Rheumatoid arthritis may be primarily associated with HLA-DR4 molecules sharing a particular sequence at residues 67–74

Genomic typing of in vitro amplified DNA with sequence-specific oligonucleotide (SSO) probes was performed for DRB1, DQA1, DQB1, DPA1 and DPB1 alleles in 54 random Norwegian rheumatoid arthritis (RA) patients and 181 healthy controls. DRB1 alleles encoding the serological specificity DR4 were found in 80% of the patients, compared to 34% of the controls (relative risk = 7.9, p less than 0.0001). All DR4-positive RA patients carried either DRB1*0401 (Dw4), 0404 (Dw14), or 0405 (Dw15), while no patients were found to carry DRB1*0402 (Dw10) or 0403 (Dw13). The frequency of the DRB1*0101 allele encoding DR1 was not increased, even among DR4-negative RA patients, and we were unable to detect any sharing of other class II alleles among DR4-negative patients. No contribution of any DQA1, DQB1, DPA1 or DPB1 alleles to RA susceptibility could be detected. The results suggest that in the Norwegian population RA is primarily associated with a shared sequence at residues 67-74 of the DR beta 1 chain, but only when this sequence is expressed on DR4 molecules.     

An enzyme-linked immunosorbent assay for the determination of the IgA subclass distribution of antigen-specific antibodies

An ELISA for the determination of the IgA subclass distribution of antigen-specific antibodies was developed using commercially available monoclonal anti-IgA1 anti-IgA2 subclass antibodies. Furthermore an anti-A2m allotype-specific antibody was included in the study. The specificity and sensitivity of the monoclonal anti-immunoglobulin antibodies used was analyzed using sera from normal and IgA class- or subclass-deficient individuals (with or without homozygous C alpha 1 subclass gene deletions). Human IgA1 and IgA2 hybridoma antibodies were also used. In this particular assay, only two out of four tested anti-IgA1 and two out of three tested anti-IgA2 antibodies proved to be specific for their corresponding IgA subclass. The anti-A2m(2) monoclonal antibody was shown to be specific for the corresponding allotype. These ELISA methods may facilitate further work on the regulation of IgA subclass production in man.     

Behavioural effects of human fetal dopamine neurons grafted in a rat model of Parkinson's disease

Summary The ventral mesencephalon, containing the developing dopaminergic neurons of the substantia nigra-ventral tegmental region, was obtained from aborted human fetuses of 9–19 weeks of gestation. The tissue was grafted into the striatum of rats previously subjected to a 6-hydroxydopamine lesion of the mesostriatal dopamine pathway. The graft recipients were immunosuppressed by daily injections of Cyclosporin A. Amphetamine-induced motor asymmetry was reduced, and finally totally reversed, only in rats receiving grafts from the 9-week old fetal donor. The fluorescence microscopic analysis revealed large numbers of surviving dopamine neurons, and extensive fiber outgrowth into the host striatum, in these rats. By contrast, rats receiving grafts from 11–19 week old donors had at most only few surviving dopamine neurons. These results indicate that human fetal mesencephalic tissue may be an efficient source of dopamine neurons for functional intracerebral grafting in patients with Parkinson's disease.A preliminary account of some of the results from this study was presented at the New York Academy of Sciences meeting on Cell and tissue transplantation into the adult brain, New York, April 4, 1986     

Functional maturity of cord blood B lymphocytes: Staphylococcus aureus Cowan 1 induces IgG secretion in the human neonate

Lymphocytes from newborn infants and adults were investigated with the polyclonal B cell activators Staphylococcus aureus Cowan 1, soluble protein A, and pokeweed mitogen (PWM). In cord blood lymphocytes (CBL), protein A and PWM induced only meagre IgM responses, whereas Cowan 1 bacteria induced synthesis of both IgM and IgG in quantities comparable to adult levels. We were also able to establish the neonatal origin of the Ig producing cells. Thus, cord blood lymphocytes seem to be functionally mature enough to produce any Ig class, provided they are given the right stimulus.     

The use of proteomics in biomarker discovery in neurodegenerative diseases

Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF), which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein, beta-amyloid (1-42), synaptic proteins, amyloid precursor protein (APP), apolipoprotein E (apoE), which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD). Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of both beta-amyloid (1-42), total-tau, and phosphorylated tau, where a combination of low levels of CSF-beta-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.     

