New dysostosis showing multilevel absence of vertebral pedicles: unique developmental anomaly of vertebral arches?

We report on an apparently normal child who shows hypopaplasia of the vertebral pedicles and posterior arches of several cervical, thoracic, and lumbar vertebrae with normally fused spinous apophyses, hypoplastic sacrum, lumbar epidural lipomatosis, synostoses of some cervical vertebral disks, and sacral spina bifida. The most likely mechanism is an abnormal differentiation of the spinal processes, due most probably to an absence of differentiation in cartilage of the dense mesenchyme forming their most anterior part. Because the anomalies affect multiple levels, we highly suspect a genetic basis to this unusual dysostosis affecting the development of the posterior sclerotomes.     

Mandibulofacial dysostosis,microtia, and limb anomalies in a newborn: a new form of acrofacial dysostosis syndrome?

Zhang Y, Dai Y, Liu Y, Ren J. Mandibulofacial dysostosis, microtia, and limb anomalies in a newborn: a new form of acrofacial dysostosis syndrome? The acrofacial dysostoses (AFDs) are a heterogeneous group of disorders involving craniofacial dysostosis and limb anomalies. Depending on the type of limb defects, two major groups have been defined: Nager syndrome with predominant preaxial anomalies and Miller syndrome with postaxial malformations. Genomic copy number variation, a common type of genomic variability, can influence gene expression by disrupting coding sequences, perturbing long‐range gene regulation, or altering gene dosage, and these effects could contribute to phenotypic variations or disease risk. We present a distinct AFD case with mandibulofacial dysostosis, microtia and limb malformations but without limb defects, which may represent a new form of AFD. To investigate the etiology of the phenotype, whole genomic high‐resolution array comparative genomic hybridization analysis was carried out, revealing two cryptic duplications, 1p36.33 and 1q21.3‐q22 duplications. Two genes, VWA1 and PYGO2, contained in the two duplications, respectively, are likely to be the candidate genes for the phenotype of our patient.     

Atopic disorders: a default pathway in the absence of infection?

Atopic disorders, such as asthma, are increasingly prevalent in the developed world. Recent epidemiological and experimental data suggest that some infectious diseases prevalent in the developing nations can inhibit the development of allergic disorders. Here, Klaus Erb reviews the data and presents a model showing how a steady decline of infectious diseases could account for an increase in atopic disorders.     

Affective temperaments: Unique constructs or dimensions of normal personality by another name?

Background

Current models theorize that affective temperaments underlie the development and expression of mood psychopathology. Recent studies support the construct validity of affective temperaments in clinical and non-clinical samples. However, one concern is that affective temperaments may be describing characteristics that are better captured by models of normal personality. We conducted two studies examining: (a) the association of affective temperaments with domains and facets of normal personality, and (b) whether affective temperaments accounted for variance in mood symptoms and disorders, impairment, and daily-life experiences over-and-above variance accounted for by normal personality.

Methods

Study 1 included 522 young adults who completed the TEMPS-A and the NEO-PI-3. Study 2 included 145 participants who were administered the TEMPS-A, NEO-FFI, interviews assessing psychopathology and impairment, and an assessment of daily life experiences.

Results

Study 1 revealed that personality domains and facets accounted for one-third to one-half of the variance in affective temperaments. However, study 2 demonstrated that affective temperaments accounted for unique variance in measures of psychopathology, impairment, and daily-life experiences after partialling variance associated with personality domains. Specifically, cyclothymic/irritable temperament predicted bipolar disorders, impairment, borderline personality traits, urgency, and anger in daily life. Hyperthymic temperament predicted hypomanic episodes, grandiosity, sensation seeking, and increased activity in daily life.

Limitations

The study was limited by the fact that only domain, not facet-level, measures of FFM were available in study 2.

Conclusions

The findings support the validity of hyperthymic and cyclothymic/irritable temperaments as indicators of clinical psychopathology and indicate that they provide information beyond normal personality.     

