (LOP) approach. This study presents a dosimetric comparison of an MRI-guided strategy with a LOP strategy taking intrafraction anatomical changes into account. METHODS: The 14 patients included in this study were treated with chemo radiation at our institute and received weekly MRIs after informed consent. The MRI-guided strategy consisted of treatment plans created on the weekly sagittal MRI with 3 mm and 5 mm planning target volume (PTV) margin for clinical target volume (CTV) cervix-uterus (MRI_3mm and MRI_5mm). The plans for the LOP strategy were based on interpolations of CTV cervix-uterus on pretreatment full and empty bladder scans. Dose volume histogram (DVH) parameters were compared for targets and OARs as delineated on the weekly transversal MRI, which was acquired on average 10 min after the sagittal MRI. RESULTS: For the MRI_5mm strategy D98% of the high-risk CTV was at least 95% for all weekly MRIs of all patients, while for the LOP and MRI_3mm strategy this requirement was not satisfied for at least one weekly MRI for 1 and 3 patients, respectively. The average reduction of the volume of the reference dose (95% of the prescribed dose) as compared to the LOP strategy was 464 cm3 for the MRI_3mm strategy, and 422 cm3 for the MRI_5mm strategy. The bowel bag constraint V40Gy < 350 cm3 was violated for 13 patients for the LOP strategy and for 5 patients for both MRI_3mm and MRI_5mm strategy. CONCLUSIONS: With online MRI-guided radiotherapy of cervical cancer considerable sparing of OARs can be achieved. If a new treatment plan can be generated and delivered within 10 min, an online MRI-guided strategy with a 5 mm PTV margin for CTV cervix-uterus is sufficient to account for intrafraction anatomical changes. TRIAL REGISTRATION: NL44492.018.13.

Anxiety-like behavior and structural changes of the bed nucleus of the stria terminalis (BNST) in gestational protein-restricted male offspring.

Animal evidence has suggested that maternal emotional and nutritional stress during pregnancy is associated with behavioral outcomes in offspring. The nature of the stresses applied may differ, but it is often assumed that the mother's hippocampus-hypothalamic-pituitary-adrenal (HHPA) axis response releases higher levels of glucocorticoid hormones. The bed nucleus of the stria terminalis (BNST) is in a pivotal position to regulate the HHPA axis and the stress response, and it has been implicated in anxiety behavior. In the current study, to search whether BNST structural changes and neurochemical alterations are associated with anxiety-related behavior in adult gestational protein-restricted offspring relative to an age-matched normal protein diet (NP) rats, we conduct behavioral tests and, BNST dendritic tree analysis by Sholl analysis, associated to immunoblotting-protein quantification [11ß-HSD2, GR, MR, AT1R, 5HT1A and 5HT2A, corticotrophin-releasing factor (CRH) and CRH1]. Dams were maintained either on isocaloric standard rodent chow [with NP content, 17% casein or low protein content (LP), 6% casein] chow throughout their entire pregnancy. Here, in rats subjected to gestational protein restriction, we found: (a) a significant reduction in dendritic length and impoverished dendritic arborization in BNST neurons; (b) an elevated plasmatic corticosterone levels; and (c) associated with enhanced anxiety-like behavior when compared with age-matched NP offspring. Moreover, altered protein (11ß-HSD2, GR, MR and type 1 CRH receptors) expressions may underlie the increase in anxiety-like behavior in LP offspring. This work represents the first demonstration that BNST developmental plasticity by maternal protein restriction, resulting in fine structural changes and neurochemical alterations that are associated with modified behavioral states.

Effects of detraining on anthropometry, aerobic capacity and functional ability in adults with Down syndrome.

BACKGROUND: Structured exercise has shown to improve parameters of functional fitness in adults with Down syndrome (DS). However, few, if any, continue to exercise after exercise intervention studies. Consequently, the purpose of this study was to determine the effects of detraining on anthropometry, aerobic capacity and functional ability of adults with DS. METHODS: In a previous study, forty-two participants either performed 12 weeks of interval training, continuous aerobic training or no training (CON). After 3 months of detraining, the same participants were tested again for anthropometry, aerobic capacity, leg strength and functional ability. RESULTS: Significant reductions in maximal aerobic capacity, time to exhaustion and both functional test items were reported for both exercise groups compared to CON (p < .05). No significant differences were reported between the exercise groups concerning aerobic and functional capacity reductions. CONCLUSION: Detraining occurred significantly in both exercise groups regarding parameters associated with aerobic and functional capacity.

