Summary Background Unruptured intracranial aneurysms (UIAs) are increasingly detected and are an important health-care burden. We aimed to assess the prevalence of UIAs according to family history, comorbidity, sex, age, country, and time period. Methods Through searches of PubMed, Embase, and Web of Science we updated our 1998 systematic review up to March, 2011. We calculated prevalences and prevalence ratios (PRs) with random-effects binomial meta-analysis. We assessed time trends with year of study as a continuous variable. Findings We included 68 studies, which reported on 83 study populations and 1450 UIAs in 94 912 patients from 21 countries. The overall prevalence was estimated as 3·2% (95% CI 1·9–5·2) in a population without comorbidity, with a mean age of 50 years, and consisting of 50% men. Compared with populations without the comorbidity, PRs were 6·9 (95% CI 3·5–14) for autosomal dominant polycystic kidney disease (ADPKD), 3·4 (1·9–5·9) for a positive family history of intracranial aneurysm of subarachnoid haemorrhage, 3·6 (0·4–30) for brain tumour, 2·0 (0·9–4·6) for pituitary adenoma, and 1·7 (0·9–3·0) for atherosclerosis. The PR for women compared with men was 1·61 (1·02–2·54), with a ratio of 2·2 (1·3–3·6) in study populations with a mean age of more than 50 years. Compared with patients older than 80 years, we found no differences by age, except for patients younger than 30 years (0·01, 0·00–0·12). Compared with the USA, PRs were similar for other countries, including Japan (0·8, 0·4–1·7) and Finland (1·0, 0·4–2·4). There was no statistically significant time trend. Interpretation The prevalence of UIAs is higher in patients with ADPKD or a positive family history of intracranial aneurysm of subarachnoid haemorrhage than in people without comorbidity. In Finland and Japan, the higher incidence of subarachnoid haemorrhage is not explained by a higher prevalence of UIAs, implicating higher risks of rupture. Funding Julius Centre for Health Sciences and Primary Care and Department of Neurology and Neurosurgery, University Medical Centre, Utrecht.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(11)70109-0.pdf

Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis

The potent immunosuppressive action of rapamycin is commonly ascribed to inhibition of growth factor-induced T cell proliferation. However, it is now evident that the serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. mTOR regulates diverse functions of professional antigen-presenting cells, such as dendritic cells (DCs), and has important roles in the activation of effector T cells and the function and proliferation of regulatory T cells. In this Review, we discuss our current understanding of the mTOR pathway and the consequences of mTOR inhibition, both in DCs and T cells, including new data on the regulation of forkhead box P3 expression.

/pdf/immunoregulatory-functions-of-mtor-inhibition-4tquguj4do.pdf

Immunoregulatory functions of mTOR inhibition

response, pathology and t] disordered function. The t scholarly throughout and pleasing emphasis on the approach. The book will be for reference purposes but tho chapters which can be read N interest for their own sake an( among these are elegant coni the pathological section Corrin and Heath. Mention be made of "Mapping resj eases" by Cliff and Haggett beautiful exposition of mod( in geographical pathology, a son's chapters on proteases a inhibitors which clarify prese underlying the aetiology of The illustrations are clear ai is easy to read as the paper is variety. Perhaps this is not a book ft pathologists to purchase-£ an effective disincentive-yet there should be a place for it in every hospital library. MS DUNNILL

https://jcp.bmj.com/content/jclinpath/35/1/123.2.full.pdf

Ackerman's Surgical Pathology

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder. The study of diverse mouse models of lupus has provided clues to the etiology of SLE. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged. Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease. The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies. Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis. Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE.

/pdf/murine-models-of-systemic-lupus-erythematosus-2yz4mrsgfq.pdf

Murine Models of Systemic Lupus Erythematosus

Cystic kidneys are common causes of end-stage renal disease, both in children and in adults. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are cilia-related disorders and the two main forms of monogenic cystic kidney diseases. ADPKD is a common disease that mostly presents in adults, whereas ARPKD is a rarer and often more severe form of polycystic kidney disease (PKD) that usually presents perinatally or in early childhood. Cell biological and clinical research approaches have expanded our knowledge of the pathogenesis of ADPKD and ARPKD and revealed some mechanistic overlap between them. A reduced 'dosage' of PKD proteins is thought to disturb cell homeostasis and converging signalling pathways, such as Ca2+, cAMP, mechanistic target of rapamycin, WNT, vascular endothelial growth factor and Hippo signalling, and could explain the more severe clinical course in some patients with PKD. Genetic diagnosis might benefit families and improve the clinical management of patients, which might be enhanced even further with emerging therapeutic options. However, many important questions about the pathogenesis of PKD remain. In this Primer, we provide an overview of the current knowledge of PKD and its treatment.

Polycystic kidney disease.

Background Rapamycin is a potent immunosuppressive drug with proven efficacy in rejection prophylaxis in solid organ transplantation. By virtue of its immunosuppressive properties, rapamycin might also be useful in the treatment of autoimmune diseases. The aim of this study was to determine the effect of rapamycin on the severity of established nephritis in lupus-prone New Zealand Black/White F(1) (NZB/W F(1)) mice. Methods Six-month-old female NZB/W F(1) mice with active nephritis (albuminuria >100 mg/dL) were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 4 months. The effect of rapamycin on the severity of nephritis was evaluated by clinical manifestations, biochemical parameters, renal histology, immunohistochemistry and semi-quantitative gene expression studies. Results Treatment with rapamycin significantly decreased albuminuria, improved survival, diminished splenomegaly, preserved renal function and reduced serum anti-dsDNA antibody levels. Kidney sections from saline-treated mice revealed marked mesangial proliferation, tubular dilation with intra-tubular protein cast deposition and leukocytic infiltration of the interstitium. The rapamycin-treated mice, in contrast, had relatively mild histological changes in their kidneys. Rapamycin treatment also significantly reduced the amount of immune complex deposition in the glomeruli, suppressed the interstitial infiltration by T-cells, B-cells and macrophages as well as down-regulated the intra-renal expression of RANTES. Conclusions We conclude that rapamycin is effective in attenuating the severity of established nephritis in NZB/W F(1) mice. The beneficial effects of rapamycin are mediated, at least in part, through inhibition of lymphoproliferation, reduced RANTES expression and decreased inflammatory cell infiltration in the kidneys. Rapamycin could be of therapeutic value in the treatment of human lupus nephritis.

