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Background: Abortions, stillbirths, PET and other serious pregnancy complications cause more than 3-4 million pregnancy failures annually worldwide. Hypofibrinolytic and thrombophilia mutations are responsible for a large number of these events. Methods: A study of 11 such genetic mutations (Table 5) in 26 Cypriot ladies after failed pregnancies from serious complications, stillbirths and abortions was carried out between 2006 and 2020. All 26 ladies had significant hypo fibrinolysis and thrombophilia mutations. Hypofibrinolytic mutation PAI-1 4G/4G, was the commonest (X2 p=0.0052) with 11 ladies, 9 of them also ACE D/D positive. Factor V Leiden was present in 5 ladies (X2 p=ns). Clinical results: After the diagnosis of hypo fibrinolysis ± thrombophilia, 19 of these 26 ladies proceeded with 1-2 more pregnancies using LMW s/c heparin and oral aspirin, all with healthy babies. The remaining 7 ladies were too stressed for another pregnancy. 12 ladies were referred after PET, 2 with stillbirths and 9 after caesareans with birthweights at 700, 900, 950, 1050+1080, 1200, 1250, 2050, 2080 and 2200g. One baby developed mental retardation. The 12th lady with PET at 20 weeks, was immediately treated with LMW s/c heparin and had a healthy baby at 32 weeks. The remaining 14 ladies had other earlier pregnancy complications, 9 of them ending as abortions. Three ladies had their pregnancies saved with an instant mutational study and therapy with LMW heparin, leading to healthy babies. Conclusion: Hypofrinolytic mutations PAI-1 4G/4G and ACE D/D are serious mutations leading to abortions and pregnancy complications and should always be taken seriously in pregnancy. Thrombophilia mutations Factor V Leiden, Factor VR2, prothrombin G20210A, and MTHFR also lead to complicated pregnancies but less frequently. LMW s/c heparin in pregnancies with such mutations saves lives. It would be ideal if these mutations were always studied prior to every first pregnancy. Keywords: Mutations PAI-1 4G/4G; ACE D/d In Pregnancy

Tumor normalization strategies aim to improve tumor blood vessel functionality (i.e., perfusion) by reducing the hyper-permeability of tumor vessels or restoring compressed vessels. Despiteprogress in strategies to normalize the tumor microenvironment (TME), their combinatorialantitumor effects with nanomedicine and immunotherapy remain unexplored.Methods: Here, we re-purposed the TGF-β inhibitor tranilast, an approved anti-fibrotic andantihistamine drug, and combined it with Doxil nanomedicine to normalize the TME, increaseperfusion and oxygenation, and enhance anti-tumor immunity. Specifically, we employed twotriple-negative breast cancer (TNBC) mouse models to primarily evaluate the therapeutic andnormalization effects of tranilast combined with doxorubicin and Doxil. We demonstrated theoptimized normalization effects of tranilast combined with Doxil and extended our analysis to investigate the effect of TME normalization to the efficacy of immune checkpoint inhibitors.Results: Combination of tranilast with Doxil caused a pronounced reduction in extracellular matrixcomponents and an increase in the intratumoral vessel diameter and pericyte coverage, indicators ofTME normalization. These modifications resulted in a significant increase in tumor perfusion and oxygenation and enhanced treatment efficacy as indicated by the notable reduction in tumor size.Tranilast further normalized the immune TME by restoring the infiltration of T cells and increasingthe fraction of T cells that migrate away from immunosuppressive cancer-associated fibroblasts.Furthermore, we found that combining tranilast with Doxil nanomedicine, significantly improved immunostimulatory M1 macrophage content in the tumorigenic tissue and improved the efficacy ofthe immune checkpoint blocking antibodies anti-PD-1/anti-CTLA-4.Conclusion: Combinatorial treatment of tranilast with Doxil optimizes TME normalization, improves immunostimulation and enhances the efficacy of immunotherapy.&nbsp

Paradoxes are historically embedded in institutions and organizations. Latent paradoxes pose danger if they become salient; sociological analyses can identify historically embedded latent paradoxes. The emergency management paradox, in which the state invests vast resources, establishing formidable organizational arrangements that rely on knowledge to respond to unanticipated events in advance of their occurrence, even though such events can only ever be known after they occur, is a paradox of this kind. Deploying methodological “dual integrity” we trace through historical description and sociological conceptualization the institutional and organizational history of the emergency management paradox in Australia, where uncontrollable bushfires are becoming increasingly common, before drawing more general conclusions about how a response to grand challenges, such as climate change, demands an interdisciplinary understanding of the rituals and realities of paradoxes that emerge historically from our collective attempts to handle uncertainty via risk. Our research serves as a warning of the grave consequences that can result from ignoring a paradox’s history, whether intentionally or unwittingly.