Assessment of Somatization and Medically Unexplained Symptoms in Later Life.

The assessment of medically unexplained symptoms and "somatic symptom disorders" in older adults is challenging due to somatic multimorbidity, which threatens the validity of somatization questionnaires. In a systematic review study, the Patient Health Questionnaire-15 (PHQ-15) and the somatization subscale of the Symptom Checklist 90-item version (SCL-90 SOM) are recommended out of 40 questionnaires for usage in large-scale studies. While both scales measure physical symptoms which in younger persons often refer to unexplained symptoms, in older persons, these symptoms may originate from somatic diseases. Using empirical data, we show that PHQ-15 and SCL-90 SOM among older patients correlate with proxies of somatization as with somatic disease burden. Updating the previous systematic review, revealed six additional questionnaires. Cross-validation studies are needed as none of 46 identified scales met the criteria of suitability for an older population. Nonetheless, specific recommendations can be made for studying older persons, namely the SCL-90 SOM and PHQ-15 for population-based studies, the Freiburg Complaint List and somatization subscale of the Brief Symptom Inventory 53-item version for studies in primary care, and finally the Schedule for Evaluating Persistent Symptoms and Somatic Symptom Experiences Questionnaire for monitoring treatment studies.

Nanodiamonds as multi-purpose labels for microscopy.

Nanodiamonds containing fluorescent nitrogen-vacancy centers are increasingly attracting interest for use as a probe in biological microscopy. This interest stems from (i) strong resistance to photobleaching allowing prolonged fluorescence observation times; (ii) the possibility to excite fluorescence using a focused electron beam (cathodoluminescence; CL) for high-resolution localization; and (iii) the potential use for nanoscale sensing. For all these schemes, the development of versatile molecular labeling using relatively small diamonds is essential. Here, we show the direct targeting of a biological molecule with nanodiamonds as small as 70 nm using a streptavidin conjugation and standard antibody labelling approach. We also show internalization of 40 nm sized nanodiamonds. The fluorescence from the nanodiamonds survives osmium-fixation and plastic embedding making them suited for correlative light and electron microscopy. We show that CL can be observed from epon-embedded nanodiamonds, while surface-exposed nanoparticles also stand out in secondary electron (SE) signal due to the exceptionally high diamond SE yield. Finally, we demonstrate the magnetic read-out using fluorescence from diamonds prior to embedding. Thus, our results firmly establish nanodiamonds containing nitrogen-vacancy centers as unique, versatile probes for combining and correlating different types of microscopy, from fluorescence imaging and magnetometry to ultrastructural investigation using electron microscopy.

Impact of long-term high-fat diet intake gestational protein-restricted offspring on kidney morphology and function.

Emerging evidence highlights the far-reaching consequences of high-fat diet (HFD) and obesity on kidney morphological and functional disorders. In the present study, we aim to evaluate the effects of early HFD intake on renal function and morphology in maternal protein-restricted offspring (LP). LP and normal protein-intake offspring (NP) were fed HFD (LPH and NPH, respectively) or standard rodent (LPN and NPN) diet from the 8th to 13th week of age. Blood pressure, kidney function, immunohistochemistry and scanning electron microscopy were analyzed. Increased total cholesterol and low-density lipoprotein serum levels were observed in LPH offspring. The adiposity index was reduced in the (LPN) group and, conversely, increased in the NPH and LPH groups. Blood pressure was higher beyond the 10th week of age in the LPH group compared with the other groups. Decreased urinary sodium excretion was observed in LP offspring, whereas the HFD-treated groups presented a decreased urine pH in a time-dependent fashion. The LPN, NPH and LPH groups showed increased expression of type 1 angiotensin II (AngII) receptor (AT1R), TGF-ß1, collagen and fibronectin in the kidneys. Moreover, the adult fetal-programmed offspring showed pronounced effacement of the podocyte foot process associated with the rupture of cell membranes and striking urinary protein excretion, exacerbated by HFD treatment. To the best of our knowledge, this is the first study demonstrating that young fetal-programmed offspring submitted to long-term HFD intake have increased susceptibility to renal structural and functional disorders associated with an accentuated stage of fibrosis and tubular dysfunction.