/pdf/rapamycin-attenuates-the-severity-of-established-nephritis-4pgoblnye1.pdf

Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice.

Rapamycin is a potent immunosuppressive drug currently used mainly for rejection prophylaxis in renal transplantation The aim of this study was to determine the effect of rapamycin treatment on the development of nephritis in lupus-prone New Zealand Black/White F1 (NZB/W F1) mice Twelve-week-old female NZB/W F1 mice were treated with rapamycin (3 mg/kg body weight) or saline once daily by oral gavage for 20 weeks The severity of nephritis was assessed by clinical and biochemical parameters, renal histology, immunohistochemistry and gene expression studies Rapamycin treatment markedly reduced proteinuria, improved renal function, decreased serum anti-double stranded DNA antibody levels and diminished splenomegaly Kidney sections from saline-treated mice showed marked mesangial proliferation, tubular dilation with protein cast deposition and interstitial inflammatory cell infiltration Rapamycin-treated mice had near normal renal histology, with marked reduction in glomerular immune deposition and the infiltration by T cells, B cells and macrophages Rapamycin treatment was associated with down-regulation of intra-renal expression of monocyte chemoattractant protein-1 (MCP-1) mRNA and protein We conclude that rapamycin is highly effective in preventing the development of nephritis in NZB/W F1 mice The beneficial effects of rapamycin are mediated through inhibition of lymphoproliferation and reduced MCP-1 expression

Rapamycin prevents the development of nephritis in lupus-prone NZB/W F1 mice.

Carcinoma of the esophagus. An autopsy study of 231 cases.

The aim of this study was to determine the effect of rapamycin on renal ischemia-reperfusion injury (IRI) in mice. Renal IRI was induced in male BALB/c mice by clamping both renal pedicles for 45 min. The mice were treated with either vehicle or rapamycin (2 mg/kg/day) by oral gavage, starting 1 day before the IRI and continued daily till killing. The mice were killed on days 1, 3 and 7 after the operation. The severity of the renal IRI was assessed by serum creatinine levels and renal histology. Proliferation of renal tubular cells was quantified by immunohistochemical staining for proliferating cell nuclear antigen (PCNA). One day after the IRI, the serum creatinine levels of rapamycin-treated mice were significantly higher than those of the vehicle-treated mice. Kidney sections from rapamycin-treated mice showed more marked tubular damage and significantly lower number of PCNA-positive cells. The number of PCNA-positive cells in the rapamycin-treated mice remained significantly lower on day 3 after the IRI. By day 7 after the IRI, the serum creatinine levels, renal histology and positive PCNA staining in the kidney sections became similar between the two treatment groups. We conclude that in this murine model of renal IRI, rapamycin treatment aggravates renal IRI during the first 3 days after the insult. This effect might be mediated, at least partly, through inhibition of renal tubular cell proliferation.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-2277.2006.00361.x

Effect of rapamycin on renal ischemia-reperfusion injury in mice.

○ Objectives.-To examine the histologic features of p21 in penile tumors and to determine the role of p21 and p53 in the pathogenesis of this group of tumors. Methods.-The clinicopathologic features of 87 patients with penile tumors were studied. The expression of p53 and p21 proteins in 49 cases was investigated by immunohistochemistry. Results.-Of the 87 tumors studied, 84 represented primary penile tumors (72 malignant and 12 benign) and 3 represented secondary tumors (2 from bladder, 1 from nasopharynx). The primary malignant penile tumors included 66 surface carcinomas with squamous differentiation (92%), 3 cases of Paget disease (4%), 1 case of Bowen disease (1%), and 2 penile urethral squamous cell carcinomas (3%). The former group was subdivided into squamous cell carcinoma (n = 50), verrucous carcinoma (n = 8), basaloid squamous cell carcinoma (n = 3), adenoid squamous cell carcinoma (n = 3), spindle cell carcinoma (n = 1), and adenosquamous carcinoma (n = 1). The benign tumors were squamous cell papillomas (n = 10) and fibromatoses (n = 2). Expression of p21 and p53 was noted in 40% and 89%, respectively, of the 47 patients with primary surface penile carcinoma with squamous differentiation. Positive p21 and p53 expression was also seen in 2 cases of Paget disease. Staining for p21 was often weak and was found in the suprabasal region of carcinomas with squamous differentiation, while p53 expression was seen in the basal region of squamous cell carcinomas. Preinvasive lesions also showed p21 and p53 expression. An inverse correlation between p53 and p21 expression (p53 + / p21 - or p53 - /p21 + ) was noted in half of the squamous cell carcinomas, 4 of 5 verrucous carcinomas, 2 of 3 basaloid squamous cell carcinomas, and in 1 spindle cell carcinoma. The other cases did not show this correlation. Conclusions.-Penile tumors had different histologic variants and p21/p53 expression patterns. Expression of p21 did play a role in some tumors and could be dependent or independent of p53 expression.

Molecular pathology and clinicopathologic features of penile tumors: with special reference to analyses of p21 and p53 expression and unusual histologic features.

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