连枷臂综合征:表现为上肢无力和萎缩的良性运动神经元病

目的回顾总结3例连枷臂综合征患者的临床、电生理和骨骼肌病理改变的特点,并分析此类患者的护理策略。方法与结果3例患者均为男性,发病年龄分别为54岁、71岁和64岁,病程2～4年。主要表现为缓慢、进行性发展的双上肢肌无力和肌肉萎缩,例1和例3均于病程发展后期出现双下肢轻度无力;例2以认知功能障碍发病;例3于疾病后期出现认知功能障碍。3例神经系统检查均呈现双上肢明显肌无力,近端和远端广泛分布的肌肉萎缩,伴随肌张力下降和腱反射减退。例2和例3还同时合并下肢上运动神经元损害及认知功能障碍。对3例患者进行电生理学及病理检查显示:(1)肌电图呈静息状态下的肌纤维颤动和肌束颤动电位,胸锁乳突肌、上肢和下肢肌肉轻收缩时运动单位电位时限增宽、波幅增高或为宽大运动单位电位,重收缩时呈单纯相或混合相。例1双侧尺神经运动神经传导未发现传导阻滞现象。3例感觉和运动神经传导速度于正常值范围,诱发电位波幅有不同程度下降。(2)骨骼肌病理检查可见小角状萎缩肌纤维呈簇分布并累及Ⅰ型和Ⅱ型,伴随明显的肌纤维肥大;有肌纤维核内移现象,还原型辅酶Ⅰ四氮唑还原酶染色偶见靶样纤维,非特异性酯酶染色显示部分萎缩的肌纤维深染。结论3例患者的临床症状、体征及病变分布均符合连枷臂综合征的诊断,以双上肢的局限性损害为突出表现,同时可合并下肢的轻微损害或亚临床改变,与其他运动神经元病一样可合并认知功能障碍。由于上肢严重病残,应当注意采取相应的保护措施,避免发生意外伤害。     

"Acro-erythro-cyanosis"--peculiar vasomotor symptoms due to cervical hernial myelopathy

Two cases of cervical myelopathy, which exhibited peculiar vasomotor symptoms ("acro-erythro-cyanosis") on distal regions of the four limbs are reported. Continuous reddening, swelling and skin temperature increase were observed on both hands and feet in case 1, a-44-year-old man, and on both hands in case 2, a-47-year-old man. Cold stimulation resulted in cyanosis and decrease of skin temperature on the affected regions paroxysmally. The condition of skin at room temperature may be caused by arteriectasia of arterioles due to hypotonia of vasomotor fibers, and this was similar to erythromelalgia. On the other hand, cold stimulation may have led to this condition, where the contraction of skin arterioles due to hypertonia of vasomotor fibers was added to the dilation of venule, and this was similar to acrocyanosis. Consequently, we provisionally named the vasomotor symptoms in the present cases as "acro-erythro-cyanosis". The other neurological signs were as follows. Case 1: mild weakness in right upper and lower limbs and left small hand muscles, mild superficial and deep sensory disturbance on bilateral palms and soles and decrease of vibration on bilateral lumbar regions and thereunder. Case 2: mild weakness of right small hand muscles, superficial sensory disturbance on distal regions of bilateral upper and lower limbs and a decrease of joint position sense on right hand. Myelography and metrizamide CT myelography revealed a high-degree deformity of the spinal cord due to the herniated disks between C4 and C5 in case 1 and between C3 and C4 in case 2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Congenital facioscapulohumeral muscular dystrophy associated with tongue atrophy and sensorineural hearing disturbance