Is the ataxia of Charlevoix-Saguenay a developmental disease?

The autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is considered a neurodegenerative disease caused by mutations in the SACS gene, located on chromosome 13q12.12. It is a syndrome that comprises skeletal, retinal and neurological manifestations, among which feature spasticity, cerebellar ataxia and peripheral neuropathy.Five patients with a molecular diagnosis of ARSACS underwent clinical, radiological, and ophthalmologic examinations. Every one of the identified causal mutations was novel. Spastic ataxia, peripheral neuropathy, pes cavus, and hammertoes were found in every case. T2 and T2-fluid attenuation inversion recovery-weighted MRI sequences demonstrated cerebellar atrophy and a hypointense linear striation at the pons. Tensor diffusion sequences revealed that the hypointense striation corresponded with hyperplasia of the pontocerebellar fibres, which gave place to abnormally thick middle cerebellar peduncles. Stereophotographs of the optic discs showed an increased number of retinal fibres, and ocular coherence tomography, increased thickness of the retinal nerve fibre layer. The authors suggest that the hyperplasic pontocerebellar fibres compress the pyramidal tracts at the pons since a very early stage of central nervous system development, causing spasticity, and may also cause cerebellar atrophy by means of glutamate-induced excitotoxicity. The abnormal amount of retinal fibres traversing the optic discs could have caused the detected mild peripheral visual field defects.Taken together, these facts point to a developmental cause in ARSACS, as it does not exhibit the tissue atrophy characteristic of degenerative diseases. Clinical deterioration in ARSACS seems to be mediated by phenomena (compression of the pyramidal tracts and cerebellar glutamate-mediated excitotoxicity) derived from the developmental anomalies referred to, while the neuromuscular symptoms are caused by a peripheral neuropathy with pathologic features suggestive of a similar origin. These observations should be taken into account when research about the origin of ARSACS is undertaken.     

Fetal origins of developmental plasticity: Are fetal cues reliable predictors of future nutritional environments?

Evidence that fetal nutrition triggers permanent adjustments in a wide range of systems and health outcomes is stimulating interest in the evolutionary significance of these responses. This review evaluates the postnatal adaptive significance of fetal developmental plasticity from the perspective of life history theory and evolutionary models of energy partitioning. Birthweight is positively related to multiple metabolically costly postnatal functions, suggesting that the fetus has the capacity to distribute the burden of energy insufficiency when faced with a nutritionally challenging environment. Lowering total requirements may reduce the risk of negative energy balance, which disproportionately impacts functions that are not essential for survival but that are crucial for reproductive success. The long-term benefit of these metabolic adjustments is contingent upon the fetus having access to a cue that is predictive of its future nutritional environment, a problem complicated in a long-lived species by short-term ecologic fluctuations like seasonality. Evidence is reviewed suggesting that the flow of nutrients reaching the fetus provides an integrated signal of nutrition as experienced by recent matrilineal ancestors, which effectively limits the responsiveness to short-term ecologic fluctuations during any given pregnancy. This capacity for fetal nutrition to minimize the growth response to transient ecologic fluctuations is defined here as intergenerational "phenotypic inertia," and is hypothesized to allow the fetus to cut through the "noise" of seasonal or other stochastic influences to read the "signal" of longer-term ecologic trends. As a mode of adaptation, phenotypic inertia may help the organism cope with ecologic trends too gradual to be tracked by conventional developmental plasticity, but too rapid to be tracked by natural selection. From an applied perspective, if a trait like fetal growth is designed to minimize the effects of short-term fluctuations by integrating information across generations, public health interventions may be most effective if focused not on the individual but on the matriline.     

Early-life stress and reproductive cost: A two-hit developmental model of accelerated aging?

