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Intra- and intermolecular reactions are promoted by TfOH, where the former are generally more efficient. [ABSTRACT FROM AUTHOR]

Aim: To assess growth plate fusion by magnetic resonance imaging (MRI) and evaluate the correlation with sex, age, pubertal development, physical activity and BMI., Methods: Wrist, knee and ankle of 958 healthy subjects aged 14.0-21.5 years old were examined using MRI and graded by two radiologists. Correlations of growth plate fusion score with age, pubertal development, physical activity and BMI were assessed., Results: Complete growth plate fusion occurred in 75%, 85%, 97%, 98%, 98% and 90%, 97%, 95%, 97%, 98% (radius, femur, proximal- and distal tibia and calcaneus) in 17-year-old females and 19-year-old males, respectively. Complete fusion occurs approximately 2 years earlier in girls than in boys. Pubertal development correlated with growth plate fusion score (ρ = 0.514-0.598 for the different growth plate sites) but regular physical activity did not. BMI also correlated with growth plate fusion (ρ = 0.186-0.384). Stratified logistic regression showed increased odds ratio (OR F: 2.65-8.71; M: 1.71-4.03) for growth plate fusion of obese or overweight subects versus normal-weight subjects. Inter-observer agreement was high (Κ = 0.87-0.94)., Conclusion: Growth plate fusion can be assessed by MRI; occurs in an ascending order, from the foot to the wrist; and is significantly influenced by sex, pubertal development and BMI, but not by physical activity., (©2020 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Aim: To explore the phenotype and response to growth hormone in patients with heterozygous mutations in the insulin-like growth factor I receptor gene (IGF1R)., Methods: Children with short stature, microcephaly, born SGA combined with biochemical sign of IGF-I insensitivity were analysed for IGF1R mutations or deletions using Sanger sequencing and Multiple ligation-dependent probe amplification analysis., Results: In two families, a novel heterozygous non-synonymous missense IGF1R variant was identified. In family 1, c.3364G > T, p.(Gly1122Cys) was found in the proband and co-segregated perfectly with the phenotype in three generations. In family 2, a de novo variant c.3530G > A, p.(Arg1177His) was detected. Both variants were rare, not present in the GnomAD database. Three individuals carrying IGF1R mutations have received rhGH treatment. The average gain in height SDS during treatment was 0.42 (range: 0.26-0.60) and 0.64 (range: 0.32-0.86) after 1 and 2 years of treatment, respectively., Conclusion: Our study presents two heterozygous IGF1R mutations causing pre- and postnatal growth failure and microcephaly and also indicates that individuals with heterozygous IGF1R mutations can respond to rhGH treatment. The findings highlight that sequencing of the IGF1R should be considered in children with microcephaly and short stature due to pre- and postnatal growth failure., (© 2020 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Objectives: Aneurysmal subarachnoid hemorrhage (SAH) is frequently associated with delayed neurological deterioration (DND). Several studies have shown that DND is not always related to vasospasm and ischemia. Experimental and clinical studies have recently documented that it is possible to diagnose and separate cerebral ischemia and mitochondrial dysfunction bedside. The study explores whether cerebral biochemical variables in SAH patients most frequently exhibit a pattern indicating ischemia or mitochondrial dysfunction., Methods: In 55 patients with severe SAH, intracerebral microdialysis was performed during neurocritical care with bedside analysis and display of glucose, pyruvate, lactate, glutamate, and glycerol. The biochemical patterns observed were compared to those previously described in animal studies of induced mitochondrial dysfunction as well as the pattern obtained in patients with recirculated cerebral infarcts., Results: In 29 patients, the biochemical pattern indicated mitochondrial dysfunction while 10 patients showed a pattern of cerebral ischemia, six of which also exhibited periods of mitochondrial dysfunction. Mitochondrial dysfunction was observed during 5162 h. An ischemic pattern was obtained during 688 h. Four of the patients (40%) with biochemical signs of ischemia died at the neurosurgical department as compared with three patients (10%) in the group of mitochondrial dysfunction., Conclusions: The study documents that mitochondrial dysfunction is a common cause of disturbed cerebral energy metabolism in patients with SAH. Mitochondrial dysfunction may increase tissue sensitivity to secondary adverse events such as vasospasm and decreased cerebral blood flow. The separation of ischemia and mitochondrial dysfunction bedside by utilizing microdialysis offers a possibility to evaluate new therapies., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Proteoglycans are a component of the extracellular matrix and are critical for cellular and tissue function. Mutations in proteoglycan components and enzymes involved in proteoglycan synthesis have been implicated in several growth disorders, with common features including short stature and skeletal dysplasia. For example, mutations in B4GALT7, a gene whose protein product catalyzes proteoglycan synthesis, have been associated with the rare progeroid variant of Ehlers-Danlos syndrome. Here, we conducted exome sequencing in a patient with a previously undiagnosed growth disorder and identified compound heterozygous mutations in B4GALT7. This patient is just the fourth individual with genetically confirmed progeroid variant of Ehlers-Danlos syndrome. The mutations include a previously characterized c.808C>T p.Arg270Cys substitution, and a novel c.122T>C p.Leu41Pro substitution. We demonstrate that the novel mutation caused decreased levels of the enzyme, supporting the pathogenicity of the mutation. Our report identifies a novel mutation in B4GALT7 causing the progeroid variant of Ehlers-Danlos syndrome and contributes an extensive phenotypic characterization of a patient with the syndrome. We also reviewed the previous literature in addition to the present patient, and conclude that the key features associated with B4GALT7 deficiency are short stature, developmental anomalies of the forearm bones and elbow, and bowing of the extremities, in addition to the classic features of Ehlers-Danlos syndrome. This report helps define the phenotype of the progeroid variant of Ehlers-Danlos syndrome and furthers our understanding of the effect of proteoglycan defects in growth disorders., (Copyright © 2013 Wiley Periodicals, Inc.)