Nano‐immunotherapy regimens have high potential to improve patient outcomes, as already demonstrated in advanced triple negative breast cancer with nanoparticle albumin‐bound paclitaxel and the immune checkpoint blocker (ICB) atezolizumab. This regimen, however, does not lead to cures with median survival lasting less than two years. Thus, understanding the mechanisms of resistance to and development of strategies to enhance nano‐immunotherapy in breast cancer are urgently needed. Here, in human tissue it is shown that blood vessels in breast cancer lung metastases are compressed leading to hypoxia. This pathophysiology exists in murine spontaneous models of triple negative breast cancer lung metastases, along with low levels of perfusion. Because this pathophysiology is consistent with elevated levels of solid stress, the mechanotherapeutic tranilast, which decompressed lung metastasis vessels, is administered to mice bearing metastases, thereby restoring perfusion and alleviating hypoxia. As a result, the nanomedicine Doxil causes cytotoxic effects into metastases more efficiently, stimulating anti‐tumor immunity. Indeed, when combining tranilast with Doxil and ICBs, synergistic effects on efficacy, with all mice cured in one of the two ICB‐insensitive tumor models investigated is resulted. These results suggest that strategies to treat breast cancer with nano‐immunotherapy should also include a mechanotherapeutic to decompress vessels., Combinatorial treatment of a mechanotherapeutic and nanomedicine normalizes metastasis microenvironment by decreasing fibrosis and hypoxia and skewing TAMs polarization from immunosuppressive M2‐like TAMs to immunostimulatory M1‐like TAMs. Improved perfusion and oxygenation leads to improved efficacy of immune checkpoint blockers and cure.

Myeloid cells include various cellular subtypes that are distinguished into mononuclear and polymorphonuclear cells, derived from either common myeloid progenitor cells (CMPs) or myeloid stem cells. They play pivotal roles in innate immunity since, following invasion by pathogens, myeloid cells are recruited and initiate phagocytosis and secretion of inflammatory cytokines into local tissues. Moreover, mounting evidence suggests that myeloid cells may also regulate cancer development by infiltrating the tumor to directly interact with cancer cells or by affecting the tumor microenvironment. Importantly, mononuclear phagocytes, including macrophages and dendritic cells (DCs), can have either a positive or negative impact on the efficacy of chemotherapy, radiotherapy as well as targeted anti-cancer therapies. Tumor-associated macrophages (TAMs), profusely found in the tumor stroma, can promote resistance to chemotherapeutic drugs, such as Taxol and Paclitaxel, whereas the suppression of TAMs can lead to an improved radiotherapy outcome. On the contrary, the presence of TAMs may be beneficial for targeted therapies as they can facilitate the accumulation of large quantities of nanoparticles carrying therapeutic compounds. Tumor infiltrating DCs, however, are generally thought to enhance cytotoxic therapies, including those using anthracyclines. This review focuses on the role of tumor-infiltrating and stroma myeloid cells in modulating tumor responses to various treatments. We herein report the impact of myeloid cells in a number of therapeutic approaches across a wide range of malignancies, as well as the efforts toward the elimination of myeloid cells or the exploitation of their presence for the enhancement of therapeutic efficacy against cancer.