An 18-year-old high-school boy presented facial muscle weakness since birth, and then developed wasting around the neck, shoulder girdle, upper arms, and thighs. He was born to un-consanguineous parents. His father had suffered from similar but milder muscle atrophy with predominance on the right side of the face and shoulder girdle since adolescence. His mother and his only sibling were clinically unaffected. Hearing disturbance was detected at the age of 6, and he also noted atrophy of the tongue and the bilateral thighs at the age of 10. The symptom progressed gradually. Neurological examination on admission revealed a well-developed boy (166 cm/60 kg) with a prominent facial diplegia with distinct proximal muscular atrophy of the extremities. Muscles of the tongue, neck, upper arms, shoulder and pelvic girdles, and hamstrings were markedly involved. The anterior tibial muscles were also affected, while the calf muscles were hypertrophic. High arched palate, X legs, mild lordoscoliosis were also noted. Serum CK was slightly increased (424 IU/l), and needle EMG in the extremities including the tongue revealed myopathic changes. Muscle CT demonstrated marked atrophy of the proximal muscles in the lower limbs and hypertrophy of the calf muscles. Audiogram showed bilateral sensorineural hearing disturbance. Muscle biopsy of the gastrocnemius showed myogenic as well as neurogenic changes consisting of atrophic and hypertrophic fibers with interstitial cellular infiltration, and type I fiber predominance. With these family history as well as clinical and laboratory examinations, this case could be diagnosed as "congenital facioscapulohumeral muscular dystrophy".(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuronal coordination of arm and leg movements during human locomotion

We aimed to study the neuronal coordination of lower and upper limb muscles. We therefore evaluated the effect of small leg displacements during gait on leg and arm muscle electromyographic (EMG) activity in walking humans. During walking on a split-belt treadmill (velocity 3.5 km/h), short accelerations or decelerations were randomly applied to the right belt during the mid or end stance phase. Alternatively, trains of electrical stimuli were delivered to the right distal tibial nerve. The EMG activity of the tibialis anterior (TA), gastrocnemius medialis (GM), deltoideus (Delt), triceps (Tric) and biceps brachii (Bic) of both sides was analysed. For comparison, impulses were also applied during standing and sitting. The displacements were followed by specific patterns of right leg and bilateral arm muscle EMG responses. Most arm muscle responses appeared with a short latency (65-80 ms) and were larger in Delt and Tric than in Bic. They were strongest when deceleration impulses were released during mid stance, associated with a right compensatory TA response. A similar response pattern in arm muscles was obtained following tibial nerve stimulation. The arm muscle responses were small or absent when stimuli were applied during standing or sitting. The arm muscle responses correlated more closely with the compensatory TA than with the compensatory GM responses. The amplitude of the responses in most arm muscles correlated closely with the background EMG activity of the respective arm muscle. The observations suggest the existence of a task-dependent, flexible neuronal coupling between lower and upper limb muscles. The stronger impact of leg flexors in this interlimb coordination indicates that the neuronal control of leg flexor and extensor muscles is differentially interconnected during locomotion. The results are compatible with the assumption that the proximal arm muscle responses are associated with the swinging of the arms during gait, as a residual function of quadrupedal locomotion.     

Effects of remote muscle contraction on transcranial magnetic stimulation-induced motor evoked potentials and silent periods in humans.

OBJECTIVE: To determine to what extent tonic contraction of the testing muscle modulates the effect of remote muscle contraction on motor evoked potentials (MEPs) and cortical silent periods (CSPs) in resting and active proximal and distal muscles following transcranial magnetic stimulation (TMS). In addition, we tested whether the remote effect on MEP was observable when the test MEP was small. METHODS: While performing tonic abductions of the first dorsal interosseous (FDI), flexor carpi radialis, or anterior deltoid muscles, subjects made phasic dorsiflexions of the right ankle at various forces. MEPs and CSPs were induced by separately optimized TMS intensities and locations in the left motor cortex and recorded electromyographically. RESULTS: Phasic dorsiflexion increased MEP amplitude and shortened CSP duration in a dorsiflexion intensity-dependent manner in all muscles tested. At test MEPs <10% of Mmax, remote effects on MEP amplitude and CSP duration were significantly attenuated while the testing muscle was active. CONCLUSIONS: Phasic contraction of remote muscles potentiates excitatory- and suppresses inhibitory intracortical neuronal pathways converging on corticospinal tract cells innervating the upper limb muscles even when they are active. However, the magnitude of the remote effect on MEP amplitude strongly depends on the test MEP amplitude. SIGNIFICANCE: Although remote effects on MEP amplitude and CSP duration are observed even when the test muscle is active, the magnitude of the remote effect strongly depends on TMS intensity.     

Patterns of motor control reorganization in a patient with mirror movements.