Ca2+–calmodulin-dependent protein kinase expression and signalling in skeletal muscle during exercise

Ca²⁺ signalling is proposed to play an important role in skeletal muscle function during exercise. Here, we examined the expression of multifunctional Ca²⁺–calmodulin-dependent protein kinases (CaMK) in human skeletal muscle and show that CaMKII and CaMKK, but not CaMKI or CaMKIV, are expressed. Furthermore, the effect of exercise duration and intensity on skeletal muscle CaMKII activity and phosphorylation of downstream targets was examined. Eight healthy men exercised at ∼67% of peak pulmonary O₂ uptake     with muscle samples taken at rest and after 1, 10, 30, 60 and 90 min of exercise. Ten other men exercised for three consecutive 10 min bouts at 35%, 60% and 85%     with muscle samples taken at rest, at the end of each interval and 30 min post-exercise. There was a rapid and transient increase in autonomous CaMKII activity and CaMKII phosphorylation at Thr²⁸⁷ in skeletal muscle during exercise. Furthermore, the phosphorylation of phospholamban (PLN) at Thr¹⁷, which was identified as a CaMKII substrate in skeletal muscle, was rapidly (< 1 min) increased by exercise, and remained phosphorylated 5-fold above basal level during 90 min of exercise. The phosphorylation of serum response factor at Ser¹⁰³, a putative CaMKII substrate, was higher after 30 min of exercise. PLN phosphorylation at Thr¹⁷ was higher with increasing exercise intensities. These data indicate that CaMKII is the major multifunctional CaMK in skeletal muscle and its activation occurs rapidly and is sustained during continuous exercise, with the activation being greater during intense exercise.     

Ventilatory response to oscillating and non-oscillatingPa CO 2 in the anesthetized cat

Summary In 11 adult cats, lightly anesthetized with chloralose-urethane, blood from both common carotid arteries was led into a plastic chamber of 15–20 ml and returned to the carotids at a point 1.5 cm more cranial. By doing so arterial blood was assumed to pool within the chamber and lose itsP _{CO 2} oscillations which are normally known to exist as a result of the respiratory cycle. In control periods blood bypassed the chamber, thus maintaining respiratoryP _{CO 2} oscillations. Spontaneous ventilation was measured spirometrically. The animals were breathing pure O₂.Results. 1. When the sinus (carotid) nerves were intact or sectioned there was no significant difference in ventilation before or after switching from non-oscillating to oscillatingPa _{CO 2}. 2. When the vertebral arteries were ligated a drop in ventilation occurred after turning to oscillatingPa _{CO 2} which was followed by a slight rise above control values after 30–50 sec. This phenomenon was independent of sinus nerve integrity. Thus in hyperoxie condition the smallPa _{CO 2} oscillations known to occur in phase with respiration do not seem to provide a respiratory stimulus to resting ventilation above that generated by the mean level ofPa _{CO 2}. The ventilatory depression after vertebral artery ligation must at this time remain unexplained.     

Increase of fetal arterial blood temperature by reduction of umbilical blood flow in chronically instrumented fetal sheep

The effect of reduced umbilical blood flow rate on fetal core temperature was investigated in five chronically instrumented fetal sheep (gestational age 124 days). On average, fetal-maternal temperature difference increased 0.13±0.02 °C when blood flow rate was decreased to about 1/3 of normal (248±69 ml min^–1) for 30 min. The small temperature rise is the consequence of predominant heat dissipation through the placenta, and of diminished oxygen consumption.     

Effect of arm-shoulder fatigue on carpenters at work

Summary The purpose of the study was to analyse the effect of arm-shoulder fatigue on manual performance. Ten experienced carpenters performed three standardized tasks (nailing, sawing and screwing). Electromyographic activity was recorded from six arm-shoulder muscles and the performances were video-filmed. After 45 min of standardized arm-cranking (arm-shoulder-fatiguing exercise of approximately 70%–80% maximal oxygen consumption), the tasks were repeated. The number of work movements and the time taken for each task were recorded and the quality of the work performed was compared. After the fatiguing exercise, only nailing was perceived as being harder and more mistakes were made during nailing and sawing. Movement performance was not influenced during nailing but was slightly slower during sawing and faster during screwing. However, there were increased mean EMG amplitudes in the upper trapezius and biceps muscles during nailing, in the upper trapezius, anterior deltoid and infraspinatus muscles during sawing and in the anterior deltoid muscle during screwing. Of the muscles studied the upper trapezius and anterior deltoid muscles increased their activity most after the arm-shoulder-fatiguing exercise.     

Current Biotechnological Approaches to the Prevention of Restenosis

No systemic pharmacological treatment has been convincingly shown to reduce the incidence of restenosis after angioplasty in patients. The lack of success of many pharmaceutical agents in reducing restenosis rates post-angioplasty and following stent implantation, as documented in dozens of clinical trials, has encouraged the development of new biotechnological approaches to the treatment of restenosis. Gene therapy and other agents, including antibodies, fusion toxins and ribozymes, have the potential to prevent some of the sequelae after arterial injury, particularly cell proliferation. Mechanical methods of preventing restenosis, for example sophisticated local drug delivery strategies and biodegradable stents using new materials, in combination with novel therapeutic agents or radiation, may also be of use.