Accuracy of the prediction equation for the determination of maximum heart rate in adults with Down syndrome.

BACKGROUND: The purpose of the study was to determine if the regression formula developed for the prediction of maximum heart rate (HR) is valid for adults with Down syndrome (DS). METHODS: Thirty-six adults with DS (31.7 ± 6.8 years; 20 men, 16 women) completed a maximal aerobic test. Maximum HR and VO2 peak were measured directly on a motorised treadmill with a metabolic analyser. Predicted HR was estimated with the regression equation developed for individuals with DS (Fernhall et al. 2001). Differences between measured versus predicted maximum HR were assessed with a dependent T-test and the relationship with Pearson correlational analyses. Agreement was assessed with Bland-Altman analysis. RESULTS: There was a significant difference between directly measured maximum HR and predicted maximum HR (P < 0.01). There was no significant relationship between these variables. Bland-Altman analysis indicated that there was measurement bias (+4.7) and large limits of agreement (+26.7 and -17.4) between measured and predicted maximum HR. The Bland-Altman plot also demonstrated the presence of heteroscedasticity. CONCLUSIONS: The results indicate that the regression formula developed for individuals with DS was not accurate in this sample of DS adults aged 19 to 46 years. Future studies should develop different prediction equations for more specific age and body mass index categories for individuals with DS.

In vivo electric conductivity of cervical cancer patients based on B1⁺ maps at 3T MRI.

The in vivo electric conductivity (σ) values of tissue are essential for accurate electromagnetic simulations and specific absorption rate (SAR) assessment for applications such as thermal dose computations in hyperthermia. Currently used σ-values are mostly based on ex vivo measurements. In this study the conductivity of human muscle, bladder content and cervical tumors is acquired non-invasively in vivo using MRI. The conductivity of 20 cervical cancer patients was measured with the MR-based electric properties tomography method on a standard 3T MRI system. The average in vivo σ-value of muscle is 14% higher than currently used in human simulation models. The σ-value of bladder content is an order of magnitude higher than the value for bladder wall tissue that is used for the complete bladder in many models. Our findings are confirmed by various in vivo animal studies from the literature. In cervical tumors, the observed average conductivity was 13% higher than the literature value reported for cervical tissue. Considerable deviations were found for the electrical conductivity observed in this study and the commonly used values for SAR assessment, emphasizing the importance of acquiring in vivo conductivity for more accurate SAR assessment in various applications.

Effect of continuous aerobic vs. interval training on selected anthropometrical, physiological and functional parameters of adults with Down syndrome.

BACKGROUND: A large percentage of adults with Down syndrome (DS) are overweight and have extremely low aerobic capacities compared with the general population and persons with intellectual disability without DS. Previous aerobic training intervention studies showed limited potential to significantly ameliorate anthropometrical and cardiovascular variables. The primary purpose of this study was to determine the effect of continuous aerobic training (CAT) vs. interval training (IT) on selected anthropometrical, health, physical and functional parameters of adults with DS. METHODS: Forty-two adults with DS (25 men and 17 women) and a mean age of 33.8 (±8.6) years were randomly allocated to one of three groups (IT, CAT and control). Training was performed for 12 weeks. The IT group performed 10-30 s all out sprints with 90 s (1:3 work-rest ratio) of low cadence, low intensity cycling or walking. The CAT group performed continuous cycling and walking at an intensity of 70-80% of VO2 peak. Heart rate monitors were used for monitoring training intensities. After 6 weeks of training, the intensity of the CAT was increased to 85% of VO2 peak, whilst the intensity of the IT group remained 'all out'. An increase of 5 min in duration was implemented after 6 weeks for both training groups. To evaluate pre-post differences between groups, a repeated analysis of covariance with post hoc Bonferroni test was performed RESULTS: After 12 weeks of training, body weight and body mass index decreased significantly more in the IT group compared with control and CAT (P < 0.05). Participants in the IT group decreased their body weight from 71.4 ± 8 to 69.4 ± 8 kg and their body mass index from 29.3 ± 4 to 28.5 ± 4 kg/m2 . Significant ameliorations for functional parameters and leg strength were shown for CAT compared with control (P < 0.05). Participants in the CAT group improved their performance in the 6 minute walk distance (499 ± 78 to 563 ± 75 m), 8-ft up-and-go (5.9 ± 1.2 to 4.8 ± 0.9) and leg strength (13.1 ± 2 to 15.2 ± 2). VO2 peak and time to exhaustion significantly improved in both the IT and CAT group compared with control (P < 0.01). Moreover, a significant improvement for relative VO2 peak was also determined for IT compared with CAT (P < 0.05). Participants in the IT group increased their VO2 peak from 32 ± 8 to 37 ± 8 mL/min/kg. Submaximal heart rate and VO2 values improved significantly within both exercise groups (P < 0.05). CONCLUSION: Interval training and CAT can both be pursued by adults with DS to positively impact on various parameters of anthropometry, fitness and functional ability, with IT more appropriate for improving body weight and aerobic capacity.

