VARIATION AND TYPE SPECIFICITY IN THE BACTERIAL SPECIES HEMOPHILUS INFLUENZAE

During the course of a study of different strains of influenza bacilli, fifteen strains have been found to form colonies of a different appearance from that usually considered typical of influenza bacilli. These colonies are smooth, more opaque, and are iridescent in oblique transmitted light. Most of these strains were isolated from patients in whom these organisms seemed to play a pathogenic rô1e. When these strains were grown repeatedly on blood agar, other colonies appeared which were smaller, less smooth, less opaque, and not iridescent, and when subcultures were made from these rough colonies, all of the colonies were of this character. Further study of the cultures obtained from these smooth and rough colonies have shown that one is a variant of the other. The strain from the smooth colony has been called an S strain, that from the rough colony an R strain. Certain differences in the morphology of the organisms in the R and S strains have been observed. Of special importance is the fact that the bacteria of the S strains are possessed of capsules. It has also been found that the S strains are somewhat more virulent for laboratory animals than are the R strains. In the supernatant fluid of broth cultures of S strains, and in the washing fluid of S bacteria grown on agar, there is present a soluble substance which, in the presence of homologous immune serum, gives rise to a precipitate. No reaction of this kind, however, occurs with the cultures of the R strains. By means of cross precipitin reactions, employing antisera against the different S strains, it has been found that the fifteen strains studied may be divided into two distinct immunological groups. Three of these strains belong in one group, Type a, and the remaining twelve in another group, Type b. Seven of the strains studied were isolated from the spinal fluid in cases of meningitis, and all of these strains are of Type b. Agglutination tests performed at 37°C. with these fifteen S strains have revealed the same specific type relationships among the organisms as did the precipitin tests. The R strains on the other hand, exhibit no similar type agglutinations. If the agglutination tests are made at a higher temperature, 47°C., the S strains also fail to show the specific type reactions which occur at 37°C. Certain differences between other biochemical reactions exhibited by the two types of strains have been noted, but it is not believed that they are sufficiently constant to be of great significance. When S strains are grown on artificial media outside the animal body, they tend to be converted into the R form. The rapidity and the readiness with which this conversion occurs depend on certain conditions, such as the kind of media employed, the temperature at which the cultures are kept, and the atmospheric conditions under which they are cultivated. The rate of conversion is increased when the S strains are grown in media containing anti-S immune serum of the homologous type. On the other hand, conversion of R strains into the S form occurs with much less readiness, and then only if very particular conditions are present. On one occasion conversion occurred when an R strain was grown in a medium containing anti-R immune serum. On two other occasions this same strain changed from the R to the S form during passage through animals. With other R strains it has so far been impossible to bring about this transformation. These studies indicate that the bacteria belonging in the group Hemophilus influenzae exhibit changes in pathogenicity and immunological specificity, which are analogous to those shown by the bacteria of the pneumococcus group. It is important to continue this study, with the technique which has been developed, to include a much larger number of strains. On account of the readiness with which the S strains of influenza bacilli lose their type specificity when grown on artificial culture media, it is important that the organisms be studied as soon as possible after removal from their pathological sources. It is not impossible that many strains lose their specificity immediately after removal from the host, and that the specific immunological differentiation of many strains may, for that reason, be very difficult, if not impossible.     

First-time anterior shoulder dislocations: should they be arthroscopically stabilised?

The glenohumeral joint is inherently unstable because the large humeral head articulates with the small shadow glenoid fossa. Traumatic anterior dislocation of the shoulder is a relatively common athletic injury, and the high frequency of recurrent instability in young athletes after shoulder dislocation is discouraging to both the patient and the treating physician. Management of primary traumatic shoulder dislocation remains controversial. Traditionally, treatment involves initial immobilisation for 4–6 weeks, followed by functional rehabilitation. However, in view of the high recurrence rates associated with this traditional approach, there has been an escalating interest in determining whether immediate surgical intervention can lower the rate of recurrent shoulder dislocation, improving the patient’s quality of life. This review article aims to provide an overview of the nature and pathogenesis of first-time primary anterior shoulder dislocations, the widely accepted management modalities, and the efficacy of primary surgical intervention in first-time primary anterior shoulder dislocations.     