Algorithms are increasingly being adopted in healthcare settings, promising increased safety, productivity and efficiency. The growing sociological literature on algorithms in healthcare shares an assumption that algorithms are introduced to ‘support’ decisions within an interactive order that is predominantly human-oriented. This article presents a different argument, calling attention to the manner in which organisations can end up introducing a non-negotiable disjuncture between human-initiated care work and work that supports algorithms, which the authors call algorithmic work. Drawing on an ethnographic study, the authors describe how two hospitals in England implemented an Acute Kidney Injury (AKI) algorithm and analyse ‘interruptions’ to the algorithm’s expected performance. When the coordination of algorithmic work occludes care work, the study finds a ‘dismembered’ organisation that is algorithmically-oriented rather than human-oriented. In the discussion, the authors examine the consequences of coordinating human and non-human work in each hospital and conclude by urging sociologists of organisation to attend to the importance of the formal in algorithmic work. As the use of algorithms becomes widespread, the analysis provides insight into how organisations outside of healthcare can also end up severing tasks from human experience when algorithmic automation is introduced.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

In spite of their widespread use in policy making in the UK and elsewhere, there is a relatively sparse literature specifically devoted to policy pilots. Recent research on policy piloting has focused on the role of pilots in making policy work in accordance with national agendas. Taking this as a point of departure, the present paper develops the notion of pilots doing policy work. It does this by situating piloting within established theories of policy formulation and implementation, and illustrating using an empirical case. Our case is drawn from a qualitative policy ethnography of a local government pilot programme aiming to extend access to healthcare services. Our case explores the collective entrepreneurship of regional policy makers together with local pilot volunteers. We argue that pilots work to mobilise and manage the ambiguity and conflict associated with particular policy goals, and in their structure and design, shape action towards particular outcomes. We conclude with a discussion of the generative but managed role which piloting affords to local implementers.

Although sociological studies of quality and safety have identified competing epistemologies in the attempt to measure and improve care, there are gaps in our understanding of how finance and accounting practices are being used to organise this field. This analysis draws on what others have elsewhere called ‘financialisation’ in order to explore the quantification of qualitatively complex care practices. We make our argument using ethnographic data of a quality improvement programme for acute kidney injury (AKI) in a publicly funded hospital in England. Our study is thus concerned with tracing the effects of financialisation in the emergence and assembly of AKI as an object of concern within the hospital. We describe three linked mechanisms through which this occurs: (1) representing and intervening in kidney care; (2) making caring practices count and (3) decision‐making using kidney numbers. Together these stages transform care practices first into risks and then from risks into costs. We argue that this calculative process reinforces a separation between practice and organisational decision‐making made on the basis of numbers. This elevates the status of numbers while diminishing the work of practitioners and managers. We conclude by signalling possible future avenues of research that can take up these processes.

Background and Aims: Cystinuria represents 3% of nephrolithiasis in humans. Two genes have been identified as the main genetic causes of cystinuria, SLC3A1 and SLC7A9, with an autosomal recessive mode of inheritance. In the present study, we studied for the first time, genetically and clinically, all the cystinuric families identified so far in the Greek-Cypriot population. Methods: Discovery of mutations was performed through polymerase chain reaction (PCR)-single analysis and DNA resequencing. New families were investigated through PCR-RFLPs. Clinical data were collected through the hospital patients' records and analytical follow-up of the families. Results and Discussion: We found a total of five mutations in 28 Greek-Cypriot cystinuric patients belonging in 12 families. The most frequent mutation among the 28 Greek-Cypriot patients is the SLC3A1-p.T216M, which is also the second most frequent mutation in Europe, representing a genetic founder effect. Sixteen of the 28 patients are homozygous for this mutation. Even though a consanguinity loop was obvious in only one family, other patients were from families in small villages where endogamy was practiced for many centuries. Timely clinical and genetic diagnosis, accompanied by early treatment, is significant for the good health of most of our patients. Only ∼14% of them developed chronic renal failure, and only one reached end-stage renal disease (ESRD). Conclusion: Five SLC3A1 and SLC7A9 mutations appear to be responsible for the genetic basis of cystinuria in the Greek-Cypriot patients having such a limited number of causative mutations will simplify diagnostics for this population. © Copyright 2015, Mary Ann Liebert, Inc. 19 641 645

