Microglial and macrophage reactions mark progressive changes and define the penumbra in the rat neocortex and striatum after transient middle cerebral artery occlusion

Transient middle cerebral artery occlusion in rats leads to infarction of the lateral part of the striatum and adjacent neocortex, with selective neuronal necrosis in the bordering penumbral zones. Administration of glutamate, cytokine, and leukocyte antagonists have rescued mainly neocortical neurons, indicating differences in the degenerative processes. The aim of this study was, therefore, to describe the microglial/macrophage activation and polymorphonuclear leukocyte recruitment patterns and to correlate these with the ischemia-induced degenerative processes. The analysis showed significant differences in the characteristics and timing of the microglial/macrophage responses between the caudate putamen and neocortical infarct zones, the infarct zones and their associated penumbral zones, as well as between the striatal and the neocortical penumbral zone. Infiltrations with polymorphonuclear leukocytes into the infarct zones were limited and shortlasting and confined to the acutely degenerating striatum and piriform cortex. A delayed, massive infiltration with lipid phagocytes into the caudate putamen infarct markedly contrasted an early recruitment and activation of microglia/macrophages in the adjacent penumbra. Within the neocortex, a later onset of degeneration along the insular-parietal axis was marked by neuronal expression of heat shock protein and a progressive microglial activation with induction of the full repertoire of microglial activation markers, including a widespread microglial major histocompatibility complex (MHC) class II antigen expression. We interpret the present results as delineating two differentially progressing penumbral zones, which are likely to reflect differences in the underlying degenerative processes. Differences in the microglial/macrophage activation pattern attract special attention, as these cells may constitute specific targets for therapeutic intervention. J. Comp. Neurol. 386:461-476, 1997. © 1997 Wiley-Liss, Inc.     

Postoperative complications and long-term functional outcome in children operated for idiopathic rectal prolapse

Purpose

The aim of the present study was to evaluate the postoperative complications and the long-term gastrointestinal functional outcome after surgical treatment for rectal prolapse on a strategy with stapled anopexy for short (<?5 cm) prolapse and Delormes procedure for longer (>?5 cm) rectal prolapse.

Methods

A total of 38 patients were included with a postoperative follow-up period ranging from 1 month to 9.1 years. Thirty patients (83%) completed the Rome III questionnaire on gastrointestinal function, with the follow-up period ranging from 2 months to 7 years.

Results

Thirty-five patients were treated with stapled anopexy as a primary surgical treatment. One minor complication with slight postoperative bleeding was observed, but the recurrence rate was 34.3%. Treatment of recurrence with re-stapling gave success rate of 44.4%. Ten patients (3 primary and 7 with recurrence after stapled anopexy) were treated with Delormes procedure with no observed complications or recurrence. Four out of nineteen patients treated with stapled anopexy fulfilled the criteria for functional gastrointestinal symptoms and in 3 out of 8 treated with Delormes procedure. No patients reported continence problems.

Conclusion

The recurrence rate for stapled anopexy was high and none with Delormes procedure. The functional outcome was comparable with a healthy population of children.

     

p53mutations in lung tumours: relationship to gender and lung DNA adduct levels

Human lung cancer exhibits a high frequency of transver-sionmutations at G: C base pairs of the p⁵³ gene, possibly the resultof DNA damage by cigarette smoke constituents, most notablybenzo[a]pyrene. We have investigated gender differences in thep⁵³ mutational spectrum and levels of hydrophobic DNA adducts.Tumour tissue was obtained from 115 non-small cell lung cancertumours and examined for mutational alterations in the p⁵³ gene(exons 4–9) using PCR and single-strand conformationalpolymorphism analysis. We have previously examined exons 5–8in lung cancer. Sequence analysis of exons 4 and 9 revealedthat almost 20% of the mutations were located in exons 4 and9. The levels of hydrophobic DNA adducts in non-tumorous lungtissue of 55 of the patients were analyzed by the ³²P-postlabellingassay. There were both a higher frequency of G: C     

Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation

Mutations in the progranulin (PGRN) gene have recently been identified in families with frontotemporal lobar degeneration and ubiquitin-positive brain inclusions linked to chromosome 17q21. We have previously described a Swedish family displaying frontotemporal dementia with rapid progression and linkage to chromosome 17q21. In this study, we performed an extended clinical and neuropathological investigation of affected members of the family and a genetic analysis of the PGRN gene. There was a large variation of the initial presenting symptoms in this family, but common clinical features were non-fluent aphasia and loss of spontaneous speech as well as personality and behavioural changes. Mean age at onset was 54 years with disease duration of close to 4 years. Neuropathological examination revealed frontotemporal neurodegeneration with ubiquitin and TAR DNA binding protein-43 immunoreactive intraneuronal inclusions. Mutation screening of the PGRN gene identified a 1 bp deletion in exon 1 causing a frameshift of the coding sequence and introducing a premature termination codon in exon 2 (Gly35GlufsX19). Analysis of PGRN messenger RNA (mRNA) levels revealed a considerable decrease in lymphoblasts from mutation carriers and fragment size separation, and sequence analysis confirmed that the mutated mRNA allele was almost absent in these samples. In conclusion, the PGRN Gly35fs mutation causes frontotemporal dementia with variable clinical presentation in a large Swedish family, most likely through nonsense-mediated decay of mutant PGRN mRNA and resulting haploinsufficiency.     