OBJECTIVE: To explore motor control reorganization in a 40-year-old, left-handed patient with perinatally acquired mirror movements. METHODS: We performed simultaneous bilateral recordings of motor evoked potentials (MEPs) following focal transcranial magnetic stimulation (fTMS) and of central silent period (cSP) during unilateral voluntary contraction in abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. RESULTS: For both muscles the MEP study showed bilateral fast-conducting corticospinal projections from the right undamaged hemisphere, and residual contralateral projections from the left hemisphere. The cSP findings differed in the two muscles: the mirror phenomenon was bilateral in the ADM, but present only on the right side in the APB muscles; the mirror activity of right ADM and APB muscles was inhibited only by fTMS of the ipsilateral right motor cortex; the mirror phenomenon in the left ADM muscle was inhibited only by fTMS of the contralateral right motor cortex. CONCLUSIONS: Mirror movements of right APB and ADM muscles were sustained by the ipsilateral connections from the undamaged motor cortex, while the mirror phenomenon in the left ADM muscle could be explained by hypothesizing a bilateral activation of motor cortices. This previously unreported electrophysiological picture demonstrates that different patterns of motor control may realize after perinatal cerebral lesions, even in different distal muscles of the same patient.     

Brown-Vialetto-van Laere syndrome; the first Turkish case

We describe a 14-year-old female patient with progressive ponto-bulbar palsy and deafness. The first symptom was present at the age of 9 as a difficulty in walking and then she was stable with mild clumsy walking till 14 year-old. It was noticed that she had rapidly progression gait disorder, hearing loss, difficulty in swallowing and speaking in a period of 2.5 months. Clinically, there were bilateral facial weaknesss, atrophic tongue with fasciculations, poor gag reflex, deafness, axial and appendicular hypotonia, severe muscular weakness involving muscles of neck, shoulder, and upper arms, hands with thenar and hypothenar amyotrophy. Hearing loss was documented by brainstem auditory evoked potentials. Other laboratory investigations, screening tests and imaging studing were normal. These clinical features are consistent with the Brown-Vialetto-van Laere syndrome.     

A case of adult T cell leukemia/lymphoma with motor and sensory polyneuropathy]

A 62-year-old man was admitted to our hospital because of two months continuing paresthesia and muscle weakness of distal portions of the four limbs. On general physical examination, skin lesions, lymphadenopathy and hepatosplenomegaly were not found. Neurological examination revealed moderate weakness in the bilateral distal muscles of the lower limbs and left distal muscles of the upper limbs, and slight weakness in the right distal muscles of the upper limbs and the bilateral proximal muscles of the four limbs. Hand grasping powers were 24 kg and 2 kg on the right and left, respectively. The biceps, triceps and radial reflexes were decreased on the right, but normal on the left. The Achilles tendon reflex was decreased on the right and absent on the left. Paresthesia and superficial sensory disturbance were observed with glove and stocking distribution, which was more severe on the left side. The vibration and position senses were slightly decreased in the distal part of the lower limbs. On the laboratory examinations, serum anti-HTLV-I antibody was positive and no abnormal lymphocytes were observed in peripheral blood. Cerebrospinal fluid findings were normal, and anti-HTLV-I antibody was negative. Motor and sensory conduction velocities were normal or slightly decreased in all of the limb nerves examined, but the amplitudes of the compound muscle action potentials and the sensory nerve action potentials were asymmetrically decreased. Needle EMG showed fibrillation potentials and giant spikes with a reduction in number of motor unit potentials. The histological examination of the biopsied sural nerve revealed severe axonal degeneration without evidence of vasculitis or infiltration of abnormal lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)     

A case of neuralgic amyotrophy manifesting bilateral anterior interosseous nerve syndrome]

A 49-year-old woman acutely developed severe bilateral shoulder pain followed by weakness of the right shoulder girdle muscles. Within a few days, an inability to flex the terminal phalanges of the bilateral thumbs and index fingers emerged. Neurologic examination 1 month after the onset of symptoms showed atrophy of the right shoulder girdle muscles and mild decreased cutaneous sensation in the distribution of the right axillary nerve. Needle electromyography examination at this time showed fibrillation potentials in the right deltoid and bilateral flexor pollicus longus muscles. Recruitment of the right deltoid, supra- and infraspinatus muscles was reduced. Motor unit potentials in these muscles were of normal configuration. Nerve conduction studies in the upper limb were normal. She was diagnosed as neuralgic amyotrophy with bilateral anterior interosseous nerve syndrome. 4 months later, the muscles innervated by the bilateral anterior interosseous nerve improved in the muscle strength. Clinical features of this case were compatible with a mononeuropathy multiplex form of neuralgic amyotrophy associated with an autoimmune etiology. We think this case is important for speculating the pathogenesis of neuralgic amyotrophy. This case reminds us that patients with neuralgic amyotrophy sometimes demonstrate anterior interosseous nerve syndrome and most patients manifesting anterior interosseous nerve syndrome are patients with neuralgic amyotrophy.     

