Insufficient Evidence for Load as the Primary Cause of Nonspecific (Chronic) Low Back Pain. A Scoping Review.

OBJECTIVE: To assess the causal role of the relationship between loading and the onset of nonspecific low back pain (NSLBP) and persistence of NSLBP (chronic low back pain [CLBP]). DESIGN: Scoping review. LITERATURE SEARCH: We searched the literature from 2010 until May 2021 using a combination of terms related to (spinal) load and the Bradford-Hill (BH) criteria. STUDY SELECTION CRITERIA: Operational definitions were developed for every criterion of the BH framework for causality. Study selection was based on the causal role of load in the onset of NSLBP and persistence of chronic low back pain. DATA SYNTHESIS: The BH criteria were operationalized, and causation was considered established when evidence supported the BH criteria strength, temporality, biological gradient, experiment, and biological plausibility. RESULTS: Twenty-two studies were included. There was no consistent support for an association between load and the incidence of NSLBP, or that more load increased the risk of NSLBP/CLBP. Half of the studies did not support specific load exposures to increase incidence of or increase pain in NSLBP/CLBP. Half of studies did not support load preceding NSLBP. No study supported plausible biological explanations to influence the relationship between load and NSLBP/CLBP, or that similar causes have similar effects on NSLBP. Nine of 10 experimental studies did not support that load results in NSLBP or that relieving load reduces NSLBP/CLBP. CONCLUSION: There was insufficient evidence to support a causal relationship between loading and the onset and persistence of NSLBP/CLBP based on the BH criteria. These results question the role of load management as the only/primary strategy to prevent onset and persistence of NSLBP/CLBP. J Orthop Sports Phys Ther 2024;54(3):1-15. Epub 25 January 2024. doi:10.2519/jospt.2024.11314.

Legionella longbeachae; don't miss it!

We here report on two immunocompetent patients admitted to our hospital within 3 weeks' time, both suffering from pneumonia caused by Legionella longbeachae (L. longbeachae). The pathogen was identified in broncho-alveolar lavage (BAL) liquid by Polymerase Chain Reaction (PCR), whereas sputum cultures remained negative. This organism is worldwide still relatively unknown and consequently underdiagnosed. However, with an increasing number of confirmed infections in Europe and more specifically in the Netherlands, early awareness and diagnostic measurements are indicated. As routine laboratory techniques like the urine antigen test do not detect L. longbeachae, we advocate early use of specific tests for non-pneumophila Legionella species such as PCR. Furthermore, we advocate the start of empirical antibiotic therapy (i.e. ciprofloxacin) and continuation in suspected cases.

Hypomorphic Rag1 mutations alter the preimmune repertoire at early stages of lymphoid development.

Hypomorphic RAG1 mutations allowing residual T- and B-cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T- and B-cell repertoire. To examine how hypomorphic Rag1 mutations affect the earliest stages of lymphocyte development, we used CRISPR/Cas9 to generate mouse models with mutations equivalent to those found in patients with CID-G/AI. Immunological characterization showed partial development of T and B lymphocytes, with persistence of naïve cells and preserved serum immunoglobulin but impaired antibody responses and presence of autoantibodies, thereby recapitulating the phenotype seen in patients with CID-G/AI. By using high-throughput sequencing, we identified marked skewing of Igh V and Trb V gene usage in early progenitors, with a bias for productive Igh and Trb rearrangements after selection occurred and increased apoptosis of B-cell progenitors. Rearrangement at the Igk locus was impaired, and polyreactive immunoglobulin M antibodies were detected. This study provides novel insights into how hypomorphic Rag1 mutations alter the primary repertoire of T and B cells, setting the stage for immune dysregulation frequently seen in patients.

Designing nucleosomal force sensors.

