Modeling additive and non-additive effects in a hybrid population using genome-wide genotyping: prediction accuracy implications.

Hybrids are broadly used in plant breeding and accurate estimation of variance components is crucial for optimizing genetic gain. Genome-wide information may be used to explore models designed to assess the extent of additive and non-additive variance and test their prediction accuracy for the genomic selection. Ten linear mixed models, involving pedigree- and marker-based relationship matrices among parents, were developed to estimate additive (A), dominance (D) and epistatic (AA, AD and DD) effects. Five complementary models, involving the gametic phase to estimate marker-based relationships among hybrid progenies, were developed to assess the same effects. The models were compared using tree height and 3303 single-nucleotide polymorphism markers from 1130 cloned individuals obtained via controlled crosses of 13 Eucalyptus urophylla females with 9 Eucalyptus grandis males. Akaike information criterion (AIC), variance ratios, asymptotic correlation matrices of estimates, goodness-of-fit, prediction accuracy and mean square error (MSE) were used for the comparisons. The variance components and variance ratios differed according to the model. Models with a parent marker-based relationship matrix performed better than those that were pedigree-based, that is, an absence of singularities, lower AIC, higher goodness-of-fit and accuracy and smaller MSE. However, AD and DD variances were estimated with high s.es. Using the same criteria, progeny gametic phase-based models performed better in fitting the observations and predicting genetic values. However, DD variance could not be separated from the dominance variance and null estimates were obtained for AA and AD effects. This study highlighted the advantages of progeny models using genome-wide information.

Survival of Coelaenomenodera lameensis (Coleoptera: Chrysomelidae) in Relation to the Physical Characteristics of Different Oil Palm (Elaeis sp.) Breeding Populations.

The edibility of different Elaeis sp. breeding populations present in Benin was tested for the leaf miner Coelaenomenodera lameensis Berti (Coleoptera: Chrysomelidae), a major oil palm pest in Africa. Experiments carried out in sleeves revealed the oviposition capacities of females and the mortality rates for the different developmental stages by comparing the populations found on two breeding populations of Elaeis oleifera (HBK) Cortes, four of Elaeis guineensis Jacquin and four (E. guineensis × E. oleifera) × E. guineensis backcrosses. Females laid their eggs similarly on all breeding populations, with a preference for the E. guineensis La Mé origin. The average hatching rate reached 80% for the La Mé origin as opposed to 28% for the Deli origin. The mortality rates for the larval instars were greater on E. oleifera, on certain backcrosses and on the Deli origin of E. guineensis. Development at the second- and third- larval instars was the most affected, with a mortality rate of three to five times greater than that seen on La Mé. Epidermis and cuticle measurements indicated which breeding populations were suitable or unsuitable for the development of C. lameensis. E. guineensis, with its thin epidermis (12 µm) and cuticle (2 µm), proved to be highly susceptible to C. lameensis attacks. On the other hand, E. oleifera, which is very resistant, exhibited a thicker epidermis (17 µm) and cuticle (4 µm). The breeding populations were thus classified according to the positive or negative influence they exerted on the insect's egg laying and feeding.

Mice lacking the myotonic dystrophy protein kinase develop a late onset progressive myopathy.

Myotonic dystrophy (DM) is an autosomal dominant disorder resulting from the expansion of a CTG repeat in the 3' untranslated region of a putative protein kinase (DMPK). To elucidate the role of DMPK in DM pathogenesis we have developed Dmpk deficient (Dmpk-/-) mice. Dmpk-/-mice develop a late-onset, progressive skeletal myopathy that shares some pathological features with DM. Muscles from mature mice show variation in fibre size, increased fibre degeneration and fibrosis. Adult Dmpk-/-mice show ultrastructural changes in muscle and a 50% decrease in force generation compared to young mice. Our results indicate that DMPK may be necessary for the maintenance of skeletal muscle structure and function and suggest that a decrease in DMPK levels may contribute to DM pathology.

Novel mutations in families with unusual and variable disorders of the skeletal muscle sodium channel.

Mutations in the skeletal muscle sodium channel gene (SCN4A) have been described in paramyotonia congenita (PMC) and hyperkalaemic periodic paralysis (HPP). We have found two mutations in SCN4A which affect regions of the sodium channel not previously associated with a disease phenotype. Furthermore, affected family members display an unusual mixture of clinical features reminiscent of PMC, HPP and of a third disorder, myotonia congenita (MC). The highly variable individual expression of these symptoms, including in some cases apparent non-penetrance, implies the existence of modifying factors. Mutations in SCN4A can produce a broad range of phenotypes in muscle diseases characterized by episodic abnormalities of membrane excitability.

