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Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

Background Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. Methods and Results A random subcohort of 349 participants was selected from the DCCT / EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT , and 1 to 2 years post‐ DCCT ( EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F 2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F 2α . Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F 2α , an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P iso prostaglandin F 2α , P =0.0092). In contrast, the oxidative markers myeloperoxidase and F 2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Conclusions Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 00360815 and NCT 00360893.

Leu-enkephalin is an endogenous pain modulating opioid pentapeptide. Its development as a potential pharmaceutic has been hampered by poor membrane permeability and susceptibility to enzymatic degradation. The addition of an unnatural amino acid containing a lipidic side chain at the N-terminus and the modification of the C-terminus to a carboxyamide was performed to enhance the nasal delivery of the peptide. Two lipidic derivatives with varying side chain lengths (C(8)-Enk-NH(2) (1), C(12)-Enk-NH(2) (2)) and their acetylated analogues were successfully synthesised. Caco-2 cell monolayer permeability and Caco-2 cell homogenate stability assays were performed. C(8)-Enk-NH(2) (1) and its acetylated analogue Ac-C8-Enk-NH(2) (3) exhibited apparent permeabilities (mean±SD) of 2.51±0.75×10(-6)cm/s and 1.06±0.62×10(-6), respectively. C12-Enk-NH(2) (2) exhibited an apparent permeability of 2.43±1.26×10(-6) cm/s while Ac-C12-Enk-NH(2) (4) was not permeable through the Caco-2 monolayers due to its poor solubility. All analogues exhibited improved Caco-2 homogenate stability compared to Leu-Enk-NH(2) with t(½) values of: C8-Enk-NH(2) (1): 31.7 min, C(12)-Enk-NH(2) (2): 14.7 min, Ac-C8-Enk-NH(2) (3): 83 min, Ac-C(12)-Enk-NH(2) (4): 27 min. However, plasma stability assays revealed that the diastereoisomers of C8-Enk-NH(2) (1) did not degrade at the same rate, with the l isomer (t(1/2)=8.9 min) degrading into Leu-enkephalinamide and then des-Tyr-Leu-Enk-NH(2), whereas the d isomer was stable (t(1/2)=120 min). In vivo nasal administration of C(8)-Enk-NH(2) to male rats resulted in concentrations of 5.9±1.84×10(-2) μM in the olfactory bulbs, 1.35±1.01×10(-2) μM in the brain and 6.53±1.87×10(-3) μM in the blood 10 min after administration.

Conotoxins are highly constrained peptide toxins that exhibit pharmaceutically relevant biological activities. We herein report the extent of absorption and profile of distribution of a native alpha-conotoxin, MII and a lipophilic analogue of MII (N-LaaMII) after intravenous (iv) and oral administration to male Sprague-Dawley rats. N-LaaMII is formed by coupling 2-amino-D,L-dodecanoic acid (Laa) to the N-terminus of MII and has previously been shown to exhibit significantly improved permeability across Caco-2 cell monolayers compared to the native MII while maintaining the potency in inhibition of nAChRs of the parent peptide. Both peptides crossed the GI tract after oral administration (similar to 6% after 30 m). While Laa conjugation did not significantly improve absorption, it did greatly increase the accumulation of the compound in the liver after iv administration. Neither peptide crossed the blood-brain barrier to any significant extent. This is the first study of the in vivo biodistribution of an alpha-conotoxin after oral administration. (c) 2007 Elsevier Inc. All rights reserved.