Two seemingly independent bodies of research suggest a two-hit model of accelerated aging, one highlighting early-life stress and the other reproduction. The first, informed by developmental models of early-life stress, highlights reduced longevity effects of early adversity on telomere erosion, whereas the second, informed by evolutionary theories of aging, highlights such effects with regard to reproductive cost (in females). The fact that both early-life adversity and reproductive effort are associated with shorter telomeres and increased oxidative stress raises the prospect, consistent with life-history theory, that these two theoretical frameworks currently informing much research are tapping into the same evolutionary-developmental process of increased senescence and reduced longevity. Here we propose a mechanistic view of a two-hit model of accelerated aging in human females through (a) early-life adversity and (b) early reproduction, via a process of telomere erosion, while highlighting mediating biological embedding mechanisms that might link these two developmental aging processes.     

Can knowledge of developmental processes illuminate the evolution of parental care?

There are two levels of investigation for elucidating the evolution of parental behavior. The macro level focuses on how parental behavior can evolve as an aspect of reproduction. The micro level focuses on how species variations in parental behavior evolve. Recently, modern evolutionary biology has turned to developmental biology as a source for information about how trait variability (the substrate upon which natural selection and other evolutionary mechanisms can operate) can emerge during development (called "evo-devo"). Application of this evo-devo approach to the phenomenon of parental behavior requires identification of those mechanisms that produce variations in developmental pathways leading to parental behavior. It is these variations that provide the phenotypes for the potential evolution of different parental behavior systems. Variations in rodent maternal behavior affect the development of the HPA and HPG axes in their offspring. These mechanisms are examined to reveal how such developmental variations could underlie the evolution of biparental behavior. Knowledge of the developmental mechanisms responsible for species variations in mammalian parental behavior systems may provide insight into those mechanisms that may have been involved in the evolution of parental behavior itself.     

Is job a viable unit of analysis? A multilevel analysis of demand-control-support models

The literature has ignored the fact that the demand-control (DC) and demand-control-support (DCS) models of stress are about jobs and not individuals' perceptions of their jobs. Using multilevel modeling, the authors report results of individual- and job-level analyses from a study of over 6,700 people in 81 different jobs. Support for additive versions of the models came when individuals were the unit of analysis. DC and DCS models are only helpful for understanding the effects of individual perceptions of jobs and their relationship to psychological states. When job perceptions are aggregated and their relationship to the collective experience of jobholders is assessed, the models prove of little value. Role set may be a better unit of analysis.     

MicroRNA-mediated dysregulation of neural developmental genes in HPRT deficiency: clues for Lesch-Nyhan disease?

Mutations in the gene encoding the purine biosynthetic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause the intractable neurodevelopmental Lesch-Nyhan disease (LND) associated with aberrant development of brain dopamine pathways. In the current study, we have identified an increased expression of the microRNA miR181a in HPRT-deficient human dopaminergic SH-SY5Y neuroblastoma cells. Among the genes potentially regulated by miR181a are several known to be required for neural development, including Engrailed1 (En1), Engrailed2 (En2), Lmx1a and Brn2. We demonstrate that these genes are down-regulated in HPRT-deficient SH-SY5Y cells and that over-expression of miR181a significantly reduces endogenous expression of these genes and inhibits translation of luciferase plasmids bearing the En1/2 or Lmx1a 3'UTR miRNA-binding elements. Conversely, inhibition of miR181a increases the expression of these genes and enhances translation of luciferase constructs bearing the En1/2 and Lmx1a 3'UTR miRNA-binding sequences. We also demonstrate that key neurodevelopmental genes (e.g. Nurr1, Pitx3, Wnt1 and Mash1) known to be functional partners of Lmx1a and Brn2 are also markedly down-regulated in SH-SY5Y cells over-expressing miR181a and in HPRT-deficient cells. Our findings in SH-SY5Y cells demonstrate that HPRT deficiency is accompanied by dysregulation of some of the important pathways that regulate the development of dopaminergic neurons and dopamine pathways and that this defect is associated with and possibly due at least partly to aberrant expression of miR181a. Because aberrant expression of miR181a is not as apparent in HPRT-deficient LND fibroblasts, the relevance of the SH-SY5Y neuroblastoma cells to human disease remains to be proven. Nevertheless, we propose that these pleiotropic neurodevelopment effects of miR181a may play a role in the pathogenesis of LND.     