Prevention and treatment of pressure ulcers/injuries: The protocol for the second update of the international Clinical Practice Guideline 2019

Aim

The European Pressure Ulcer Advisory Panel, the Pan Pacific Pressure Injury Alliance, and the National Pressure Ulcer Advisory Panel are updating the ‘Prevention and Treatment of Pressure Ulcers: Clinical Practice Guideline’ (CPG) in 2019. The aim of this contribution is to summarize and to discuss the guideline development protocol for the 2019 update.

Metabolism of native and of lactosylated human low density lipoprotein: evidence for two pathways for catabolism of exogenous proteins in rat hepatocytes.

Human low density lipoprotein (LDL) covalently conjugated with 200-250 residues of lactose per LDL particle (Lac-LDL) was bound and rapidly taken up by the galactose-specific receptor of rat hepatocytes. Uptake of Lac-LDL was associated with inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase and stimulation of cholesterol esterification. Uptake of native human LDL had no significant effects on these enzyme activities even when the rates of LDL uptake equaled those of Lac-LDL. When injected into rats, Lac-LDL was selectively removed by the liver (98% of injected dose). The hepatic subcellular distribution of simultaneously injected native 125I-labeled LDL and 131I-labeled Lac-LDL differed significantly, Lac-LDL was associated with fractions enriched in lysosomal hydrolases whereas native LDL was found predominantly in the supernatant fraction enriched in lactate dehydrogenase. Chloroquine (0.1 mM) markedly suppressed uptake of Lac-LDL by cultured rat hepatocytes (> 80%) but had only a small effect on uptake of native LDL. Leupeptin (0.625 mM) inhibited degradation of Lac-LDL more than it did degradation of native LDL. Colchicine (0.25 microM) dramatically suppressed uptake of Lac-LDL (> 70%) but did not affect native LDL uptake even at concentrations as high as 10 microM. Uptake of human LDL by rat hepatocytes occurs largely by nonspecific mechanisms, including fluid endocytosis, whereas Lac-LDL, as shown here, is taken up by a specific receptor-mediated mechanism. The results show further that native human LDL, representing an example of a protein taken up nonspecifically, is processed intracellularly by a pathway qualitatively distinct from that for Lac-LDL, an example of a protein taken up by a specific mechanism. Lac-LDL may serve as a vehicle for specifically delivering drugs, hormones, or radioactive compounds to hepatocytes for therapeutic or diagnostic purposes.     

GWAS with longitudinal phenotypes: performance of approximate procedures

Analysis of genome-wide association studies with longitudinal data using standard procedures, such as linear mixed model (LMM) fitting, leads to discouragingly long computation times. There is a need to speed up the computations significantly. In our previous work (Sikorska et al: Fast linear mixed model computations for genome-wide association studies with longitudinal data. Stat Med 2012; 32.1: 165–180), we proposed the conditional two-step (CTS) approach as a fast method providing an approximation to the P-value for the longitudinal single-nucleotide polymorphism (SNP) effect. In the first step a reduced conditional LMM is fit, omitting all the SNP terms. In the second step, the estimated random slopes are regressed on SNPs. The CTS has been applied to the bone mineral density data from the Rotterdam Study and proved to work very well even in unbalanced situations. In another article (Sikorska et al: GWAS on your notebook: fast semi-parallel linear and logistic regression for genome-wide association studies. BMC Bioinformatics 2013; 14: 166), we suggested semi-parallel computations, greatly speeding up fitting many linear regressions. Combining CTS with fast linear regression reduces the computation time from several weeks to a few minutes on a single computer. Here, we explore further the properties of the CTS both analytically and by simulations. We investigate the performance of our proposal in comparison with a related but different approach, the two-step procedure. It is analytically shown that for the balanced case, under mild assumptions, the P-value provided by the CTS is the same as from the LMM. For unbalanced data and in realistic situations, simulations show that the CTS method does not inflate the type I error rate and implies only a minimal loss of power.     