Background: About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). Methods: Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. Results: In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. Conclusions: A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts. 2018 The Author(s). The work was supported from the Cyprus Research Promotion Foundation through the grant NEW INFRASTRUCTURE/STRATEGIC/0308/24 to CD (co-funded by the European Regional Development Fund and the Republic of Cyprus). The funding body did not contribute to the design of study, collection, analysis and interpretation of data, or in manuscript writing. Scopus

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11

Familial Mediterranean fever (FMF) is caused by mutations in the MEFV gene and the spectrum of mutations among Greek-Cypriots with FMF-related symptoms was examined. Sequence analysis for exons 2, 3, 5, and 10 of the MEFV gene was performed in a cohort of 593 patients. A total of 70 patients carried mutations in the homozygote or compound heterozygote state, 128 were identified with one MEFV mutation and 395 had no mutations. Of the 268 identified alleles, p.Val726Ala (27.61%) was the most frequent followed by p.Met694Val (19.40%). The missense mutations p.Arg761His (3.73%) and p.Ala744Ser (2.24%) were identified as the rarest. An interesting finding is the high frequency (18.28%) of the complex p.Phe479Leu-p.Glu167Asp that was identified in 49 of the mutated alleles. The MEFV genotypes did not follow a binomial distribution and proved not to satisfy the HWE (P < 0.001). The high percentage (66.61%) of patients with unidentified mutations could be due to mutations in the rest of the coding or noncoding MEFV gene or due to mutations in other genes that are also causing Hereditary Recurrent Fevers. Results from this work indicate the high incidence of FMF in Cyprus and describe the spectrum of the mutations which occur in the country.

A growing proportion of inguinal hernia patients are at least 65 years old. Assessing operational benefits versus risks in this group of elderly patients merits research.Patients in two prospective trials (1:n = 134, 89 elderly; 2:n = 398, 70 elderly) completed RAND-36 questionnaires preoperatively (response rate 100 and 98.5 %, respectively) and at 3 (98.5 %) or 12 months (89.6 %) after open inguinal hernia repair. In both groups, preoperative and postoperative quality of life data were statistically compared within age categories. Quality of life change was compared between age categories. Immediate complications were recorded.The dimensions physical functioning and pain improved significantly in the elderly and under 65-year-olds. Role functioning/physical and social functioning showed improvement as well, but less constantly. No statistical difference in complication rates was found across age groups.Inguinal hernia surgery improves physical and social dimensions of quality of life among elderly and under 65-year-olds similarly.

Background Familial hematuria (FH) is associated with at least two pathological entities: Thin basement membrane nephropathy (TBMN), caused by heterozygous COL4A3/ COL4A4 mutations, and C3 nephropathy caused by CFHR5 mutations. It is now known that TBMN patients develop proteinuria and changes of focal segmental glomerulosclerosis when biopsied. End-stage kidney disease (ESKD) is observed in 20% of carriers, at ages 50-70. A similar progression is observed in CFHR5 nephropathy. Recent evidence suggests that NPHS2-R229Q, a podocin polymorphism, may contribute to proteinuria in TBMN and to micro-albuminuria in the general population. Case-Diagnosis/Treatment NPHS2-R229Q was screened in a Cypriot FH cohort. 102 TBMN patients with three known COL4 mutations and 45 CFHR5 male patients with a single mutation were categorized as "Mild" or "Severe", based on the presence of microhematuria only, or proteinuria and chronic kidney disease. Nine R229Q carriers were found in the "Severe" category and none in the "Mild" (p00.010 for genotypic association p00.043 for allelic association, adjusted for patients' relatedness), thus supporting the possible contribution of 229Q allele in disease progress. Conclusions Our results offer more evidence that in patients with FH, NPHS2-R229Q predisposes to proteinuria and ESKD. R229Q may be a good prognostic marker for young hematuric patients © IPNA 2011. 27 675 679 Cited By :23