Polycystic ovary syndrome: a hypothalamic or a gonadal anomaly?

Evidence obtained from the study of polycystic ovarian disease in the female is reviewed. The etiology of this problem remains unknown, in spite of advances achieved by means of biochemical and morphologic studies. No correlation has been observed between histological findings and the pituitary or gonadal hormone production. However, an abnormal hypothalamic-pituitary-gonadal interaction prevails, characterized by a increased LH-FSH ratio associated with high level of androgens, mainly androstenedione. The pituitary reserve test performed with potent GnRH agonists have confirmed the hyper-response of LH along with that of androstenedione, as well as augmentation of 17-hydroxyprogesterone. Since the pattern of gonadotropins and steroid hormone secretion in women with polycystic ovarian disease resembles that seen in normal men, the basic alteration may well consist in a functionally "masculinized" hypothalamus.     

Motor unit double discharges: statistical anomaly or functional entity?

Motor unit double discharges, or doublets, have been described as two consecutive motor unit discharges that occur with a short interspike interval of 2.5 - 20 ms (Simpson, 1969). Double discharges have been reported in the literature for over 70 years. For instance, Eccles and Hoff (1932) found that double discharges were elicited occasionally at the onset of a crossed extension reflex in the soleus muscle of the anaesthetized cat. With the use of electrical stimulation protocols, short interspike intervals inserted at the beginning of a stimulation train have been shown to increase both the peak force and rate of rise of force production, and also decrease the range of fatigue. The extent to which double discharges occur in naturally-occurring voluntary behaviours remains relatively unexplored. This review examines the issue of whether double discharges occur solely because of an intrinsic property of motoneurones, thereby representing a "statistical anomaly," or whether they may result from a neural control strategy to augment force production, i.e., a "functional entity."     

Notch signaling in glioblastoma: a developmental drug target?

Malignant gliomas are among the most devastating tumors for which conventional therapies have not significantly improved patient outcome. Despite advances in imaging, surgery, chemotherapy and radiotherapy, survival is still less than 2 years from diagnosis and more targeted therapies are urgently needed. Notch signaling is central to the normal and neoplastic development of the central nervous system, playing important roles in proliferation, differentiation, apoptosis and cancer stem cell regulation. Notch is also involved in the regulation response to hypoxia and angiogenesis, which are typical tumor and more specifically glioblastoma multiforme (GBM) features. Targeting Notch signaling is therefore a promising strategy for developing future therapies for the treatment of GBM. In this review we give an overview of the mechanisms of Notch signaling, its networking pathways in gliomas, and discuss its potential for designing novel therapeutic approaches.     

Current developmental surveillance: is it time for change?

Developmental screening tools are an integral part of child health surveillance, but only few valid and reliable tests are currently in use in the community. Early detection and referral of children with developmental delay is critical for long term outcomes. Developmental screening, using standardised tests, is increasingly important. The public health nurses in the Midlands currently use a modified version of Denver Development Screening Tool (DDST) for screening infants at 9 months of age. The DDST however fails to identify a high proportion of children developmentally at risk, because of its poor sensitivity, an outcome of which is a high proportion of under-referrals. The low sensitivity of the test is a source of potentially misleading information and may be responsible for many at-risk children remaining undetected. Sensitive and specific screening questionnaires need to be introduced in community child health screening surveillance to minimise the risk of missing children with developmental delay.     

Atherosclerosis in the vertebral artery: an intrinsic risk factor in the use of spinal manipulation?