We compared the sensitivity and specificity of the two metabolite tests, methylmalonic acid (MMA) and total homocysteine (Hcy) in serum, and serum cobalamin (Cbl) in patients referred to our hospital because of suspected cobalamin deficiency and a serum cobalamin value at the referring unit <200 pmol/L. All 111 patients included were investigated using upper gastrointestinal endoscopy with biopsy specimens taken from the gastric and duodenal mucosa to find a morphological basis for cobalamin malabsorption as well as the Schilling test for the validation of the serum tests. All patients were treated with cobalamin and new blood samples were taken after 4 weeks. We found no difference in sensitivity and specificity between serum MMA, Hcy, and Cbl in identifying patients with and without conditions compatible with cobalamin malabsorption. Elevated serum MMA and Hcy were also found in about 15% of the group of patients with normal Schilling tests and without a morphological basis for cobalamin malabsorption. Moreover, most patients in this group responded with decreased values of the metabolite tests following cobalamin treatment, suggesting that neither elevated metabolites nor a decrease in these values following cobalamin treatment are specific for cobalamin deficiency.

3,4-Diaminopyridine (3,4-DAP) given alone or combined with pyridostigmine is the recommended basic therapy in the Lambert-Eaton myasthenic syndrome (LEMS). We present and exemplify our routine test protocol for monitoring drug introduction and treatment regimen of cholinergic drugs in LEMS. The individual drug responses vary and no recommended standard doses exist. Routine electrophysiological repetitive nerve stimulation studies recording amplitude of initial compound muscle action potential (CMAP) in thenar muscles correlate excellently with clinical myasthenic muscle power tests in clinically affected muscle groups. Therefore repetitive clinical muscle power tests, that often are complicated by painful myalgia and activation potentiation, can be replaced by recordings of CMAP in the introduction and clinical follow up of cholinergic drug treatment in LEMS. Also, adverse effects and other treatment problems from the experience of continuous treatment of 19 LEMS patients with 3,4-DAP for up to 10 years are presented.

Prognostic information is provided for 74 young adults (age 16-40 yrs, mean age at stroke 29.5 yrs), who suffered from ischemic stroke and survived the first month after the stroke. The patients were followed for 13-26 yrs; in total for 1190 yrs after their stroke. At follow-up 12 of the patients were dead, mostly from severe underlying disease that was complicated by ischemic stroke. In 3 cases death was unrelated to cerebrovascular disease. Among the surviving 62 patients, 7 had experienced recurrent ischemic events (3 reinfarctions, 4 TIA:s). These 7 patients all had risk factors for cerebrovascular complications already at the time of their primary stroke. It is concluded that the long-term prognosis for ischemic stroke in the young adult is favourable. The recovery from neurological deficits is usually good (exceptions are occlusions within the internal carotid and middle cerebral arteries), the risk for recurrence is low (1.1-1.2% annually), and the social prognosis with respect to working capacity and family relation is fair.