Alport syndrome (AS) is a hereditary progressive glomerulonephritis with a high life-time risk for end-stage renal disease (ESRD). Most patients will reach ESRD before the age of 30 years, while a subset of them with milder mutations will do so at older ages, even after 50 years. Frequent extrarenal manifestations are hearing loss and ocular abnormalities. AS is a genetically heterogeneous collagen IV nephropathy, with 85% of the cases caused by mutations in the X-linked COL4A5 gene and the rest by homozygous or compound heterozygous mutations in either the COL4A3 or the COL4A4 gene on chromosome 2q36-37. There is no radical cure for the disease and attempts to use various stem cell therapies in animal models have been met with ambiguous success. However, effective treatment has been accomplished with pharmacological intervention at the renin-angiotensin-aldosterone system (RAAS), first in animal models of AS and more recently in humans. Angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) have been shown to significantly delay the progression of chronic kidney disease and the onset of ESRD. Also, renin inhibitors and aldosterone blockade were used with positive results, while the combination of ACEis and ARBs was met with mixed success. An important study, the EARLY-PROTECT, aims at evaluating the efficacy of ACEis when administered very early on in children with AS. Novel therapies are also tested experimentally or are under design in animal models by several groups, including the use of amniotic fluid stem cells and synthetic chaperones. 107 205 210 Cited By :3

Familial microscopic hematuria (MH) of glomer-ular origin represents a heterogeneous group of monogenic conditions involving several genes, some of which remain unknown. Recent advances have increased our understanding and our ability to use molecular genetics for diagnosing such patients, enabling us to study their clinical characteristics over time. Three collagen IV genes, COL4A3, COL4A4, and COL4A5 explain the autosomal and X-linked forms of Alport syndrome (AS), and a subset of thin basement membrane nephropathy (TBMN). A number of X-linked AS patients follow a milder course reminiscent of that of patients with heterozygous COL4A3/COL4A4 mutations and TBMN, while at the same time a significant subset of patients with TBMN and familial MH progress to chronic kidney disease (CKD) or end-stage kidney disease (ESKD). A mutation in CFHR5, a member of the complement factor H family of genes that regulate complement activation, was recently shown to cause isolated C3 glomerulopathy, presenting with MH in childhood and demonstrating a significant risk for CKD/ ESKD after 40 years old. Through these results molecular genetics emerges as a powerful tool for a definite diagnosis when all the above conditions enter the differential diagnosis, while in many at-risk related family members, a molecular diagnosis may obviate the need for another renal biopsy. © 2011 IPNA. 27 1221 1231 Cited By :25

Background and objectives Complement factor H and related proteins (CFHR) are key regulators of the alternative complement pathway, where loss of function mutations lead to a glomerulopathy with isolated mesangial C3 deposits without immunoglobulins. Gale et al. (12) reported on 26 patients with the first familial, hematuric glomerulopathy caused by a founder mutation in the CFHR5 gene in patients of Cypriot descent living in the United Kingdom. CFHR5 nephropathy is clinically characterized by continuous microscopic hematuria whereas some patients present with additional episodes of synpharyngitic macrohematuria, associated with infection and pyrexia. A subgroup of patients, particularly men, develop additional proteinuria, hypertension, and chronic renal disease or ESRD. Design, setting, participants, & measurements We herewith expand significantly on the study by Gale et al., reporting on histologic, molecular, and clinical findings in 91 patients from 16 families with the same founder mutation. Results Eighty-two patients (90%) exhibited microscopic hematuria 51 (62%), exhibited only microscopic hematuria, whereas the remaining 31 additionally had proteinuria (38%) 28 proteinuric patients developed chronic renal failure (CRF). Among carriers of CFHR5 mutation aged >50 years, 80% of the men and 21% of the women developed CRF 18 developed ESRD (14 men [78%], 4 women [22%]). Conclusions The diagnosis of CFHR5-related, isolated C3 glomerulopathy was established in 2009 using newly described mutation analysis after decades of follow-up with unclear diagnoses, occasionally confused with IgA nephropathy. This larger patient cohort establishes the clinical course, significant variable expressivity, and marked gender difference regarding the development of CRF and ESRD. © 2011 by the American Society of Nephrology. 6 1436 1446 Cited By :75

Complement factor H-related protein 5 (CFHR5) nephropathy is a familial renal disease endemic in Cyprus. It is characterized by persistent microscopic hematuria, synpharyngitic macroscopic hematuria and progressive renal impairment. Isolated glomerular accumulation of complement component 3 (C3) is typical with variable degrees of glomerular inflammation. Affected individuals have a heterozygous internal duplication in the CFHR5 gene, although the mechanism through which this mutation results in renal disease is not understood. Notably, the risk of progressive renal failure in this condition is higher in males than females. We report the first documented case of recurrence of CFHR5 nephropathy in a renal transplant in a 53-year-old Cypriot male. Strikingly, histological changes of CFHR5 nephropathy were evident in the donor kidney 46 days post-transplantation. This unique case demonstrates that renal-derived CFHR5 protein cannot prevent the development of CFHR5 nephropathy.