Resume Les neuropathies motrices multifocales avec blocs de conduction (NMM) repondent a court terme aux immunoglobulines polyvalentes a fortes doses par administration intraveineuse (IgIV), mais plusieurs etudes ont documente a long terme l’augmentation du degre de la degenerescence axonale et du nombre de blocs de conduction, facteurs de mauvais pronostic. Notre objectif dans le present travail a ete d’evaluer l’effet a long terme des IgIV sur les parametres cliniques et neurophysiologiques. Methodes Nous avons revu les dossiers de 10 patients ayant initialement repondu aux IgIV et traites regulierement a long terme. Les parametres etudies etaient la force musculaire, l’etat fonctionnel (echelle de Rankin modifiee), ainsi que le nombre et l’evolution des blocs de conduction et du degre de degenerescence axonale. Les patients ont ete suivis pendant une moyenne de 7,25 annees (3,5-12). Ils ont tous ete traites initialement par 2 g d’IgIV/kg en cinq jours toutes les quatre semaines pendant 3 mois. Le traitement d’entretien a ete administre toutes les quatre semaines avec ajustement des doses afin d’eviter tout declin de la force musculaire. Resultats Nous avons note une amelioration significative et persistante de la force musculaire et de l’echelle fonctionnelle de Rankin sans phenomene d’echappement au long cours. Le nombre de blocs de conduction et le degre de degenerescence axonale ont diminue de facon marquee. Conclusion Les IgIV sont un traitement qui reste efficace a long terme dans les NMM. Ces conclusions different de celles d’autres auteurs dans des etudes anterieures. Par comparaison, nos patients ont ete traites par des doses significativement plus elevees d’IgIV. Ces resultats ont des implications importantes pour le traitement a long terme des patients atteints de NMM.

We present a numerical and experimental characterization of high-Q whispering gallery resonant modes excited in a fused quartz spherical shell operated in the 18-26.5 GHz band; easy coupling and selection of modes is a most advantageous feature of the proposed structure with respect to ordinary bulk resonators. The numerical results, based on a finite element algorithm, well match experimental data, which also show the capability of our device to perform gaseous spectroscopy measurements.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

The rapid and direct delivery of a neuroactive endomorphin 1 derivative to the brain via nasal delivery is reported. A synthetic derivative of the native opioid peptide, endomorphin 1 bearing a lactose unit on the N-terminus of the peptide has been previously reported to exhibit antinoceceptive activity similar to morphine after both intravenous and oral administration. This compound has been administered nasally to rats and appeared in the olfactory bulb within 10 min of administration with negligible levels appearing in the circulating blood or in the rest of the brain. These results indicate that the peptide is absorbed into the brain via the olfactory epithelial pathway suggesting nasal delivery may be a viable alternative route of delivery in clinical applications.

The circular polarization of the magnetic field of the whispering-gallery (WG) modes of resonance of a dielectric disk resonator was tested in the evanescent-field region outside the dielectric material. Microwaves in the frequency range from 18 to 26.5 GHz (K-band) and the techniques of electron spin response (ESR) were used. The distribution of the electromagnetic fields was obtained with a finite element method, and it was found to be in agreement with the experimental results. >

For the original article see ibid., vol.38, no.11, p.1667-74 (1990). The commenter points out a discrepancy in the above-titled power by D. Cros and P. Guillon. The resonances on the plot are attributed to whispering gallery (WG) modes WGE/sub 6-10,/ /sub 0,0/ and WGH/sub 6-10,/ /sub 0-0/ for an alumina resonator of 5-mm diameter and 0.635 mm high. The result of the commenter's analysis, showing that a set of higher order radial modes are being measured (WGE/sub 6-10,/ /sub 1,/ /sub 0/ and WGH/sub 6-10,/ /sub 1,/ /sub 0/) are presented. In their reply, the authors present further results in support of their conclusions. >

A 30-year-old man presented with sagittal sinus thrombosis. He had a history of multiple thrombotic events since adolescence, and his father had had a similar history. Laboratory studies revealed the complete absence of free protein S in his plasma. Protein S deficiency, an autosomal dominant disorder, is an identifiable cause of cerebral thrombosis. The literature and our experience with this case suggest that long-term anticoagulant therapy may prevent thrombotic episodes in patients with this disorder.