Modulation of human cervical premotoneurons during bilateral voluntary contraction of upper-limb muscles

A greater proportion of the voluntary command to the affected upper limb of well-recovered stroke patients descends via the putative C3/4 propriospinal system compared with the unaffected limb or the limbs of control subjects. We have examined whether there are differences in the pattern and extent of the modulation in intact subjects when the upper-limb muscles are bilaterally activated compared with unilateral activation. Motor evoked potentials (MEPs) recorded from flexor carpi radialis (FCR) in response to transcranial magnetic stimulation (TMS) were assessed for an effect of cocontraction with biceps brachii (BB) and subthreshold electrical conditioning of the musculocutaneous (MC) nerve. No between-hand differences were revealed, but there was less facilitation during bilateral than unilateral contraction. The findings suggest that the C3/4 propriospinal system is more active during unilateral muscle contraction and less active during bilateral contraction of upper-limb muscles. Therefore, bimanual rehabilitation strategies for patients with upper-limb hemiparesis should be developed with caution.     

Contralateral reinnervation of midline muscles in facial paralysis.

We report on a patient with recovery of activity of the left orbicularis oris and nasalis muscles 3 months after a complete left facial palsy. Stimulation of the affected facial nerve evoked no responses, whereas contralateral facial nerve stimulation showed polyphasic responses with very long latencies in the nasalis and orbicularis oris muscles. Needle electromyography (EMG) revealed abnormal spontaneous activity in the left orbicularis oris muscle. The motor unit action potentials on the left side of the face could be recruited only during marked contraction of the corresponding muscles on the right and were of low voltage and polyphasic ("nascent potentials"). Contralateral reinnervation is probably due to sprouting of terminal branches crossing the midline of the face and innervating bundles of muscle fibers on the affected side. This phenomenon seems unfamiliar to most clinicians. Whether the activity is due to conduction along nerve fibers or muscle fibers crossing the midline is discussed.     

Case report of muscle cramp versus focal epilepsy]

We report here a boy suffering from muscle cramps in the right upper extremity. At 32 days of age, he developed purulent meningitis followed by paresis of the right upper extremity. From infancy he had intermittent episodes myoclonus-like involving the right hand. Since he also had true epileptic seizures with loss of consciousness, ocular deviation, and vomiting at 6 and 8 years of age, he was treated with anti-epileptic drugs as therapy for focal motor seizures. At 6 years of age, these episodes increased in frequency. The cramps spread from the right hand to involve the entire upper extremity with pain. At the age of 10, he was referred to Hirosaki University Hospital and was admitted. Using closed circuit television with continuous EEG and EMG monitoring we observed during his episodes repeated EMG abnormalities consisting of continuous discharges of polyphasic motor unit potentials, but no epileptic EEG discharges. We diagnosed these episodes as muscle cramp. His muscle cramps were controlled by medication with muscle relaxants and Chinese medicines. This case illustrates that the differential diagnosis between muscle cramps and epileptic seizures is important for proper treatment.     

Effect of antagonistic voluntary contraction on motor responses in the forearm.