Long-term effects of intravenous immunoglobulin in CIDP.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired demyelinating disease of the peripheral nervous system characterized by muscle weakness, areflexia or hyporeflexia, and sensory disturbances. Although short-term efficacy of intravenous immunoglobulin (IVIg) has been demonstrated in randomized-controlled trials, the data pertaining to long-term outcome in CIDP are limited. Consequently, the aim of the present study was to assess the long-term effects of IVIg on neurophysiological parameters in CIDP. METHODS: Neurophysiological records from 11 CIDP patients, treated with IVIg for 12 months, were reviewed. Nerve conduction studies were assessed at baseline, 1-year, and last follow-up. RESULTS: There was a significant reduction in the frequency of conduction blocks (pre-treatment nerve segments affected 61%; last follow-up 39%, P<0.01) and a reduction in ongoing axonal loss (pre-treatment regions with spontaneous activity, 47%; post-treatment 29%, P<0.01) with IVIg treatment. Further, there was significant improvement in sensory nerve conduction studies with IVIg treatment (sensory amplitudes reduced pre-treatment, 90% nerves tested; post-treatment, 62%, P<0.01). CONCLUSIONS: The present study suggests that long-term IVIg maintenance therapy improves neurophysiological parameters in CIDP. However, CIDP patients remain IVIg dependent and new conduction blocks may develop. SIGNIFICANCE: The present study suggests that long-term IVIg maintenance therapy improves neurophysiological parameters in CIDP, possibly by reducing the immune response and thereby fostering nerve healing.

Facial onset sensory and motor neuronopathy (FOSMN syndrome): a novel syndrome in neurology.

A 'syringomyelia-like' syndrome has been infrequently reported in neurological disorders such as Tangiers disease and lepromatous leprosy. This study reports a novel 'syringomyelia-like' syndrome in four adult male patients, which we have termed facial onset sensory and motor neuronopathy, or FOSMN syndrome, that appears to have a neurodegenerative aetiology. Clinical, neurophysiological and pathological data of four patients were reviewed, including the autopsy in one patient. Four male patients (mean age at onset 43), initially developed paraesthesiae and numbness in a trigeminal nerve distribution, which slowly progressed to involve the scalp, neck, upper trunk and upper limbs in sequential order. Motor manifestations, including cramps, fasciculations, dysphagia, dysarthria, muscle weakness and atrophy developed later in the course of the illness. Neurophysiological findings revealed a generalized sensory motor neuronopathy of caudally decreasing severity in all four patients. Autopsy in one patient disclosed loss of motoneurons in the hypoglossal nucleus and cervical anterior horns, along with loss of sensory neurons in the main trigeminal sensory nucleus and dorsal root ganglia. FOSMN syndrome appears to be a slowly progressive neurodegenerative disorder, whose pathogenesis remains to be determined.

[Multifocal motor neuropathies with conduction block: long-term follow-up of ten patients treated with IVIg]. / Neuropathie motrice multifocale avec blocs de conduction: suivi à long terme de 10 patients traités par IgIV.

UNLABELLED: Multifocal motor neuropathy (MMN) with conduction block responds to high-dose i.v. polyvalent immunoglobulins (IVIg) over the short term, but several studies have demonstrated a long-term increase in the degree of axonal degeneration and the number of conduction blocks, factors indicating a poor prognosis. The objective of this study was to evaluate the long-term effect of IVIg on clinical and neurophysiological parameters. METHODS: We reviewed the records of ten patients who had initially responded well to IVIg and received regular, long-term treatment. The parameters studied were muscular strength, motor function status (modified Rankin scale), as well as the number and progression of conduction blocks and the degree of axonal degeneration. Patients were followed up for a mean of 7.25 years (range, 3.5-12). They were all initially treated with 2 g IgIV/kg in 5 days every 4 weeks for 3 months. Maintenance therapy was administered every 4 weeks with dose adjustment to prevent muscular strength deterioration. RESULTS: We noted a significant and persistent improvement in muscular strength and in the Rankin motor function score over the long term, with no escape phenomenon. The number of conduction blocks and the degree of axonal degeneration decreased markedly. CONCLUSION: IVIg treatment remains effective over the long term in MMN. These conclusions differ from those of other authors in earlier studies, but our patients were treated with significantly higher doses of IVIg. These results have important implications for long-term treatment of patients with MMN.