A bulk acoustic wave filter, which can be used in EDGE transmitter, is presented in this paper. It attenuates power amplifier harmonic frequencies and out-of-band noise generated by sigma-delta modulator needed in linear architecture. This filter achieves 2.4 dB insertion loss including matching network to 50 Omega and more than 15 dB of return loss. Power handling capability and linearity performance of bulk acoustic wave devices are detailed and satisfy to power application requirements. Antenna mismatch effect has been evaluated using an active load-pull bench. This filter is connected in series to power amplifier to form a prototype of power amplifier module for GSM/EDGE standard in the DCS frequency band. The power amplifier is realized using STMicroelectronics 0.25 mum BiCMOS technology

We present a method for BAW (bulk acoustic wave) filters computation. This method compares the equivalent impedance of the BUTTERWORTH-VAN DYKE (BVD) model based on an electrical equivalent circuit with the impedance obtained by piezoelectric equations in one dimension for a piezoelectric structure. Using the least squares method, the three elements of the BVD model can be determined as a function of the dimensions and the properties of the piezoelectric resonator. Based on the proposed method, a ladder piezoelectric 7 pole filter can be easily optimized using an electrical synthesis. The frequency of the proposed filter is around 1.84GHz and the band pass close to 100MHz. This method can be used either for FBAR (film bulk acoustic resonator) or SMR (solidly mounted resonator) structure.

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.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.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.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.

In this paper, it is shown that the method of lines (MOL) with a nonequidistant discretization scheme can be successfully applied to the rigorous design and modeling of certain classes of practical planar filters. Elliptic or quasi-elliptic microwave filters for HTS applications and membrane supported filters for millimeter-wave communication systems are analyzed. Experimental results are presented to prove the validity and accuracy of the formulation.

A device is presented that combines the output power of several millimeter-wavelength devices in a single step by means of a dielectric resonator (DR) with whispering-gallery modes. After a brief description of whispering-gallery modes, definitions are given for both electromagnetic and electrical parameters of these resonators when they are coupled with transmission lines. The design and the test results of the W-band whispering-gallery mode DR power combiner are then given. >

This paper presents a general method to characterize a dielectric resonator coupled to two parallel microstrip lines. The scattering parameters of such a structure are calculated using the finite element method and the coupled transmission lines properties. This method is applied to the case of a dielectric resonator excited on a whispering gallery mode. Thus, the structure is used as a resonant two ways power combiner. In order to optimize the combiner efficiency, the optimum spacings between the resonator and each microstrip line are computed using an equivalent model. Two configurations of the device with different resonators are studied. The results given by the method of characterization are in good agreement with the measurements. A combiner efficiency greater than 82% is obtained at 15.6 GHz.

A free space microwave measurement system has been developed to simultaneously determine complex permittivity and permeability of materials. The set up has been recently improved to permit high and low temperature measurements from C band up to W band.

This paper describes MEMS thermally actuated RF switches. The switches are constructed using a stress controlled dielectric membrane, with patterned metallic contacts. The structure allows one to build resistive switches at RF frequencies. The process is CMOS compatible and the resulting switches can be easily operated below 5 V. A wafer scale packaging technique has been developed to protect the components during the dicing stage, and for long term durability. Measured performances show 0.25 dB loss for a double series switch and isolation better than 55 dB at 2 GHz.

Our aims were to use posturography to see if sway pattern differed between patients with large-fiber peripheral neuropathy and normal control subjects and, if it did, to compare posturography with conventional electromyography (EMG) as screening tools for large-fiber peripheral neuropathy. Thirteen patients who came to our neurophysiology laboratory with a preliminary diagnosis of peripheral neuropathy (made by their referring physicians) were compared with 7 nonmatched control subjects. All subjects received a neurologic examination and underwent posturography and conventional EMG. Results of posturography and conventional EMG were compared. Posturography showed abnormal sway patterns only in patients who had EMG abnormalities consistent with large-fiber peripheral neuropathy. These sway patterns differed significantly from those of the control subjects. Posturography seems to be a useful and well-tolerated screening test for patients with a history suggestive of peripheral neuropathy, and results of posturography agree with those of conventional EMG. Moreover, posturography directly measures increased sway in these patients and may be used as a more direct screen for risk of falls in this population.