Autosomal dominant polycystic kidney disease (ADPKD), is a heterogeneous disorder, primarily characterized by the formation of cysts in the kidneys, and the late development in life of progressive chronic kidney failure. Three genes are implicated in causing ADPKD. One on chromosome 16, PKDI, accounts for 85-90% of all cases, and the PKD2 gene on chromosome 4 accounts for the remainder. A very rare third locus is still of unknown location. We used PKD1- and PKD2-linked polymorphic markers to make the diagnosis of ADPKD in young presymptomatic members in affected families. We showed that in young members of families where clinical diagnosis cannot be definitively established, molecular linkage analysis can assist clinicians in the diagnosis. In one family a 24-year old had one cyst on the right kidney ; however, molecular analysis showed clearly that he had inherited the normal haplotype. In another family, in one part of the pedigree there was co-inheritance of the disease with a PKD1-linked haplotype which originated in a non-affected 78-year-old father. Analysis with PKD2-linked markers excluded this locus. The data can be explained in one of two ways. Either this family phenotype is linked to a third locus, or the proband was the first affected person, most probably because of a novel mutation in one of her father's chromosomes. In conclusion, the combined use of markers around the PKD I and the PKD2 locus provides more definitive answers in cases where presymptomatic diagnosis is requested by concerned families.

Introduction: Chronic postherniorrhaphy pain is the foremost setback of today's inguinal hernia repair. Finding predictors for it affects implants, operative techniques and allows for preventive measures. Methods: Prospectively collected data from 932 outpatient open inguinal hernia operations between 2003 and 2010 were subjected to regression analysis. Visual analogue scale score (VAS) at least a year after operation and a measurement of chronic pain at one year were the target variables. Results: Chronic pain was present in 99 (11.5%) patients one year after operation. Independent predictors for the occurrence of chronic pain were positively recurrence (Odds ratio, OR 6.77 vs. no recurrence, P = 0.005), complication (OR 5.16 vs. no complication, P = 0.002), mid-density mesh (OR 2.28 vs. lightweight mesh, P = 0.012), higher preoperative VAS score (OR 1.15, P = 0.006) and negatively higher age (OR 0.98, P = 0.027). Predictors for a higher postoperative VAS score were recurrence (regression coefficient, RC, 1.49 vs. no recurrence, P = 0.001), complication (RC 0.76 vs. no complication, P = 0.016), heavyweight mesh (RC 0.50 vs. lightweight mesh, P = 0.046) and higher preoperative VAS level (RC 0.10, P

Collagen IV nephropathies (COL4Ns) comprise benign familial microscopic hematuria, thin basement membrane nephropathy (TBMN), X-linked Alport syndrome (AS) and also autosomal recessive and dominant AS. Apart from the X-linked form of AS, which is caused by hemizygous mutations in the COL4A5 gene, the other entities are caused by mutations in the COL4A3 or COL4A4 genes. The diagnosis of these conditions used to be based on clinical and/or histological findings of renal biopsies, but it is the new molecular genetics approach that revolutionised their investigation and proved particularly instrumental, especially, in many not so clear-cut cases. More recently, the spectrum of COL4N has expanded to include late onset focal segmental glomerulosclerosis (FSGS) that develops on top of TBMN in later life. Also, other reports showed that some patients with a primary diagnosis of familial FSGS proved to have variants in COL4 genes. In the presence of a renal biopsy picture of FSGS and in the absence of either electron microscopy studies or molecular genetic studies that point to TBMN and COL4N, the patient and his family may be mistakenly diagnosed with hereditary FSGS leading to unnecessary further investigations, erroneous family counselling and improper corticosteroid treatment. TBMN is a frequent finding in the general population, and according to several recent reports, it may be the underlying cause and the explanation for many familial and sporadic cases of late-onset FSGS with non-nephrotic proteinuria. This is an important new finding that needs widespread recognition. It is anticipated that the molecular genetic analysis with next generation sequencing will certainly offer timely correct diagnosis.

