Modification of chemokine pathways and immune cell infiltration as a novel therapeutic approach in liver inflammation and fibrosis

Despite increasing knowledge about molecular pathways in pathogenesis of chronic liver disease, selective therapeutic options are scarce, especially in advanced diseases characterized by scarring of the liver (termed fibrosis) or even complete cirrhosis. Sustained hepatic inflammation as a result to various types of injury (e.g., hepatitis C, nonalcoholic steatohepatitis) is generally accepted to represent the key prerequisite for fibrogenesis. Liver inflammation is characterized by an activation of distinct chemokine pathways in the liver and the circulation allowing distinct immune cell populations to enter the liver via sinusoids and postsinusoidal venules. Recent investigations have shed light on the intimate interactions between the fibrogenic hepatic stellate cell (HSC) and infiltrating immune cells, which fundamentally drive liver scarring. Experimental fibrosis and inflammation models have demonstrated that disruption of chemokine pathways such as CCL2 (MCP-1) or its receptor CCR2, CCL5 (RANTES) or CCR1 / CCR5 and others may efficiently prevent collagen deposition, by targeting monocytes and macrophages, T-cell populations or NKT cells. However, immigration of certain mononuclear cells may even be beneficial in the course of fibrosis. Infiltrating NK cells and monocyte-derived macrophage subsets can promote resolution of extracellular matrix. This emphasizes that hepatic fibrosis is not a unidirectional process, but can be reverted up to a certain point. The present review aims at summarizing the contribution of immune cell infiltration as well as related chemokine systems to experimental liver fibrosis and will discuss possible therapeutic applications in humans, with a special emphasis on the monocyte/macrophage lineage and their related chemokine pathways.     

Vascularity for healing of meniscus repairs

Vascularity in the human meniscus is poor beyond 1-2 mm from the meniscosynovial junction, yet 22% of the tears in this series occur with a greater than or equal to 3-mm peripheral white rim. It is possible to suture these tears with the wider peripheral white rims, but healing rates are reduced because it is more difficult to obtain a satisfactory vascular supply. This article describes the history of our efforts at obtaining blood supply for healing of meniscus tears with a peripheral white rim up to 5 mm. Resection of the peripheral white rim to the vascular bed was unsatisfactory because it reduced the size of the meniscus and, by 3 years, the subsequent degenerative changes in the knee were comparable to meniscectomy. Holes made in the rim with a biopsy needle were again unsuccessful at improving healing. The present technique involves using rasps to abrade the parameniscal synovium on both the superior and inferior surface of the peripheral white rim. None of the peripheral white rim is resected. In the first series of 240 patients in whom peripheral white rim resection or the biopsy punch was used, the failure rate of meniscus healing was 22%. In a subsequent series of 68 patients (52 males, 16 females) who had 81 meniscal repairs by means of the rasp for parameniscal synovial abrasion, the failure rate was 9%. The rasp appears to be the safest and most effective method to gain vascularity for healing of meniscus repairs. It is possible to obtain healing with 5-mm peripheral white rims without resection of any portion of this rim, thus maintaining the full size of the meniscus.     

No association between incisal tooth wear and temporomandibular disorders

STATEMENT OF PROBLEM: Incisal tooth wear may be a sign of long-term bruxing behavior. Bruxism is purported to be a risk factor for temporomandibular disorders (TMD). PURPOSE: The purpose of this clinic-based case-control study was to investigate whether the wear of anterior teeth is associated with TMD. MATERIAL AND METHODS: Two hundred eight TMD patients and 172 control subjects were selected for participation. After exclusion of subjects with more than 1 missing premolar or molar zone in opposite arches, as well as subjects with missing or severely restored anterior teeth, 154 TMD patients and 120 control subjects were included in the study (age 31.2 +/- 13.4 years; range 13 to 76 years). Anterior tooth wear was assessed on casts with a 0 to 5 scale. A multiple logistic regression analysis, controlling for the effects of age and gender, was performed to investigate the relationship between tooth wear and TMD. RESULTS: An odds ratio of 0.76 (95% confidence interval: 0.51 to 1.15) indicated that after adjusting for gender and age, the odds in favor of TMD decreased an estimated 24% for each additional unit of the mean tooth wear score. This result was not significant (P=.20). CONCLUSION: Within the limitations of this study, incisal tooth wear (assessed on dental casts) was not significantly associated with TMD when the influence of age and gender was controlled. Based on these findings, a clinically relevant risk for TMD from incisal tooth wear can be excluded. Hence, the presented evidence does not support the idea that treatment of incisal tooth wear is indicated to prevent TMD.     