OBJECTIVE: We investigated the effects of voluntary contraction of agonist and antagonist muscles on motor evoked potentials (MEP) and on myoelectric activities in the target (agonist) muscle following transcranial magnetic stimulation (TMS). METHODS: The left extensor carpi radialis (ECR) and flexor carpi radialis (FCR) muscles were studied in 16 healthy subjects. H reflexes, MEP induced by TMS, and background electromyographic (EMG) activity were recorded using surface electrodes at rest and during voluntary contraction of either agonist or antagonist muscles. RESULTS: Voluntary contraction of antagonist muscles (at 10% of maximum contraction) enhanced the amplitudes of MEP for both muscles. The H reflex of the FCR muscle was inhibited by contraction (10% of maximum) of the ECR muscle. Background EMG activity did not differ between H-reflex trials and TMS trials. Enhancement of MEP amplitudes and background EMG activity during voluntary antagonist contraction was comparable in the two muscles. Appearance rate of MEP recorded by needle electrodes in response to subthreshold TMS was increased by antagonistic voluntary contraction. CONCLUSION: Facilitation occurs during voluntary contraction of antagonist muscles. Differences between the effects of voluntary contraction of the ECR muscle for the MEP and the H reflex of the FCR suggest that cortical facilitatory spread occurs between agonist and antagonist muscles.     

Delayed finger opening caused by a midbrain lesion]

We report a 25 year-old woman with delayed finger opening caused by a midbrain lesion. Magnetic resonance imaging revealed an abnormal intensity area in the left midbrain in the vascular territory corresponding to the mesencephalic inferomedian branch and central posteromedian branch of posterior cerebral artery. Clinically, she suffered from Weber's syndrome, and in the course of recovery, she developed marked delayed finger opening. Her weakness was slight, this delayed finger opening was observed only after maximal grip, and she required about ten seconds to open her right fingers. She could open and grip her fingers easily and quickly in moderate contraction. In the electromyogram, the action potentials of flexor digitorum profundus muscle did not disappear promptly upon instruction to open her fingers, and they lasted for approximately six seconds with gradual decrease. On the other hand, the action potentials of extensor digitorum muscle were reciprocally inhibited and increased gradually after the decrease of the flexor muscle potentials. The abnormally continuing discharges in the flexor muscles were thought to be the cause of her delayed finger opening. The phenomenon of delayed finger opening caused by cervical root lesions, peripheral nerve lesions, or a brain stem (pons-medulla oblongata) lesion have been reported. But, the phenomenon caused by a midbrain lesion, like our case, has not been reported. The present case was different from the previously reported cases with this phenomenon showing simultaneous discharges from both agonistic and antagonistic muscles.     

Is one motor cortex enough for two hands?

We report on a patient with mirror movements sustained by a mono‐hemispheric fast control of bilateral hand muscles and normal hand function. Transcranial magnetic stimulation of the right motor cortex evoked contractions of muscles in both hands while no responses were observed from the left hemisphere. Somatosensory‐evoked potentials, functional magnetic resonance, and diffusion tractography showed evidence of sensorimotor dissociation and asymmetry of corticospinal projections, suggestive of reorganization after early unilateral left brain lesion. This is the first evidence that, in certain rare conditions, good hand function is possible with ipsilateral corticospinal reorganization, supporting the role of unexplored mechanisms of motor recovery.     

Three cases of subacute panencephalitis showing asterexis-like movements

We reported 3 cases with subacute sclerosing panencephalitis (SSPE) showing recurrent and involuntary motor phenomena. Their electroclinical correlates were analyzed using CCTV-EEG. Clinically, they slanted their trunks and/or heads, and dropped their upper limbs momentarily only when their antigravity muscles were suitably contracting (sitting, standing, or stretching out their arms). Electrographically, the motor phenomena corresponded with the occurrence of periodic synchronous discharges (PSD) (in one-to-one manner). EMG potentials associated with the muscle contraction subsided at the very moment. These motor phenomena observed in patients with SSPE were discussed in relation to asterexis.     

A large German kindred with cold-aggravated myotonia and a heterozygous A1481D mutation in the SCN4A gene

Muscle sodium-channel disorders cover a spectrum of rare myotonic diseases. In a German family with 17 affected individuals in four generations, we identified a heterozygous missense mutation in exon 24 A1481D (c.4442 C>A) of the voltage-gated sodium channel gene (SCN4A) alpha subunit. Phenotypes of 12 family members were characterized by a mild myotonia with cold sensitivity but without paramyotonia. The index patient presented with fluctuating cold- and exercise-induced stiffness of ocular, facial, and distal muscles. The myotonia became more severe at the age of 22 years. His father had had cold- and exercise-induced periodic weakness with fluctuating myotonia since age 10. Later he developed a more severe, purely exercise- and cold-aggravated myotonia of arms, hands, and facial muscles. The father's mother presented with cold-induced myotonia until age 65, when progressive weakness of proximal limb muscles developed. Her muscle biopsies revealed considerable myopathic changes with a variety of fine structural alterations. This study presents a family with cold-aggravated myotonia and progression of myopathic changes in the muscle biopsy with increasing age. In older patients, sodium channelopathies may mimic the phenotypic features of myotonic dystrophy type 2.     