About three quarters of our DNA is wrapped into nucleosomes: DNA spools with a protein core. It is well known that the affinity of a given DNA stretch to be incorporated into a nucleosome depends on the geometry and elasticity of the basepair sequence involved, causing the positioning of nucleosomes. Here we show that DNA elasticity can have a much deeper effect on nucleosomes than just their positioning: it affects their "identities". Employing a recently developed computational algorithm, the mutation Monte Carlo method, we design nucleosomes with surprising physical characteristics. Unlike any other nucleosomes studied so far, these nucleosomes are short-lived when put under mechanical tension whereas other physical properties are largely unaffected. This suggests that the nucleosome, the most abundant DNA-protein complex in our cells, might more properly be considered a class of complexes with a wide array of physical properties, and raises the possibility that evolution has shaped various nucleosome species according to their genomic context.

Perioperative hospital mortality at a tertiary paediatric institution.

BACKGROUND: Research in postoperative mortality is scarce. Insight into mortality and cause of death might improve and innovate perioperative care. The objective for this study was to report the 24-hour and 30-day overall, and surgery and anaesthesia-related, in-hospital mortality at a tertiary paediatric hospital. METHODS: All patients <18 yr old who underwent anaesthesia with or without surgery between January 1, 2006, and December 31, 2012, at the Wilhelmina Children's Hospital, Utrecht, The Netherlands, were included in this retrospective cohort study. Causes of death within 30 days were identified and tabulated into four major categories according to principal cause. RESULTS: A total of 45,182 anaesthetics were administered during this 7-yr period. The all-cause 24-hour hospital mortality was 13.1 per 10,000 anaesthetics (95% CI: 9.9-16.8) and the all-cause 30-day in-hospital mortality was 41.6 per 10,000 anaesthetics (95% CI: 35.9-48.0). In total five patients were partially contributable to anaesthesia (30-day mortality: 1.1/10,000, 95% CI: 0.4-2.6) and four patients were partially contributable to surgery (30-day mortality: 0.9/10,000, 95% CI: 0.2-2.3). Mortality was higher in neonates and infants, children with ASA physical status III and IV, and emergency- and cardiothoracic surgery. CONCLUSIONS: Neonates and infants, children with ASA physical status III or poorer, and emergency- and cardiothoracic surgery are associated with a higher postoperative mortality. Anaesthesia- or surgery-related complications contribute to mortality in only a small amount of the deaths, indicating the relative safety of paediatric surgical and anaesthetic procedures.

Lack of claudin-7 is a strong predictor of regional recurrence in oral and oropharyngeal squamous cell carcinoma.

OBJECTIVES: Adequate treatment of oral and oropharyngeal squamous cell carcinoma (OSCC) is dependent on correctly predicting the presence of lymph node metastases. Current methods to diagnose nodal metastases partly result in overtreatment with associated morbidity and undertreatment with decreased disease-free survival. E-cadherin has been studied extensively as potential marker for lymph node metastases. EpCAM and claudin-7 have a functional relationship with E-cadherin, forming a complex that promotes tumourigenicity in vitro. We hypothesize that the co-expression patterns of these related molecules is a better prognostic marker for nodal status and regional recurrences. MATERIALS AND METHODS: We constructed separate tissue microarrays of tumour centre and tumour invasive front of 227 OSCC with complete clinicopathological and follow-up data, including HPV status, and performed immunohistochemistry for these molecules. RESULTS: Lack of E-cadherin and presence of cytoplasmic EpCAM expression in the tumour front were predictive for nodal metastasis, but no co-expression pattern was found clinically relevant. Lack of claudin-7 in the tumour centre was highly and independently predictive for shorter regional disease-free survival (HR=0.19; 95%CI: 0.06-0.62) and disease-specific survival (HR=0.43; 95%CI: 0.21-0.87). High-risk HPV was not associated with any marker. CONCLUSIONS: The expression of E-cadherin and EpCAM, depending on the specific tumour sublocalization, is predictive for nodal status. However, co-expression did not improve the prediction of nodal status, indicating that the proposed in vitro complex is not functional in clinical samples. Additionally, lack of claudin-7 expression in the tumour centre may be used to identify patients with increased risk for regional recurrence.

Microbial diversity differences within aerobic granular sludge and activated sludge flocs.