875 Cases of bacterial meningitis: Diagnostic procedures and the impact of preadmission antibiotic therapy Part III of a three-part series

Data on the bacteriological findings, diagnostic measures and clinical course of 875 patients with bacterial meningitis are presented. Findings from the medical records and from a follow-up questionnaire survey of 667 of these cases revealed no significant difference between patients treated with antibiotics before admission (pretreated) and those who were not treated before admission (non-pretreated) with respect to clinical condition on admission, mortality and late sequelae. Pretreatment was, however, associated with a longer duration of symptoms. Apart from cases due to Neisseria meningitidis, there were no significant differences in diagnostic findings between pretreated and non-pretreated cases. In the group of pretreated meningococcal patients, however, positive blood cultures, pleiocytosis in the cerebrospinal fluid (CSF) and positive cultures from sites other than blood and CSF were less frequent than in the non-pretreated cases.     

The interaction of p53 with replication protein A mediates suppression of homologous recombination

The tumor suppressor protein p53 is emerging as a central regulator of homologous recombination (HR) processes and DNA replication. P53 may downregulate HR through multiple mechanisms including the reported associations with the Rad51 and Rad54 recombinases, and the BLM and WRN helicases. Here, we investigated whether the interaction of p53 with human replication protein A (RPA) is necessary for the regulation of HR. By employing a plasmid-based HR assay in p53-null H1299 lung carcinoma cells, we studied the HR-suppressing properties of a panel of p53 mutants, which varied in their ability to interact with RPA. Both wild-type p53 and a transactivation-deficient p53 mutant (L22Q/W23S) suppressed HR and prevented RPA binding to ssDNA in vitro and in vivo. Conversely, p53 mutations that specifically disrupt the RPA-binding domain, while not compromising p53 transactivation function (D48H/D49H and W53S/F54S), did not affect HR. Suppression of HR was also not seen with missense mutations in the p53 core domain (His175 and His273), which retained the ability to interact with RPA, suggesting that the disruption of additional binding interactions of p53, for example, with Rad51 or recombination intermediates, also impacts on HR. We hypothesize that sequestration of RPA by p53 at the sites of recombination is one means by which p53 can inhibit HR processes. Our data support and extend the previously formulated 'dual model' of p53's role as guardian of the genome.     

Automated quality assessment of structural magnetic resonance images in children: Comparison with visual inspection and surface‐based reconstruction

Motion‐related artifacts are one of the major challenges associated with pediatric neuroimaging. Recent studies have shown a relationship between visual quality ratings of T₁ images and cortical reconstruction measures. Automated algorithms offer more precision in quantifying movement‐related artifacts compared to visual inspection. Thus, the goal of this study was to test three different automated quality assessment algorithms for structural MRI scans. The three algorithms included a Fourier‐, integral‐, and a gradient‐based approach which were run on raw T₁‐weighted imaging data collected from four different scanners. The four cohorts included a total of 6,662 MRI scans from two waves of the Generation R Study, the NIH NHGRI Study, and the GUSTO Study. Using receiver operating characteristics with visually inspected quality ratings of the T₁ images, the area under the curve (AUC) for the gradient algorithm, which performed better than either the integral or Fourier approaches, was 0.95, 0.88, and 0.82 for the Generation R, NHGRI, and GUSTO studies, respectively. For scans of poor initial quality, repeating the scan often resulted in a better quality second image. Finally, we found that even minor differences in automated quality measurements were associated with FreeSurfer derived measures of cortical thickness and surface area, even in scans that were rated as good quality. Our findings suggest that the inclusion of automated quality assessment measures can augment visual inspection and may find use as a covariate in analyses or to identify thresholds to exclude poor quality data.     