Fibroblast growth factor and epidermal growth factor in hair development.

Hair follicles arise in developing skin as a result of a complex of interactions that are likely to be mediated by diffusible, cell- and matrix-bound factors. Growth factors such as fibroblast growth factor (FGF) and epidermal growth factor (EGF) have been implicated in the control of epidermal and mesenchymal cell function, and it is likely that they also affect proliferation and differentiation of the cells of the cutaneous appendages during development. Immunolocalization of basic FGF adjacent to areas of proliferation in developing and in mature follicles suggests that this factor may regulate the mitotic activity of epithelially-derived cells; acidic FGF, on the other hand, appears in the differentiating cells of the follicle bulb and may therefore participate in the formation of structural components of the follicle or of the fiber. EGF has been identified as a potent modulator of cellular growth and is also present during follicle differentiation. These factors may act through autocrine and paracrine mechanisms because their receptors are also found on epidermally derived and mesenchymal structures in the skin. We have studied the effects of these growth factors on hair follicle development in the newborn mouse. Daily injections for 1 week after birth resulted in significant changes in the morphogenesis of the hair follicle population. Histologic examination of skin of FGF-treated mice suggested that the growth factor had affected hair follicle initiation and development, which resulted in a significant delay in the first and subsequent hair cycles when compared to control animals. Because aFGF and bFGF are not readily diffusible, these effects remained confined to the area of treatment. In contrast, EGF affected the whole body coat of the treated animals, induced hyperkeratinization of the skin, and caused a significant delay in hair follicle development.

Association of versican with dermal matrices and its potential role in hair follicle development and cycling.

Versican is a member of the group of aggregating proteoglycans involved in matrix assembly and structure and in cell adhesion. We examined changes in the distribution of versican in mammalian skin, with emphasis on hair follicle development and cycling. In adult human skin, immunostaining for versican appeared predominantly in the dermis, with intense staining of the reticular dermis. Weak staining was observed at the dermoepidermal junction and the connective tissue sheath of hair follicles. Versican expression was also noted in the reticular dermis of rat skin, within dermal papillae, and possibly associated with follicle basement membranes. During mouse hair follicle development, versican was not expressed until the hair follicles were beginning to produce fibers. With follicle maturation, versican expression intensified in the dermal papillae, reaching a maximum at the height of the growth phase (anagen), after which it diminished as the end of this phase approached. Versican immunoreactivity in the papillae decreased further during catagen and was absent from these structures during telogen. However, intense staining for versican was then observed in the neck regions of telogen follicles. As the follicles entered the next hair cycle, versican disappeared from the necks and was again seen in the dermal papillae when follicles began producing fibers. This type of expression continued throughout subsequent hair cycles and is unlike any other dermal papilla component. The results of this study are consistent with a distinct supportive role for versican in the follicle matrices during hair follicle morphogenesis and cycling.

Localization of epidermal growth factor immunoreactivity in sheep skin during wool follicle development.

Interactions among the cells and matrices of the epidermis and mesenchyme of skin are essential for hair follicle initiation and development. The identification of receptors for epidermal growth factor (EGF) on epithelial components of the follicle during growth has suggested that the ligand participates in some of these events. We have used affinity-purified antibodies together with an alkaline phosphatase detection procedure to investigate the distribution of EGF in the skin of the sheep during wool follicle formation. Immunoreactivity was restricted to the periderm and intermediate layers of fetal epidermis at 55 d of gestation, when the first wave of wool follicles are initiated. This particular distribution persisted during subsequent development but never became associated with the basal cells of the epidermis. The activity was lost around 118 d, coinciding with sloughing of the periderm. No immunoreactivity was found in the plugs or the dermal condensations of the developing follicles. At approximately 105 d of gestation, however, reactions were detected in the outer root sheath as the follicles matured and in the differentiating cells of the sebaceous glands. A similar distribution pattern was also noted at 140 d, just prior to birth, and in adult animals, indicating that EGF was sequestered and perhaps synthesized within the follicle. The presence of immunoreactive material was also associated with the pilary canals and the skin surface, suggesting that this may have had its origin in the sebaceous glands. We examined this using a radioreceptor assay for EGF. Material washed from the skin surface and sebaceous gland extracts were found to displace 125I-EGF from rat liver membranes, in parallel with mouse EGF.