In this study, we investigated during 400 days the microbial community variations as observed from 16S DNA gene DGGE banding patterns from an aerobic granular sludge pilot plant as well as the from a full-scale activated sludge treatment plant in Epe, the Netherlands. Both plants obtained the same wastewater and had the same relative hydraulic variations and run stable over time. For the total bacterial population, a similarity analysis was conducted showing that the community composition of both sludge types was very dissimilar. Despite this difference, general bacterial population of both systems had on average comparable species richness, entropy, and evenness, suggesting that different bacteria were sharing the same functionality. Moreover, multi-dimensional scaling analysis revealed that the microbial populations of the flocculent sludge system moved closely around the initial population, whereas the bacterial population in the aerobic granular sludge moved away from its initial population representing a permanent change. In addition, the ammonium-oxidizing community of both sludge systems was studied in detail showing more unevenness than the general bacterial community. Nitrosomonas was the dominant AOB in flocculent sludge, whereas in granular sludge, Nitrosomonas and Nitrosospira were present in equal amounts. A correlation analysis of process data and microbial data from DGGE gels showed that the microbial diversity shift in ammonium-oxidizing bacteria clearly correlated with fluctuations in temperature.

An association account of false belief understanding.

The elicited-response false belief task has traditionally been considered as reliably indicating that children acquire an understanding of false belief around 4 years of age. However, recent investigations using spontaneous-response tasks suggest that false belief understanding emerges much earlier. This leads to a developmental paradox: if young infants already understand false belief, then why do they fail the elicited-response false belief task? We postulate two systems to account for the development of false belief understanding: an association module, which provides infants with the capacity to register congruent associations between agents and objects, and an operating system, which allows them to transform these associations into incongruent associations through a process of inhibition, selection and representation. The interaction between the association module and the operating system enables infants to register increasingly complex associations on the basis of another agent's movements, visual perspective and propositional attitudes. This allows us account for the full range of findings on false belief understanding.

Vaccination in paediatric patients with auto-immune rheumatic diseases: a systemic literature review for the European League against Rheumatism evidence-based recommendations.

OBJECTIVES: To analyze available evidence on vaccinations in paediatric patients with rheumatic and autoinflammatory diseases. This evidence formed the basis of the recently constructed European League against Rheumatism (EULAR) recommendations for vaccination of these patients. METHODS: A systematic literature review in the MEDLINE and EMBASE databases was conducted using various terms for vaccinations, paediatric rheumatic and autoinflammatory diseases and immunosuppressive drugs. Only papers on paediatric patients (<18 years of age) were selected. A panel of 13 experts in the field graded methodological quality and extracted data using predefined criteria. RESULTS: 27 papers were available. No studies were found on autoinflammatory diseases. 14 studies considered live-attenuated vaccines. Evidence so far supports the safety and immunogenicity of non-live composite vaccines, although studies were underpowered to accurately assess safety. Live-attenuated vaccines did not cause disease flares or severe adverse events, not even in patients on methotrexate and low dose glucocorticosteroids. Seven patients on anti-TNFalpha therapy were described receiving the live-attenuated measles, mumps, rubella (n=5) or varicella (n=2) booster without severe adverse events. CONCLUSIONS: Data on safety and efficacy of vaccinations in paediatric patients with rheumatic diseases is reassuring, but too limited to draw definite conclusions. More research is needed on the safety and efficacy of especially live-attenuated vaccines in patients with rheumatic and autoinflammatory diseases using high dose immunosuppressive drugs.

EULAR recommendations for vaccination in paediatric patients with rheumatic diseases.

Evidence-based recommendations for vaccination of paediatric patients with rheumatic diseases (PaedRD) were developed by following the EULAR standardised procedures for guideline development. The EULAR task force consisted of (paediatric) rheumatologists/immunologists, one expert in vaccine evaluation, one expert in public health and infectious disease control, and one epidemiologist. A systematic literature review was conducted in MEDLINE, EMBASE, and abstracts of the EULAR and American College of Rheumatology meetings of 2008/9. The level of evidence and strength of recommendation were based on customary scoring systems. Delphi voting was applied to assess the level of agreement between task force members. 107 papers and eight abstracts were used. The majority of papers considered seasonal influenza (41) or pneumococcal (23) vaccination. 26 studies were performed specifically in paediatric patients, and the majority in adult rheumatoid arthritis and systemic lupus erythematosus patients. Fifteen recommendations were developed with an overall agreement of 91.7%. More research is needed on the safety and immunogenicity of (live-attenuated) vaccination in PaedRD, particularly in those using biologicals, and the effect of vaccination on prevention of infections.