Background/Aims: A subset of patients who present with proteinuria and are diagnosed with focal segmental glomerulosclerosis (FSGS) have inherited heterozygous COL4A3/A4 mutations and are also diagnosed with thin basement membrane nephropathy (TBMN-OMIM: 141200). Two studies showed that co-inheritance of NPHS2-p.Arg229Gln, a podocin variant, may increase the risk for proteinuria and renal function decline. Methods: We hypothesized that additional podocin variants may exert a similar effect. We studied genetically a well-characterized Cypriot TBMN patient cohort by re-sequencing the NPHS2 coding region. We also performed functional studies in cell culture experiments, investigating the interaction of podocin variants with itself and with nephrin. Results: Potentially disease-modifying podocin variants were searched for by analyzing NPHS2 in 35 ‘severe' TBMN patients. One non-synonymous variant, p.Glu237Gln, was detected. Both variants, p.Arg229Gln and p.Glu237Gln, were tested in a larger cohort of 122 TBMN patients, who were categorized as ‘mild' or ‘severe' based on the presence of microscopic hematuria alone or combined with chronic renal failure and/or proteinuria. Seven ‘severe' patients carried either of the 2 variants; none was present in the ‘mild' patients (p = 0.05, Pearson χ2). The 7 carriers belong in 2 families segregating mutation COL4A3-p.Gly1334Glu. Inheritance of the wild-type (WT) and mutant alleles correlated with the phenotype (combined concordance probability 0.003). Immunofluorescence (IF) experiments after dual co-transfection of WT and mutant podocin suggested altered co-localization of mutant homodimers. IF experiments after co-transfection of WT podocin and nephrin showed normal membrane localization, while both podocin variants interfered with normal trafficking, demonstrating perinuclear staining. Immunoprecipitation experiments showed stronger binding of mutant podocin to WT podocin or nephrin. Conclusion: The results support the hypothesis that certain hypomorphic podocin variants may act as adverse genetic modifiers when co-inherited with COL4A3/A4 mutations, thus predisposing to FSGS and severe kidney function decline.

The spectrum of distal renal tubular acidosis (dRTA) includes a genetically heterogeneous group of inherited conditions of both autosomal-dominant and recessive mode of inheritance. The basic defect is linked to the renal part of acid-base homeostasis, which is partly achieved by the regulated luminal secretion of H+ at the apical surface of the alpha-intercalated cells of renal collecting ducts. This is coupled to bicarbonate reabsorption with chloride counter transport across the basolateral membranes. Here, we describe the molecular findings of the first two Greek Cypriot families with recessive dRTA and the long-term clinical findings in four of five affected members. DNA linkage analysis with four polymorphic markers flanking the ATP6V1B1 gene on chromosome 2 gave evidence for positive linkage; direct DNA analysis by automated DNA sequencing revealed that patients in one family were homozygous for mutation 229+1G>T (IVS7+1G>T) and that patients in the second family were compound heterozygous for 229+1G>T and R157C. The mutations were found on four different haplotypes. Both the mutations were previously reported in patients of Turkish origin. Three known polymorphic variants were also identified. The five patients demonstrated the whole clinical spectrum of the disease including death in infancy, failure to thrive, rickets, nephrocalcinosis, nephrolithiasis, and episodes of hypokalemic paralysis. Some of the family members are now in their mid 30s and late 20s, and nephrolithiasis with recurrent renal colics is their main problem. Renal function has remained normal. In conclusion, early diagnosis in infancy and prompt treatment with alkali and potassium supplements is of great benefit to the patient with dRTA and ensures normal growth. The identification of responsible mutations facilitates antenatal or postnatal diagnosis in concerned families and improves the prognosis.