Brainstem hematoma is generally considered a very rare condition with a grave prognosis. This report presents two patients with extensive brainstem hematomas who both recovered without major sequele. A brainstem hematoma is often impossible to differentiate from an infarction despite angiographic and cerebrospinal fluid examinations, but is readily disclosed by computerized tomography. It is suggested that the seriousness of the prognosis in brainstem hematoma may earlier have been exaggerated as there may have been a tendency to classify cases exhibiting a good recovery as infarcts, while the diagnosis hematoma was reserved for cases verified at autopsy.

The literature on in vitro test of sensitivity to brain antigen in multiple sclerosis is summarized in the tables. A study is presented using leukocyte migration in agarose as test system and a wide range of concentration of bovine encephalitogenic protein as antigen. Definite reactivity was seen in 12 out of 28 patients with MS. Some occurred in patients who had had no signs of disease activity for at least 5 years. Reactivity occurred more often in patients with active disease studied within 5 days after a relapse. The significance of the in vitro reactivity is briefly discussed.

Sixty-four young adults (aged 16 to 40 years) with ischemic stroke were analyzed in retrospect with regard to possible pathogenetic mechanisms. In older patients various predisposing factors emerge (arterial hypertension, hyperlipidemia etc.) which are rare among younger age groups. In patients lacking predisposing causes the stroke incidence exhibits a seasonal variation. It is suggested that infection may be important for the development of ischemic stroke.

The report provides prognostic information on 60 patients (aged 16 to 40 years) with ischemic stroke. Immediate mortality from stroke is low and long-term mortality is due to other causes than cerebrovascular disease. The recovery from neurological deficits is good except for patients with occlusions of the internal carotic artery or the proximal parts of the middle cerebral artery. Reinfarction is rare (about 0.5 per cent annually) and other late neurological complications do not seriously affect long-term prognosis. More than 80 per cent of the patients will be able to resume work on a full or part-time basis.

The stretch reflex at rest and after muscle work was studied in three cases of Eaton Lambert syndrome. After muscle work a potentiation of the stretch reflex was demonstrated clinically and electrophysiologically. The presence of muscle stretch reflexes and their potentiation after muscle work was correlated with the clinical stage of the disease. The enhancement of the stretch reflex after voluntary effort was absent in normal subjects, myasthenia gravis and myotonic dystrophy.

We have extended the results from our previous investigation of the reactivity of leucocytes from patients with multiple sclerosis and some other neurological diseases to bovine encephalitogenic protein, using the migration in agarose technique. 1. Reactivity (i.e. behaviour in the test deviating from that expected with cells from healthy subjects) is manifested either as an enhancement or an inhibition of leucocyte migration. 2. The incidence of subjects with cells showing reactivity to encephalitogenic protein is higher in the group of patients with multiple sclerosis than in the group of patients with other neurological diseases. 3. Reactivity to encephalitogenic protein is correlated to disease course score; patients with a chronic progression of the disease show the strongest reactivity in the test. 4. The tryptophan-containing region of the encephalitogenic protein appears to be a major determinant of significance for this test. 5. Patients tested during corticotrophin treatment tend to show a higher degree of reactivity in the test than expected-the increased reactivity seems to be primarily directed to the tryptophan-containing region.

Brief episodes of neurological dysfunction may sometimes occur in an afebrile patient with no overt vascular disorder, nor any history of previous migraine. In such a case, the cerebrospinal fluid (CSF) may exhibit a predominantly lymphocytic pleocytosis with plasma cells and an increased protein content indicating a lesion of the blood-brain barrier. This syndrome of remitting hemispheric dysfunction is accompanied by migraine-like headache. The available evidence suggests that an aseptic meningitis is the triggering event.