Selective sludge removal in a segregated aerobic granular biomass system as a strategy to control PAO-GAO competition at high temperatures.

An aerobic granular sludge (AGS) reactor was run for 280 days to study the competition between Phosphate and Glycogen Accumulating Organisms (PAOs and GAOs) at high temperatures. Numerous researches have proven that in suspended sludge systems PAOs are outcompeted by GAOs at higher temperatures. In the following study a reactor was operated at 30 °C in which the P-removal efficiency declined from 79% to 32% after 69 days of operation when biomass removal for sludge retention time (SRT) control was established by effluent withdrawal. In a second attempt at 24 °C, efficiency of P-removal remained on average at 71 ± 5% for 76 days. Samples taken from different depths of the sludge bed analysed using Fluorescent in situ hybridization (FISH) microscopy techniques revealed a distinctive microbial community structure: bottom granules contained considerably more Accumulibacter (PAOs) compared to top granules that were dominated by Competibacter (GAOs). In a third phase the SRT was controlled by discharging biomass exclusively from the top of the sludge bed. The application of this method increased the P-removal efficiency up to 100% for 88 days at 30 °C. Granules selected near the bottom of the sludge bed increased in volume, density and overall ash content; resulting in significantly higher settling velocities. With the removal of exclusively bottom biomass in phase four, P-removal efficiency decreased to 36% within 3 weeks. This study shows that biomass segregation in aerobic granular sludge systems offers an extra possibility to influence microbial competition in order to obtain a desired population.

Aerobic granular sludge technology: an alternative to activated sludge?

Laboratory experiments have shown that it is possible to cultivate aerobic granular sludge in sequencing batch reactors. In order to direct future research needs and the critical points for successful implementation at large scale, a full detailed design of a potential application was made. The design was based on the laboratory results, and two variants of a full-scale sewage treatment plant based on Granular sludge Sequencing Batch Reactors (GSBRs) were evaluated. As a reference a conventional treatment plant based on activated sludge technology was designed for the same case. Based on total annual costs both GSBR variants proved to be more attractive than the reference alternative (7-17% lower costs). From a sensitivity analysis it appeared that the GSBR technology was less sensitive to the land price and more sensitive to a rain weather flow (RWF). This means that the GSBR technology becomes more attractive at lower permissible RWF/DWF ratios and higher land prices. The footprint of the GSBR variants was only 25% compared to the reference. However, the GSBR with primary treatment only cannot meet the present effluent standards for municipal wastewater in The Netherlands, mainly because of a too high suspended solids concentration in the effluent. A growing number of sewage treatment plants in the Netherlands are going to be faced with more stringent effluent standards. In general, activated sludge plants will have to be extended with a post treatment step (e.g. sand filtration) or be transformed into Membrane Bioreactors. In this case a GSBR variant with primary treatment as well as post treatment can be an attractive alternative.

Tumorigenic behaviour of c-Ha-ras oncogene transfected CaCo 2 cells is associated with increased proteolytic potency.