Guillain-Barré syndrome is a well-defined clinical entity corresponding to primary inflammatory demyelinating lesions of peripheral nerves and spinal roots in the majority of cases seen in Western Europe and North America. Documentation of conduction abnormalities characteristic of demyelination in the context of rapidly developing weakness confirms the clinical diagnosis of acute inflammatory demyelinating polyradiculoneuropathy. These abnormalities include (1) conduction block, (2) markedly prolonged distal latencies, (3) marked slowing of motor conduction velocities, and (4) absent or impersistent F responses. Other abnormalities are of ambiguous significance: (1) low amplitude compound muscle responses, (2) absent sensory nerve potentials, (3) reduction in the maximum EMG recruitment pattern, which may all (1, 2, and 3) indicate conduction block or axonal degeneration, and (4) fibrillation potentials due to breakdown of motor axons, a frequent non-specific effect of primary inflammatory demyelination. A Guillain-Barré variant due to immune-mediated primary axonal degeneration has also been recently described.

We used transcranial magnetic stimulation in humans to investigate the effect of focal unilateral stimulation of the motor cortex on the function of the contralateral motor cortex. Surface-recorded, rectified, averaged electromyography (EMG) showed relative silent periods in small hand muscles at 35-64 and 123-158 ms following ipsilateral cortical stimulation over the hand area. The first inhibitory phase started 11 ms after the minimum corticospinal conduction time from the contralateral cortex, appropriate for transcallosal conduction. Foot muscles (with focal stimulation over the ipsilateral hand area) also showed silent periods at 61-104 ms, indicating a marked spread of the inhibitory effect throughout the opposite motor cortex. H-reflex studies in the upper limb showed that this inhibitory effect was not mediated at the level of the alpha motoneuron. Single motor unit peristimulus time histogram studies in upper limb muscles showed inhibition similar to that seen in the surface recordings and no evidence of excitation following ipsilateral motor cortex stimulation. Transcranial magnetic stimulation performed with large circular coils centered at the vertex activates both excitatory and inhibitory processes bilaterally so that focal unilateral stimulation is preferable in detailed studies of motor system physiology.

In this work, we present results obtained in the design of both a 30 GHz FET oscillator and a 98 GHz Gunn diode oscillator using whispering gallery dielectric resonators modes. The results obtained show the interest of utilization of these dielectric resonators modes for the conception of millimeter wave sources in a large frequency band.

A 70-year-old man required prolonged ventilation after surgery to remove a rectal neoplasm. The cause of the slow recovery from the effects of neuromuscular blocking agents used during his anesthetic was the Lambert-Eaton myasthenic syndrome (LEMS). Before surgery, he had no neuromuscular symptoms, even in retrospect. LEMS should be considered in the diagnosis of prolonged recovery from neuromuscular blockade, even in previously asymptomatic patients.

Voluntary contraction of a muscle greatly increases the amplitude and decreases the latency of the motor potentials evoked by electromagnetic coil brain stimulation (facilitation). Facilitation has also been observed with contraction of a nearby ipsilateral and a contralateral homologous muscle. We studied these facilitatory relationships in 5 normal subjects in small hand, forearm and upper arm muscles using surface-recorded compound motor action potentials, single motor unit recordings, and post-stimulus time histograms. There was no evidence for spread of facilitation between any pair of muscles if the muscle from which motor evoked potentials (MEPs) were recorded was completely at rest during brain stimulation, although this sometimes required training to accomplish or could not be achieved. Thus, although spread of facilitation has been observed by others under these conditions, we did not find this effect. There may be significant interindividual variations in the degree of facilitatory spread.

We used the 9 cm Cadwell magnetic coil, stimulating at the wrist, to obtain simultaneous median and ulnar nerve F-responses. Surface recording was performed from conventional thenar and hypothenar sites. It is known that with this type of coil it is difficult to accomplish selective supramaximal stimulation of the median or ulnar nerve individually. We found it possible, however, to record a compound muscle action potential of supramaximal or near supramaximal amplitude, as well as F-responses, in both thenar and hypothenar muscles simultaneously. We assessed this technique for F-response latency determination in controls and patients with carpal tunnel syndrome. In controls, there was no significant difference in the F-minimal latency or the F-minimum-maximum range obtained by the two methods. In patients with carpal tunnel syndrome, with median F-responses very delayed or absent on conventional testing, magnetically elicited thenar F-responses were of shorter latency, similar to F's recorded in the hypothenar muscles, suggesting they were recorded from ulnar innervated thenar muscles. Although magnetic stimulation allows simultaneous determination of median and ulnar F-latencies, sparing patients several painful stimuli, and shortening the electrophysiologic examination, magnetic stimulation in patients with carpal tunnel syndrome may elicit thenar recorded F-responses that are not of median origin. Use of this technique is limited by the lack of focality of the stimulus, which has been the major limiting factor in its use on peripheral nerves.