Clonal dysregulation of the antibody response to tetanus-toxoid after bone marrow transplantation

After bone marrow transplantation (BMT), a prolonged dysregulation of humoral immunity can be observed. In the present study, we investigated whether this is reflected in an abnormal production of specific antibodies (Ab) to the T-cell-dependent recall antigen tetanus-toxoid (TT). The study group consisted of children receiving transplants of an unmodified allogeneic graft and of adults receiving either a T-cell- depleted allogeneic or an unmodified autologous BM graft. Findings were compared with those in healthy controls. In pediatric graft recipients, who were routinely revaccinated early after BMT, the Ab response was quantitatively superior to that in adult graft recipients who did not receive early revaccination. In the majority of graft recipients, the time period after vaccination required to reach the peak level of antibodies was prolonged and the number of responding TT-specific B- cell clones was markedly decreased in comparison with controls. In controls, a low frequency of dominant B-cell clones may produce low quantities of homogeneous Ab components (H-Ab) against a heterogeneous background. However, in BM graft recipients, "overshooting" of Ab production by separate B-cell clones was observed, resulting in the development of H-Ab at a relatively high concentration. These abnormalities were present up to 10 years after BMT, irrespective of either the age of the recipient, the modulation of the graft, or the vaccination schedule used. It is hypothesized that the dysregulated Ab production is the consequence of activation of a restricted number of resting memory B cells, present in germinal centers, repopulating gradually after BMT. Our data show that routine revaccination early after BMT improves the humoral immune response. However, because of a clonally dysregulated Ab production, long-lasting qualitative defects may be present even after normalization of Ab titers.     

Group Cognitive Rehabilitation and Exposure/Sorting Therapy: A Pilot Program

While cognitive-behavioral therapy for hoarding disorder (HD) has resulted in significant reductions in symptoms, most individuals continue to have significant hoarding symptoms following treatment. This investigation sought to extend the literature on the behavioral treatments for hoarding by examining (1) group cognitive rehabilitation and exposure/sorting therapy (CREST) and (2) group exposure therapy (ET) for hoarding. Participants in both studies reported significant decreases in hoarding symptom severity from baseline to post-treatment on all primary outcome measures using mixed-effects linear regression models with the intent to treat sample. Participants who received group CREST reported statistically significant reductions in anxiety, depression, and overall severity at post-treatment, while participants who received group ET did not. Results provide preliminary evidence for both group CREST and group ET as effective treatments for hoarding disorder.     

Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine

Some schizophrenia patients are more sensitive to amphetamine (AMPH)-induced exacerbations in psychosis–an effect that correlates with higher striatal dopamine release. This enhanced vulnerability may be related to gamma-aminobutyric acid (GABA) deficits observed in schizophrenia. We hypothesized that a pharmacologically induced GABA deficit would create vulnerability to the psychotomimetic effects to the ‘subthreshold'' dose of AMPH in healthy subjects, which by itself would not induce clinically significant increase in positive symptoms. To test this hypothesis, a GABA deficit was induced by intravenous infusion of iomazenil (IOM; 3.7 μg/kg), an antagonist and partial inverse agonist of benzodiazepine receptor. A subthreshold dose of AMPH (0.1 mg/kg) was administered by intravenous infusion. Healthy subjects received placebo IOM followed by placebo AMPH, active IOM followed by placebo AMPH, placebo IOM followed by active AMPH, and active IOM followed by active AMPH in a randomized, double-blind crossover design over 4 test days. Twelve healthy subjects who had a subclinical response to active AMPH alone were included in the analysis. Psychotomimetic effects (Positive and Negative Syndrome Scale (PANSS)), perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)), and subjective effects (visual analog scale) were captured before and after the administration of drugs. IOM significantly augmented AMPH-induced peak changes in PANSS positive symptom subscale and both subjective and objective CADSS scores. There were no pharmacokinetic interactions. In conclusion, GABA deficits increased vulnerability to amphetamine-induced psychosis-relevant effects in healthy subjects, suggesting that pre-existing GABA deficits may explain why a subgroup of schizophrenia patients are vulnerable to AMPH.