Relapsing bilateral brachial plexopathy during pregnancy. Report of a case.

We describe a case of relapsing bilateral brachial plexopathy occurring during pregnancy and the postpartum period. This condition is known to occur with a familial predilection, but it has not been previously reported on a sporadic basis. The outcome was poor and associated with several psychosocial consequences.

RR interval variation and the sympathetic skin response in the assessment of autonomic function in peripheral neuropathy.

The diagnostic value of two simple tests of autonomic function, the RR interval variation and the sympathetic skin response, was evaluated relative to symptoms of dysautonomia in 53 patients with peripheral neuropathy. Of 22 patients with peripheral neuropathy and clinical dysautonomia, 15 showed abnormal results on both tests, and 7 had abnormal results on one test only. In none of the patients with dysautonomia were both tests' results normal. Conversely, all 15 patients with abnormal results of both sympathetic skin response and RR interval variation had symptoms of dysautonomia, while 7 of 15 patients with abnormalities limited to one test had such symptoms. No patient with normal results on both tests had clinical dysautonomia. These data indicate that RR interval variation and sympathetic skin response, both of which can easily be performed in the electromyography laboratory, are helpful in combination in the assessment of autonomic function in peripheral neuropathies.

Herpes simplex labialis and trigeminal neuropathy.

Three patients had a transient trigeminal sensory disturbance associated with an ipsilateral herpes simplex (HS) labialis lesion. These cases support the theory that isolated trigeminal sensory disturbance may be caused by intermittent reactivation of HS virus in the trigeminal ganglion.

Liquid crystal thermography: quantitative studies of abnormalities in carpal tunnel syndrome.

We performed liquid crystal thermography (LCT) in 38 normal hands and in 23 hands with carpal tunnel syndrome (CTS) documented by nerve conduction studies (NCS). Two of the authors unaware of the clinical situation read the 2 palmar thermograms taken at a 5-minute interval. They determined the absolute temperatures of the tip of digit 1 (D1), D2, D3, D4, D5, and of the thenar and hypothenar eminences. We calculated the temperature differences (absolute values throughout) between any 2 of these 7 sites, and computed the median index (MI = [D1 - D2] + [D1 - D3] + [D2 - D3]). Comparison of the control and CTS groups revealed greater temperature differences in CTS between D1 - D3, D1 - D4, D3 - D5, D4 - D5, and MI. There was a marked overlap between the 2 groups. Comparison of individual CTS hands with controls revealed definite thermographic abnormalities in 0 of 9 hands with mild NCS abnormalities, and in 7 of 14 hands with marked NCS abnormalities. These findings indicate that the sensitivity of LCT in CTS is low compared with NCS, and previous favorable reports concerning thermography in CTS may have been due to lack of control series or absence of quantitation.

Facilitation of magnetic motor evoked potentials during the cortical stimulation silent period.

We investigated the relationship between stimulus intensity and magnetic motor evoked potentials (MEPs) elicited 100 msec after a conditioning stimulus that was 25% of stimulator output above resting motor threshold (RMT) during tonic contraction of abductor pollicis brevis. In five subjects, MEPs elicited with stimuli less than 25% above RMT were inhibited during the EMG cortical stimulation silent period (CSSP) produced by the conditioning stimulus, relative to MEPs elicited with the test stimulus given at rest. However, increasing the intensity of the test stimulus increased the amplitude of MEPs elicited during the CSSP relative to MEPs elicited at rest, such that MEPs elicited with stimuli 30 to 45% above RMT were facilitated during the CSSP. Increasing the intensity of the test stimulus also increased the amplitude of MEPs elicited with paired stimulation at rest, and caused facilitation in one subject. Since facilitation of MEPs was never accompanied by shortening of MEP latency, our observations point to supraspinal facilitory mechanisms. We suggest that facilitation of MEPs during the CSSP reflects temporal and spatial summation of conditioning and test stimuli.

Hemispheric threshold differences for motor evoked potentials produced by magnetic coil stimulation.

A brief monophasic pulse through an electromagnetic coil preferentially activates motor pathways of each hemisphere, depending on the direction of coil current flow. Using the preferred direction for each hemisphere, the minimum stimulus intensity (threshold) that evoked compound muscle action potentials in the contralateral abductor digiti minimi (ADM) muscle was significantly less for the left hemisphere than the right. Threshold for biceps on each side was significantly higher than ADM, but there was no side-to-side difference. Assessing handedness using a standard handedness index, those who had less tendency to use the right hand for everyday tasks had greater differences between hemispheres for ADM thresholds. The lower threshold of the left-hemisphere projection to hand muscles is probably related to the asymmetry of corticomotoneuronal monosynaptic connections; a greater number project to the motor neuron pool of the right- than left-hand muscles.