A population‐based and cross‐sectional study of the long‐term prognosis in multifocal motor neuropathy

A population‐based, cross‐sectional study of patients referred to the Danish hospital system between 1985 and 2006 was conducted to evaluate the long‐term outcome in Danish patients treated for multifocal motor neuropathy (MMN). Thirty‐four MMN patients were identified, three had died of unrelated diseases, 10 were excluded, one did not reply to study request and 20 were included. The median disease duration was 24 years (interquartile range: 18.5‐31.0). Compared to 24 healthy matched control subjects, the Rasch‐built Overall Disability Scale for Multifocal Motor Neuropathy was reduced by 9%, the Neuropathy Impairment Score showed a 3‐fold increase, the isokinetic strength was reduced by 29%, the grip strength by 56%, the Timed 25‐Foot Walk was prolonged by 13% and the EQ‐5D‐5 L‐Index value was impaired by 20%. The isokinetic strength was significantly more impaired at the wrist and ankle as compared to the elbow and knee, and one patient had lost ambulation because of instability at the ankle. Patients were considerably more fatigued and had substantially impaired hand dexterity, while mood, aerobic capacity, social adjustment, and working capacity were not affected. Regression analysis showed that lag‐time until start of initial therapy lead to impaired long‐term outcome without any effect of disease duration. Long‐term prognosis in treated MMN is characterized by moderate to severe impairment primarily affecting dexterity and stability at the ankle. Our observations support previous observations that the long‐term impairment in MMN might be improved following earlier start of therapy and that an effect of disease duration cannot be demonstrated.     

Comparison of outcomes between complete and incomplete congenital duodenal obstruction

BACKGROUND Congenital duodenal obstruction (CDO) can be complete (CCDO) or incomplete (ICDO). To date there is no outcome analysis available that compares both subtypes. AIM To quantify and compare the association between CCDO and ICDO with outcome parameters. METHODS We retrospectively reviewed all patients who underwent operative repair of CCDO or ICDO in our tertiary care institution between January 2004 and January 2017. The demographics, clinical presentation, preoperative diagnostics and postoperative outcomes of 50 patients were compared between CCDO (n = 27;atresia type 1-3, annular pancreas) and ICDO (n=23;annular pancreas, web, Ladd′s bands). RESULTS In total, 50 patients who underwent CDO repair were enrolled and followed for a median of 5.2 and 3.9 years (CCDO and ICDO, resp.). CCDO was associated with a significantly higher prenatal ultrasonographic detection rate (88% versus 4%;CCDO vs ICDO, P<0.01), lower gestational age at birth, lower age and weight at operation, higher rate of associated congenital heart disease (CHD), more extensive preoperative radiologic diagnostics, higher morbidity according to Clavien-Dindo classification and comprehensive complication index (all P≤0.01). The subgroup analysis of patients without CHD and prematurity showed a longer time from operation to the initiation of enteral feeds in the CCDO group (P<0.01). CONCLUSION CCDO and ICDO differ with regard to prenatal detection rate, gestational age, age and weight at operation, rate of associated CHD, preoperative diagnostics and morbidity. The degree of CDO in mature patients without CHD influences the postoperative initiation of enteral feeding.     

Neuromuscular electrical stimulation in early rehabilitation of Guillain-Barré syndrome: A pilot study

Introduction: In Guillain-Barré syndrome (GBS), patients often develop muscle atrophy from denervation and immobilization. We, therefore, conducted a pilot study of neuromuscular electrical stimulation (NMES) to evaluate feasibility, safety, and effect on muscle wasting in the early phase of GBS. Methods: Seventeen patients were randomized to receive 20 min of muscle fiber stimulation followed by 40 min of NMES of the right or left quadriceps muscle with the untreated side as control. Cross-sectional area (CSA) of the muscle measured by ultrasound and isometric knee extensor strength were the primary and secondary outcome measures. Results: No treatment related adverse effects were recorded. Change in CSA was -0.25 cm² (confidence interval [CI], -0.93–0.42) on the stimulated side versus -0.60 cm² (CI, -1.32–0.11) on the nonstimulated side (P = 0.08). No effect was observed on muscle strength. Conclusions: NMES seems safe and feasible in the early phase of GBS. Further studies are needed to explore effect on muscle function. Muscle Nerve 59:481–484, 2019     

Short Communication: West Nile fever imported from Austria to Germany

This is the first report of West Nile virus (WNV) infection imported by a traveller returning from a neighbouring country to Germany (Austria). Physician s should be aware of the expansion of WNV endemic areas in Europe.