Test-retest reliability and minimal detectable change scores of twelve functional fitness tests in adults with Down syndrome.

AIM: The purpose of the study was to explore the test-retest reliability and minimal detectable change of selected functional fitness test items in adults with Down syndrome. METHODS: Forty-three adults with Down syndrome (24 men and 19 women) aged 18-50 years completed a battery of tests twice in a two-week period. The battery of tests consisted of two balance items, two flexibility items, five muscular strength and endurance items, two aerobic items, and one functional task. All items were considered valid and reliable tests in a general elderly or intellectually disabled population. The test-retest relative reliability for all repeated tests was assessed with intraclass correlation coefficient performing one-way analysis of variance. The test-retest absolute variability was measured by using the standard error of measurement (SEM) to calculate the minimal detectable change at the 90% confidence interval (MDC90). Reliability data was visualised with a Bland-Altman plot. RESULTS: All tests showed excellent intraclass correlation coefficients (ICC's>0.9). All SEM values demonstrated acceptable measurement precision (SEM

Translational neurophysiological markers for activity of the metabotropic glutamate receptor (mGluR2) modulator JNJ-40411813: Sleep EEG correlates in rodents and healthy men.

Alterations in rapid eye movement sleep (REM) have been suggested as valid translational efficacy markers: activation of the metabotropic glutamate receptor 2 (mGluR2) was shown to increase REM latency and to decrease REM duration. The present paper addresses the effects on vigilance states of the mGluR2 positive allosteric modulator (PAM) JNJ-40411813 at different circadian times in rats and after afternoon dosing in humans. Due to its dual mGluR2 PAM/serotonin 2A (5-HT2A) receptor antagonism in rodents, mGlu2R specificity of effects was studied in wild-type (WT) and mGluR2 (-/-) mice. 5-HT2A receptor occupancy was determined in humans using positron emission tomography (PET). Tolerance development was examined in rats after chronic dosing. EEG oscillations and network connectivity were assessed using multi-channel EEG. In rats, JNJ-40411813 increased deep sleep time and latency of REM onset but reduced REM time when administered 2 h after 'lights on' (CT2): this was sustained after chronic dosing. At CT5 similar effects were elicited, at CT10 only deep sleep was enhanced. Withdrawal resulted in baseline values, while re-administration reinstated drug effects. Parieto-occipital cortical slow theta and gamma oscillations were correlated with low locomotion. The specificity of functional response was confirmed in WT but not mGluR2 (-/-) mice. A double-blind, placebo-controlled polysomnographic study in healthy, elderly subjects showed that 500 mg of JNJ-40411813 consistently increased deep sleep time, but had no effect on REM parameters. This deep sleep effect was not explained by 5-HT2A receptor binding, as in the PET study even 700 mg only marginally displaced the tracer. JNJ-40411813 elicited comparable functional responses in rodents and men if circadian time of dosing was taken into account. These findings underscore the translational potential of sleep mechanisms in evaluating mGluR2 therapeutics when administered at the appropriate circadian time.

Single-cell analysis of peptide expression and electrophysiology of right parietal neurons involved in male copulation behavior of a simultaneous hermaphrodite.