Revisiting the Nordic long-term care model for older people—still equal?

With the extensive long-term care services for older people, the Nordic countries have been labelled ‘caring states’ as reported (Leira, Welfare state and working mothers: the Scandinavian experience, Cambridge University Press, Cambridge, 1992). The emphasis on services and not cash benefits ensures the Nordics a central place in the public service model (Anttonen and Sipilä, J Eur Soc Policy 6:87–100, 1996). The main feature of this ideal model is public social care services, such as home care and residential care services, which can cover the need for personal and medical care, as well as assistance with household chores. These services are provided within a formally and professionally based long-term care system, where the main responsibility for the organization, provision and financing of care traditionally lays with the public sector. According to the principle of universalism (in: Antonnen et al. (eds), Welfare state, universalism and diversity, Elgar, Cheltenham, 2013), access to benefits such as home care and residential care is based on citizenship and need, not contributions nor merit. Also, care services should be made available for all and generally be used by all, with no stigma associated. Vabø and Szebehely (in: Anttonen (ed), Welfare State, universalism and diversity, Edward Elgar Publishing, London, 2012)) further argue that the Nordic service universalism is more than merely issues of eligibility and accessibility, in that it also encompasses whether services are attractive, affordable and flexible in order to meet a diversity of needs and preferences. However, recent decades have seen a continuous tendency towards prioritization of care for the most frail, contributing to unmet need, informalization of care and privatization in the use of topping up with market-based services. These changes have raised questions about increasing inequalities within Nordic long-term care systems. We investigate in the article what effect changes have for equality across social class and gender, for users and informal carers. The article is based on analysis of comparable national and international statistics and a review of national research literature and policy documents.     

Intron 12 in NTRK3 is associated with bipolar disorder

Based on the important role of neurotrophic factors in brain development and plasticity and reports of association between schizophrenia and the gene neurotrophic tyrosine kinase receptor 3 (NTRK3), we investigated associations of bipolar disorder with polymorphisms in NTRK3. Recently, our group reported evidence for a possible association of NTRK3 polymorphisms with hippocampal function and schizophrenia. In the present study, we used a homogenous Norwegian case-control sample (the TOP study) consisting of 194 patients diagnosed with bipolar disorder and 336 healthy controls genotyped on the Affymetrix Genome-wide Human SNP Array 6.0. In total 149 markers were investigated for SNP-disease association. Polymorphisms in over 20 markers were nominally associated with bipolar disorder, covering intron 5 to intron 12. Interestingly, our markers appeared to be located close or within the linkage regions reported in schizophrenia, early-onset major depressive disorder and eating disorder, supporting the hypothesis that some genes influence risk beyond traditional diagnostic boundaries.     

Locally performed postoperative circulating tumour DNA testing performed during routine clinical care to predict recurrence of colorectal cancer

Background

Identifying patients at high risk for colorectal cancer recurrence is essential for improving prognosis. In the postoperative period, circulating tumour DNA (ctDNA) has been demonstrated as a significant prognostic indicator of recurrence. These results have been obtained under the strict rigours of clinical trials, but not validated in a real-world setting using in-house testing. We report the outcomes of locally performed postoperative ctDNA testing conducted during routine clinical care and the association with the recurrence of colorectal cancer.

Methods

We recruited 36 consecutive patients with newly diagnosed colorectal cancer between 2018 and 2020. Postoperative plasma samples were collected at the first outpatient review following resection. Tumour-informed ctDNA analysis was performed using droplet digital polymerase chain reaction or targeted next-generation sequencing.

Results

At the time of surgery, there were 24 patients (66.7%) with localized cancer, nine (25%) with nodal spread, and three (8.3%) with metastatic disease. The median time from surgery to plasma sample donation was 22 days (IQR 20–28 days). At least one somatic mutation was identified in primary tumour tissue for 28 (77.8%) patients. Postoperative ctDNA was detected in five patients (13.9%). The median duration of follow-up was 32.0 months (IQR 27.2–38.1 months). Two patients (5.56%) developed metastatic recurrence. However, neither had detectable postoperative ctDNA. There were no instances of loco-regional recurrence.

Conclusion

Analysis of postoperative ctDNA testing can be performed locally, however this study did not reproduce the adverse association between detectable postoperative ctDNA and the development of colorectal cancer recurrence seen in clinical trials.