The conventional estimation of motor, sensory, and mixed nerve conduction velocities reflects activity in the fastest conducting, heavily myelinated nerve fibers that are only a small proportion of the total. Unmyelinated and thinly myelinated fibers are not evaluated by this technique and numerically represent the largest group of fibers in human cutaneous nerves. The availability of new quantitative techniques to study this aspect of sensory function is an important addition to standard electrodiagnosis. Patient understanding and cooperation is essential because subjective responses are evaluated. We evaluated a reference range for 20 healthy subjects as well as variability on repeated testing. Vibration and thermal thresholds were measured bilaterally at several sites. Measurements were repeated at intervals ranging from two days to three months. There was no side difference but substantial site differences were noted for all measurements. Intraindividual variation was substantial but within the expected range for a psychophysiologic test. Close correlation was noted between various measurements at same and different sites, indicating a great degree of interindividual variation. The Marstock method is recommended for routine clinical use.

Report on the perceptions on the connections between chemistry and pollution among high school and college students.

Unmyelinated afferent fibres are the most numerous of the whole afferent component. Their function in nociception is now well established. However some recent data allow to think that their function is much more complex. Cutaneous unmyelinated afferences are evaluated in controls and in 3 groups of patients (painful neuropathies, painless neuropathies with hypesthesia, diabetic neuropathies). Amyelinic myelinic ratio is not in accordance with the gate control theory. Muscular afferent fibres are studied, especially the lateral gastrocnemius soleus nerve of cat. Their predominance is obvious. Our study was conducted by recording single unit activity from a micro electrod inserted in dorsal root ganglia. But 45% of unmyelinated fibres are not activated by various algesic stimuli. It is suggested that they have a function in cardio-pulmonary adaptation to effort and possibly segmental vascular control as homonymous reflex effect on moto-neuron. Their several properties are a possible explanation of muscular cramps.

In order to investigate the pathological basis of muscle hypertrophy in Duchenne dystrophy, 9 biopsy specimens of the lateral gastrocnemius and 7 of the vastus lateralis were compared. All patients had calf hypertrophy and normal strength in gastrocnemius-soleus, whereas the quadriceps biopsied were all atrophied and weak. The patients' ages ranged from 4 to 11 years. The pathological and histochemical changes were assessed semi-quantitatively. Comparison of the gastrocnemius and quadriceps groups showed that the number of hypercontracted fibres, the degree of endomysial fibrosis and the degree of fat infiltration were significantly higher in the quadriceps. The fibre type differentiation was better in the gastrocnemius group. The mean fibre diameter was above normal in all gastrocnemius biopsies and showed no increase with age. In the quadriceps, fibre hypertrophy was found early in the disease but had changed into fibre atrophy in the three oldest patients. When present, fibre hypertrophy involved both fibre types. The amount of fat-fibrosis per unit area was increased in both groups, but more severely so in the quadriceps. These results indicate that there is no true muscle hypertrophy in the gastrocnemius, in which the fat-fibrosis component was increased in all patients and that the dystrophic process is more active in the quadriceps. The finding of persistent fibre hypertrophy in the gastrocnemius is discussed with respect to the postural abnormalities observed in the lower limbs in Duchenne dystrophy.