A case of mortor neuron syndrome with onset 9 months after electrical injury]

A 72-year-old man noticed progressive weakness of both upper limbs, more severe on the left side, 9 months after an electric shock of a 20,000 V alternating current. He had diffuse scars of superficial burns with skin graft in four limbs, more on the right side. A neurological examination revealed diffuse muscle atrophy, weakness and fasciculation in both upper limbs, predominantly on the left side, hyper-reflexia in four limbs with mildly exaggerated jaw jerk, left Babinski sign, and mild decrease of touch and pain sensation in the right C6 and C7 segments. Painful dysesthesia was present in the left hand and right lower limb. The search for serum antibodies against GM1, GM2, GM3, GD1a, Gd1b, GQ1b, GA1, and GT1b was negative. No abnormality except mild cervical spondylotic changes was evident in the magnetic resonance imaging of the brain and spinal cord. The upper limb motor evoked potentials (MEPs) were not elicited by the left cortical stimulation and the central motor conduction time by the right cortical stimulation was remarkably prolonged in the upper limb MEPs. Nerve conduction study showed a delay of motor conduction velocity and distal latency in the right median and bilateral ulnar nerves with low amplitude and delayed velocity of sensory nerves of those nerves. Needle EMG revealed diffuse ongoing denervation potentials in bilateral upper limbs and giant motor unit potentials in the right triceps and first dorsal interossei muscles. These findings indicate that the delayed motor neuron syndrome induced by electrical shock is characteristic for having demyelination as well as axonal changes in both central and peripheral nervous systems.     

The bilateral long thoracic nerve palsy presenting with "scapula alata", as a result of weight training. A case report]

A 28-year-old male barber with no similar disease in his family admitted to our hospital because of difficulty of raising his arms in March 2003. When he was 18 years old, he broke his left clavicle. He started weight training from January 2003, then he gradually felt difficulty to raise his arms. Physical examination on admission showed weakness and atrophy of both serratus anterior muscles and there was no weakness in the other muscles. Serum CK level was 806 IU/l and CT scan of the upper thoracic levels revealed atrophy of the serratus anterior muscles on the both sides. Needle electromyography showed neurogenic change in the right serratus anterior muscle. Thus the diagnosis of bilateral long thoracic nerve palsy was made. Bilateral scapular winging (scapula alata) is commonly caused by systemic disease, especially muscular dystrophy or spinal muscular atrophy. Bilateral long thoracic nerve palsy by weight training should be known as one of the cause for the "scapula alata".     

Effect of voluntary contraction of the masseter and other muscles upon the masseteric reflex in man

Experiments were carried out on seven adult subjects in order to establish the relationship between the magnitude of the masseteric reflex and the amount of voluntary activity present in the muscle at the time the reflex was evoked. At the same time, an effort was made to determine whether the magnitude of the reflex could be enhanced by the simultaneous voluntary contraction of muscles other than that being tested (the Jendrassik manoeuvre). The reflex was evoked by applying controlled downward thrusts to the mandible so as to produce a constant displacement in each case, and the response of the masseter muscle was recorded by means of small bipolar surface electrodes attached to the skin over the muscle. These responses were averaged by a computer in the presence of various static loads supported by the mandible. It was found that in all subjects the amplitude of the masseteric reflex appeared to increase as the weight supported by the mandible increased, and that in the majority of subjects it was possible to demonstrate Jendrassik facilitation by simultaneous contraction of the muscles of the upper limbs. The results of the experiments suggest that the enhancement of the masseteric reflex by voluntary contraction of the jaw-closing muscles may be due to autogenetic factors, synergistic factors, or both, and that at least two processes contribute to the amplitude of the masseteric reflex evoked by tooth contact during mastication—namely, the stimulation of muscle spindles by the impact of opposing teeth and facilitation caused by voluntary activity in the jaw-closing muscles before tooth contact.