Cervical magnetic stimulation.

We stimulated the cervical region with a 9-cm-diameter magnetic coil on centered on the spinous processes in 21 normal subjects. We obtained maximal amplitudes with clockwise coil current in right-sided upper extremity muscles and counterclockwise coil current in left-sided upper extremity muscles. Optimal stimulation sites for biceps, triceps, and abductor digiti minimi were C-3 or C-4, C-4 or C-5, and C-4, C-5, or C-6, respectively. The latencies of the muscle responses varied little in the same subject in spite of marked amplitude changes due to suboptimal position of the coil or submaximal stimulator output. In abductor digiti minimi, the amplitude of the muscle response on cervical magnetic stimulation was 9 to 100% of the supramaximal amplitude on wrist electrical stimulation. We established normal values for latency, amplitude, and interside differences for the above 3 upper extremity muscles. The findings were reproducible, and the latencies obtained with large coils from different manufacturers in the same subjects were comparable. We found no advantage in bipolar recording over tendon-belly montage. Comparison of magnetic and electrical needle root stimulation in the same subjects showed that the magnetic stimulus was more proximal in biceps and triceps, and that the site of excitation was approximately the same in abductor digiti minimi. Indirect assessment of the longitudinal site of excitation based on F-wave minimal latency indicated that excitation occurred within millimeters of the emergence of axon of the peripheral motor neuron.

Pilot study of myoblast transfer in the treatment of Becker muscular dystrophy.

We evaluated myoblast implantation therapy in three subjects with Becker muscular dystrophy who received 60 million myoblasts in one tibialis anterior (TA) muscle 2 months after beginning cyclosporine immunosuppression (5 to 10 mg/kg) that continued for 1 year. Strength of the implanted and control TA muscles was measured before and after treatment using a gauge to record TA contraction force. Our protocol controlled for the effects of cyclosporine and myoblast injections. In this pilot study, myoblast implantation did not improve strength of the implanted TA muscles.

Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease.

OBJECTIVE: To evaluate the sensitivity of transcranial magnetic stimulation (TMS) to identify upper motor neuron involvement in patients with motor neuron disease. BACKGROUND: Diagnosis of ALS depends on upper and lower motor neuron involvement. Lower motor neuron involvement may be documented with electromyography, whereas definite evidence of upper motor neuron involvement may be elusive. A sensitive, noninvasive test of upper motor neuron function would be useful. METHODS: TMS and clinical assessment in 121 patients with motor neuron disease. RESULTS: TMS revealed evidence of upper motor neuron dysfunction in 84 of 121 (69%) patients, including 30 of 40 (75%) patients with only probable upper motor neuron signs and unsuspected upper motor neuron involvement in 6 of 22 (27%) patients who had purely lower motor neuron syndromes clinically. In selected cases, upper motor neuron involvement identified with TMS was verified in postmortem examination. Increased motor evoked potential threshold was the abnormality observed most frequently and was only weakly related to peripheral compound muscle action potential amplitude. In a subset of 12 patients reexamined after 11+/-6 months, TMS showed progression of abnormalities, including progressive inexcitability of central motor pathways and loss of the normal inhibitory cortical stimulation silent period. CONCLUSIONS: TMS provides a sensitive means for the assessment and monitoring of excitatory and inhibitory upper motor neuron function in motor neuron disease.

Respiratory failure revealing mitochondrial myopathy in adults.

Two patients, a 70-yr-old black woman and a 56-yr-old black man, presented with respiratory failure unexplained by intrinsic lung disease. Both had been dependent on a respirator for several weeks. No abnormalities of the central or peripheral nervous system or long-standing muscle weakness was noted. The findings from ophthalmologic and cardiac evaluations were normal. The serum creatinine kinase concentration was mildly elevated in case 1, and needle electromyography showed myopathic potentials in case 2. In both instances, muscle biopsy established the diagnosis of mitochondrial myopathy. Biochemical studies of muscle extracts showed partial deficiency of complex 3 in patient 2 and of complex 4 in patient 1. Both patients were weaned from the ventilator after long periods of ventilatory assistance. These observations document a hitherto undescribed presentation of adult-onset mitochondrial myopathy.