Four patients with typical signs of congenital muscular dystrophy (C.M.D.), as described in the literature, are reported. In two young sisters born from consanguineous parents the presenting signs were severe congenital hypotonia in one and hypotonia with arthrogryposis in the other. The two other cases were adult patients with a long standing disease, the onset haring been marked by a transient neonatal hypotonia in one and by a congenital torticollis in the other. All 4 patients had progressively increasing muscle retractions, with absent reflexes in three. C.P.K. was moderately increased in all patients. Electromyography demonstrated myopathic abnormalities in 3 cases, associated in 2 cases with misleading pseudo-neurogenic signs. MUscle biopsy showed non specific changes compatible with muscular dystrophy: fibrosis and/or fat involution was marked in all cases, while necrosis of fibers was rarely observed. Histoenzymology and morphometry confirmed the absence of lesion specificity and their results were variable from case to case. A review of 92 published cases demonstrated that the course of the disease is very variable. A fatal outcome occurs in 15% of cases, while the affection becomes worse or remains stable with about the same frequency. A progressive worsening of muscle retractions is a characteristic finding in C.M.D. Genetically, most cases are of recessive autosomic. The current nosology of C.M.D. is probably inadequate, the clinical picture including cases that are likely to be due to different mechanisms that 2 present methods of investigation cannot demonstrate.

The authors report two cases of arthrogryposis in two children of 7 1/2 and 13 years; the diagnostic criteria were those of Fisher, combining the joint limitations present since birth in at least two different regions, the absence of progressive neurological involvement, and evident amyotrophy. The different etiopathogenic theories are then discussed: review of the literature concerning cases of myopathic arthrogryposis is not very useful; the twelve cases mentioned in the literature are not homogenous, the histopathological findings were very variable, and the histoenzymological studies have been insufficient. The combination of neurological anomalies with arthrogryposis is undeniable (cerebral atrophy, depopulation of the anterior cornu, anterior radicular changes). They are not always present, however, and are insufficient to explain the symptoms. Consideration should be given to the question of whether the importance of the changes in the connective tissue are not underestimated: the proliferation of the connective tissue is, in fact, most of the time, the essential feature to be seen in a histological section. In connection with this "connective theory" it is important to recall the work of Ionasescu et al. (1970) who demonstrated in vitro the excessive synthesis of connective proteins in the muscles of patients with arthrogryposis.

Two patients with a syndrome of relapsing myalgia are described. In both cases nonspecific inflammatory features were present and electromyography disclosed a myositic pattern in one. Muscle biopsy in both patients showed a perimysial infiltrate of eosinophils although peripheral eosinophilia was only noted in one patient. In each, relapse occurred after a recovery phase, but eventually recovery was complete, spontaneously in one, and after therapy in the other. The known causes of eosinophilic myositis are reviewed, with emphasis on a companion with the myositis of eosinophilic fascitis (Shulman's syndrome). Because our cases exhibited distinctive features, this new syndrome should be considered in the differential diagnosis of any eosinophilic myositis.

Four cases of amiodarone neuropathy are reported. Patients presented a sensorimotor neuropathy with distal predominance. Improvement occurred after drug discontinuation. Nerve conduction velocities were significantly decreased. Other secondary effects of amiodarone were noted in two cases. In one case serum levels of amiodarone and N-monodesethylamiodarone were evaluated during and after treatment. Pathological study of nerve with morphometric evaluation was performed. Axonal degeneration changes were predominant in 3 cases. Aspects of segmental demyelination and remyelination were noted in one case and related to secondary demyelination. Numerous lysosomal inclusions were present in Schwann cells, fibroblasts, capillary endothelial and perithelial cells and in perineural cells. Similar inclusions have been observed in other drug-induced lipidosis. The factors responsible for this neuropathy are unknown. In one case, amiodarone-induced hepatic failure might explain the persisting high serum levels of the drug.

Osteomalacic myopathies are rare. They can prevail, however, and occur before bone abnormalities. The diagnosis must rest on clinical observation since the histopathologic images are not specific. On the other hand the demonstration of muscular weakness is very frequent during osteomalacia. In fact two types of manifestations correspond to the same anatomopathologic lesions. These are myopathic changes observed also during light microscopy, histoenzymologic and ultrastructural examination in the 10 patients examined. On the basis of these morphologic changes, muscular involvement can be considered to be part of the osteomalacia syndrome. The contribution of various factors including secondary hyperparathyroidism, vitamin D metabolism disorders, and phosphorus depletion is discussed. It is probable that many of them act together, causing reversible changes in muscular fibers. The intimate mechanisms of these changes are unknown.