BACKGROUND: Point mutations within the family of the ras genes are detected in approximately 50% of human colorectal adenomas and carcinomas. Therefore, it is generally accepted that the occurrence of ras-point mutations constitute an important step in colorectal carcinogenesis. In addition, many studies have demonstrated that the tumorigenicity of the human colorectal carcinoma cell line, CaCo 2, strongly increases after transfection with the c-Ha-ras oncogene. This cell line is suitable for gaining more insight into the mechanism of c-Ha-ras induced tumorigenesis. MATERIAL AND METHODS: Proliferation, differentiation, and proteolytic capacity of c-Ha-ras oncogene transfected CaCo 2 cells were studied in vitro. RESULTS: It was found that gelatinolytic capacity and production of urokinasetype plasminogen activator increased, whereas the production of tissue-type plasminogen activator was similar. Proliferative activity, as measured by the potential doubling time, did not alter. The expression of the differentiation markers sucraseiso-maltase, mucin, and chromogranin A was not different from that of the parental CaCo 2 cell line, which indicates that an increased tumorigenic capacity of c Ha-ras oncogene transfected CaCo 2 cells is not accompanied by loss of differentiation. CONCLUSION: These data demonstrate that the highly increased tumorigenic capacity of c Ha-ras oncogene-transfected CaCo 2 cells is associated with an enchanced proteolytic capacity.

Heat shock improves ischemic tolerance of hypertrophied rat hearts.

The postischemic recovery of hypertrophied hearts was studied 24 h after total body hyperthermia. To this end, anesthetized aortic-banded and sham-operated rats were subjected to heat shock (AoBHS and ShamHS, respectively). Cardiac hypertrophy was induced 8 wk earlier. In isolated ejecting hearts, functional recovery after 45 min of global ischemia was poor and moderate in nonheated (control) hypertrophied (AoBC) and nonheated (control) nonhypertrophied (ShamC) hearts, respectively. Heat shock significantly improved postischemic recovery in both AoBHS and ShamHS hearts. This improvement of functional recovery was associated with a significant reduction of the duration of arrhythmias. In addition, coronary flow was significantly higher in both types of heat-shocked hearts than in the corresponding control hearts during the preischemic as well as the postischemic period. Postischemic endocardial flow, assessed using radioactive microspheres, was significantly improved in AoBHS hearts. Compared with the corresponding control hearts, the native endogenous catalase activity was not changed in AoBHS hearts but was significantly increased in ShamHS hearts. The present findings suggest that the postischemic functional improvement after total body hyperthermia can be explained by increased and more homogeneous myocardial perfusion, which may also reduce the duration of postischemic arrhythmias. This effect is especially beneficial for the hypertrophied heart, which is known to be extremely vulnerable to the ischemic insult probably caused by subendocardial underperfusion.

Effects of stress and exercise on rat hippocampus and striatum extracellular lactate.

Extracellular lactate was continuously monitored (lactography) to determine the effect of various stressors to assess glucose metabolism in the rat hippocampus and striatum. It appeared that immobilization, emotional stress, and exercise (physiological stress) all resulted in an increase in hippocampal extracellular lactate. Exercise had the most pronounced effect. These increases were different for rats raised in different laboratories. Only during exercise a transient increase in lactate was seen in striatum. Peripheral infusions of epinephrine and/or corticosterone did not affect the basal levels of hippocampal lactate. Adrenodemedullated rats showed an attenuated lactate increase compared with control rats during and shortly after exercise. Administration of ipsapirone, an anxiolytic drug, attenuated the stress-induced formation of the hippocampal lactate. The present study demonstrates the usefulness of lactography to monitor regional brain metabolism in freely moving animals, exposed to various stressors, breeding conditions, or drugs. The observed different responsiveness of the two brain-region studies emphasizes the different involvement of the striatum and hippocampus in motor and emotional behavior, respectively. Lactate formation is stimulated by excitatory neuronal activity, presumably originating in the cerebral cortex, although adrenal hormones appear to contribute.

Mild stress stimulates rat hippocampal glucose utilization transiently via NMDA receptors, as assessed by lactography.

Lactography is a novel technique that allows the continuous on-line registration of brain extracellular lactate in the freely behaving animal and that is based on a fluorimetric enzymatic assay of brain dialysates. Electroconvulsive shock, activation of the glutamate receptor (NMDA-type) and mild stress (immobilization, cold stress or handling) result in transient increases in the efflux of lactate from the rat hippocampus. The increase following immobilization stress was attenuated by the NMDA-receptor antagonist 2-amino-5-phosphopentanoic acid and after several pre-exposures to this stressor. These experiments suggest that mild stress activates glutamatergic neurons, which may be less after habituation to stress.