The presence of atherosclerotic plaques and their influence on the vertebral artery is of clinical importance within the scope of spinal manipulation. Manipulation may stimulate the development of atherosclerotic plaques, could detach an embolus with ensuing infarction, injure the endothelium or may directly cause a dissection in the presence of atherosclerotic plaques. In order to identify the sites and frequency of atherosclerotic plaques and to determine its relation to the tortuous course of the vertebral artery, a cadaveric study was performed. The vertebral arteries of 57 human cadavers were studied. The vertebral artery was virtually divided into four segments: the pre-vertebral (V1), the vertebral (V2), the atlanto-axial (V3), and the intracranial segment (V4). Abnormalities in the origin and course of the vertebral artery were noted, along with any associated osseous, or cartilaginous anomalies in the neck. After dissection, the artery was opened and macroscopically screened for the presence of atherosclerotic plaques. In 22.8% of the cases, no atherosclerotic plaques were present. In 35.1% of the cases, the atherosclerotic plaques were unilateral, of which 60.0% was on the left side, 40.0% on the right side, and in 42.1%, the occurrence was bilateral. Atherosclerotic plaques were significantly more present in the V3 segment than in the V1 (0.007) and V2 segment (0.049). In the V1 (P=0.008) and V2 segment (P=0.002), there was a correlation between a tortuous course of the vessel and the occurrence of atherosclerotic plaques. In individuals with marked atherosclerotic disease, stretching and compression effects of rotational manipulative techniques on atherosclerotic vessels impose a further risk factor for vertebrobasilar insufficiency. As direct evidence of atherosclerotic plaques are rarely available, therapists should avoid manipulative techniques at all levels of the cervical spine in the presence of any indirect sign of atherosclerotic disease or in the presence of calcified arterial walls or tortuosities of the vessels visible on routinely available X-ray images of the cervical or thoracic spine. It is strongly recommended, that if any doubt exists about the nature of a clinical presentation, vigorous manual procedures should be avoided until either the diagnosis is definitive or gentle manual therapy has proven effective.     

Endometrial brush cytology of advanced postmenopausal endometrium: Does endometrial intraepithelial neoplasia exist in the absence of hyperplasia?

Postmenopausal uterine bleeding is an indication to sample the endometrium for diagnostic purposes. The endometrial brush cytologies of 20 advanced postmenopausal women collected at the time of hysterectomy in order to benchmark the expected morphology of postmenopausal endometrial brushings were reviewed. No women had symptoms or gross findings of primary endomyometrial disease. Endometrium was collected at the surgical pathology laboratory using the Tao Brush and CytoRich Fixative System. After formalin fixation of the uterus, the entire endometrium was embedded for routine histology. Sixteen endometrial brushings and matched endometrial sections showed endometrial atrophy, one brushing showed many ciliated epithelial cells, and three brushings showed focal (less than 10%) epithelial-cell atypia. In two atypias, abnormal endometrial epithelial-cell sheets contained enlarged, clear nuclei with nuclear notches and grooves resembling papillary thyroid cancer. One case showed no histological counterpart to this finding. The other case showed thickening of the pericornual fundic endometrium with cystic glands. The third case with epithelial atypia showed abnormal endometrial-cell sheets with nuclei resembling atypical hyperplasia or type I endometrial adenocarcinoma; corresponding endometrial tissue sections showed rare, irregular glands and back-to-back gland clusters with equivalent nuclear features. Atypical epithelium may be found in atrophic uteri in the absence of gross endometrial thickening. This may be a common event related either to de novo intraepithelial dysplasia in a noncycling endometrium or to hyperplasia that has partly regressed with estradiol withdrawal. This study shows that, in addition to endometrial intraepithelial carcinoma (EIC), isolated atypical glands with morphological and immunohistochemical features of atypical hyperplasia or type I endometrial adenocarcinoma may be found in grossly normal advanced postmenopausal endometrium of asymptomatic patients. This atypical epithelium is readily apparent in endometrial brush preparations, but requires serial sectioning of the endometrium to be demonstrated histologically. We have not established the natural history of this lesion, and in the absence of EIC or gross endometrial thickening indicative of atypical hyperplasia, we do not know whether this degree of epithelial atypia should be an indication for hysterectomy. Diagn. Cytopathol. 1998;19:338–343. © 1998 Wiley-Liss, Inc.