Ten patients with MS were studied with leukocyte migration in agarose technique to detect changes in reactivity ot encephalitogenic protein in connexion with a relapse. Six showed significant reactivity within a few days after the relapse. It decreased or disappeared during the 2 weeks after the relapse, but sometimes reappeared and was found in tests performed 2-3 months later. Five patients with cerebral infarction were studied in a similar way--in three, marked reactivity was noted within a few days after the stroke; in these, reactivity decreased or disappeared in later tests. In the two other patients, reactivity appeared in the second and/or third test. The possbility of a reactivity as an epiphenomenon due to CNS tissue destruction is discussed, and the need for antigens with a more restricted specificity for such an analysis is stressed.

Seven patients with isolated spinal cord symptoms, and with evoked potential (EP) recordings and/or cerebrospinal fluid (CSF) findings supporting a demyelinating cause for their myelopathy, were examined with cervical and cranial magnetic resonance imaging (MRI). Lesions in the cervical spinal cord were detected in 6 of the patients, including 2 who also had disseminated lesions in the brain compatible with multiple sclerosis (MS). In one patient MRI of the cervical spinal cord was normal, while plaques were seen in the periventricular region of the brain and in the brain stem. Thus, in the 3 patients with cerebral plaques, MRI supported the diagnosis of MS by showing dissemination in space. In the remaining 4 patients MRI provided support for the diagnosis of MS by demonstrating the cervical spinal cord plaques while excluding other potential causes of myelopathy, such as spinal cord compression and intramedullary tumor.

The reactivity to three antigens: bovine encephalitogenic protein (EP), PPD, and tetanus toxoid, was studied with blood leukocytes from healthy humans using Clausen's (5) leukocyte migration in agarose technique. There is an obvious correlation between the reaction of EP (all concentrations studied) and to low concentrations of PPD; and between the reactivity to low concentrations of EP and low concentrations of tetanus toxoid. After vaccination with tetanus vaccine, a marked increase in reactivity to the toxoid sometimes occurred; at the same time, a marked reactivity to EP appeared. Various explanations are discussed: a true immunological cross-reactivity, that the correlations are due to a variability in individual response with respect to lymphokine production, and that BCG and tetanus vaccinations produce an adjuvant effect increasing a pre-existing low reactivity to EP.

Two patients with maysthenic syndrome apparently not associated with carcinoma were studied in detail with repetitive stimulation of motor nerves, single fibre electromyography and histology. One patient showed signs of widespread autonomic dysfunction and the other patient had multifocal CNS symptoms of unclear etiology. Both cases showed a marked improvement with guanidine treatment which could be documented by the electrophysiological investigations. Due to severe adverse effects of the guanidine treatment on kidney, pancreatic and bone marrow functions the drug had to be withdrawn. Edrophonium given intravenously caused a marked and longlasting improvement of the muscle weakness and of the neurophysiological parameters. The mechanism of action is suggested to be different from that seen in myasthenia gravis. Single fibre electromyography showed a marked increase of neuromuscular jitter and blockings which decreased with increasing innervation frequency. The morphological study showed a selective affection of type II (fast twitch) fibres, a finding which is suggested to be secondary to an impaired neuromuscular transmission in the type II motor units.

Electrocardiograms in young adults with ischaemic stroke were analysed for abnormalities within 24 h after the onset of symptoms. Fifteen patients out of 44 had some ECG abnormality, mainly ST-T changes, sinus tachycardia and minor disturbances of intraventricular conductance. In most cases the ECG abnormality could be attributed to some extracerebral cause. It is concluded that ischaemic brain lesion per se never, or very rarely, affects the electrocardiogram.

Compared with the mixed leukocyte reaction (MLR) between cells from healthy individuals, the MLR between cells from two patients with multiple sclerosis (MS) is, on average, reduced in strength. There is a tendency for the most marked reduction of MLR to occur when both or neither of the members in a tested pair carry HL-A7, and when cells from patients in a relatively early stage of the disease (short duration, relapses but no permanent disablement) are studied; especially when cells from these patients are used as reactor clels in the MLR. Repeated studies of the same cell combinations with varying intervals showed that when both members of the pair carry HL-A7,--and therefore have a large chance also to carry LD-7a--the MLR strength is relatively constant. When only one or neither of the members carry HL-A7, the strength of MLR varies considerably. Probably two different mechanisms exist in MLR impairment: similarity of LD genes, and "immunosuppressive" factors which can vary during the course of the disease.