Male copulation is a complex behavior that requires coordinated communication between the nervous system and the peripheral reproductive organs involved in mating. In hermaphroditic animals, such as the freshwater snail Lymnaea stagnalis, this complexity increases since the animal can behave both as male and female. The performance of the sexual role as a male is coordinated via a neuronal communication regulated by many peptidergic neurons, clustered in the cerebral and pedal ganglia and dispersed in the pleural and parietal ganglia. By combining single-cell matrix-assisted laser mass spectrometry with retrograde staining and electrophysiology, we analyzed neuropeptide expression of single neurons of the right parietal ganglion and their axonal projections into the penial nerve. Based on the neuropeptide profile of these neurons, we were able to reconstruct a chemical map of the right parietal ganglion revealing a striking correlation with the earlier electrophysiological and neuroanatomical studies. Neurons can be divided into two main groups: (i) neurons that express heptapeptides and (ii) neurons that do not. The neuronal projection of the different neurons into the penial nerve reveals a pattern where (spontaneous) activity is related to branching pattern. This heterogeneity in both neurochemical anatomy and branching pattern of the parietal neurons reflects the complexity of the peptidergic neurotransmission involved in the regulation of male mating behavior in this simultaneous hermaphrodite.

Real-time PCR detection of Campylobacter spp.: A comparison to classic culturing and enrichment.

The major disadvantage of the current gold standard for detection of the food pathogen Campylobacter, i.e. culturing, is the lengthy procedure. In this study we assessed the use of real-time PCR for detection of Campylobacter. To this end, 926 poultry samples, taken from transport containers and broiler caeca in The Netherlands in 2007, were subjected to three different real-time PCR detection methods: one targeting the Campylobacter jejuni hipO gene, one targeting the Campylobacter coli glyA gene, and one generically targeting Campylobacter spp. 16S rDNA sequence. The PCR results from the three different PCR protocols were compared to the work of Nauta et al. (2009) who analyzed the same set of samples collected from 62 broiler flocks by means of enrichment culturing. The results indicate that the generic 16S campylobacter PCR detection is equally reliable but much faster (4 h instead of ≥2 days) than detection by means of culturing. Moreover, PCR detection targeting the hipO and the glyA gene provide the possibility of C. jejuni and C. coli species discrimination. The generic Campylobacter spp. PCR analysis also confirmed the high incidence of Campylobacter spp. in poultry samples (∼90%) and the species specific PCR showed the simultaneous presence of C. jejuni and C. coli in ∼24% of the samples. Furthermore, the results from the three PCR analyses suggested the occurrence of alternative Campylobacter species in almost 10% of the samples. The campylobacter PCR detection methods reported here can replace traditional culturing because of being quicker and more reliable.

A mutation study of sperm head shape and motility in the mouse: lessons for the clinic.

Mouse mutants that show effects on sperm head shape, the sperm tail (flagellum), and motility were analysed in a systematic way. This was achieved by grouping mutations in the following classes: manchette, acrosome, Sertoli cell contact, chromatin remodelling, and mutations involved in complex regulations such as protein (de)phosphorylation and RNA stability, and flagellum/motility mutations. For all mutant phenotypes, flagellum function (motility) was affected. Head shape, including the nucleus, was also affected in spermatozoa of most mouse models, though with considerable variation. For the mutants that were categorized in the flagellum/motility group, generally normal head shapes were found, even when the flagellum did not develop or only poorly so. Most mutants are sterile, an occasional one semi-sterile. For completeness, the influence of the sex chromosomes on sperm phenotype is included. Functionally, the genes involved can be categorized as regulators of spermiogenesis. When extrapolating these data to human sperm samples, in vivo selection for motility would be the tool for weeding out the products of suboptimal spermiogenesis and epididymal sperm maturation. The striking dependency of motility on proper sperm head development is not easy to understand, but likely is of evolutionary benefit. Also, sperm competition after mating can never act against the long-term multi-generation interest of genetic integrity. Hence, it is plausible to suggest that short-term haplophase fitness i.e., motility, is developmentally integrated with proper nucleus maturation, including genetic integrity to protect multi-generation fitness. We hypothesize that, when the prime defect is in flagellum formation, apparently a feedback loop was not necessary as head morphogenesis in these mutants is mostly normal. Extrapolating to human-assisted reproductive techniques practice, this analysis would supply the arguments for the development of tools to select for motility as a continuous (non-discrete) parameter.