Background. Autosomal dominant medullary cystic kidney disease (ADMCKD) is an inherited, distinct, chronic, tubulointerstitial, cystic-type nephropathy, often described together with juvenile nephronophthisis as a single disease complex (NPH-MCD). However, since the recent localization of two genes responsible for ADMCKD, namely MCKD1 and MCKD2, ADMCKD has gained independent status. Unfortunately, there appears to be a distinct lack of up-to-date information in the currently available medical literature concerning worldwide patient and graft survival after renal transplantation in ADMCKD. This report is based on all 41 transplanted patients [19 suffering from autosomal dominant medullary cystic kidney disease type 1 (ADMCKD1) and 22 from other causes] who were referred for kidney transplantation from our centre in Pafos, Cyprus between 1976 and 2000. All patients had regular follow-up examinations. This report aims to present the results of kidney transplantation of the 19 ADMCKD1 patients and to compare them with those for the 22 non-ADMCKD patients. Methods. Patient and graft survival times in both groups were recorded, analysed and compared 1 and 5 years post-transplant. Patient and graft survival times were calculated according to the Kaplan-Meier method and some descriptive statistical comparisons were based on the χ2-test. Results. The 1 year patient and graft survival rates for ADMCKD1 (group A) were 100%, while the 5 year figures were 100% and 90%, respectively. For non-ADMCKD1 patients (group B) the 1 year figures were 95% for both parameters, while the 5 year figures were 93.3% for both parameters. There were no statistically significant differences in patient and graft survival times between the two groups. Conclusions. Kidney transplantation is the treatment of choice for patients suffering from ADMCKD, with an excellent outcome and no specific complications. 18 2165 2169 Cited By :10

Background Recent data emphasize that thin basement membrane nephropathy (TBMN) should not be viewed as a form of benign familial hematuria since chronic renal failure (CRF) and even end-stage renal disease (ESRD), is a possible development for a subset of patients on longterm follow-up, through the onset of focal and segmental glomerulosclerosis (FSGS). We hypothesize that genetic modifiers may explain this variability of symptoms. Methods We looked in silico for potentially deleterious functional SNPs, using very strict criteria, in all the genes significantly expressed in the slit diaphragm (SD). Two variants were genotyped in a cohort of well-studied adult TBMN patients from 19 Greek-Cypriot families, with a homogeneous genetic background. Patients were categorized as 'Severe' or 'Mild', based on the presence or not of proteinuria, CRF and ESRD. A larger pooled cohort (HEMATURIA) of 524 patients, including IgA nephropathy patients, was used for verification. Additionally, three large general population cohorts [Framingham Heart Study (FHS), KORAF4 and SAPHIR] were used to investigate if the NEPH3-V353M variant has any renal effect in the general population. Results and conclusions Genotyping for two high-scored variants in 103 TBMN adult patients with founder mutations who were classified as mildly or severely affected, pointed to an association with variant NEPH3-V353M (filtrin). This promising result prompted testing in the larger pooled cohort (HEMATURIA), indicating an association of the 353M variant with disease severity under the dominant model (p = 3.0×103, OR = 6.64 adjusting for gender/age allelic association: P = 4.2×103 adjusting for patients' kinships). Subsequently, genotyping 6,531 subjects of the Framingham Heart Study (FHS) revealed an association of the homozygous 353M/M genotype with microalbuminuria (p = 1.0×103). Two further general population cohorts, KORAF4 and SAPHIR confirmed the association, and a meta-analysis of all three cohorts (11,258 individuals) was highly significant (p = 1.3×105, OR = 7.46). Functional studies showed that Neph3 homodimerization and Neph3-Nephrin heterodimerization are disturbed by variant 353M. Additionally, 353M was associated with differential activation of the unfolded protein response pathway, when overexpressed in stressed cultured undifferentiated podocyte cells, thus attesting to its functional significance. Genetics and functional studies support a 'rare variant-strong effect' role for NEPH3-V353M, by e×erting a negative modifier effect on primary glomerular hematuria. Additionally, genetics studies provide evidence for a role in predisposing homozygous subjects of the general population to microalbuminuria. © 2017 Voskarides et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 12

Background. Heterozygous mutations in the COL4A3 COL4A4 genes are currently thought to be responsible for familial benign microscopic haematuria and maintenance of normal long-term kidney function.Methods. We report on 11 large Cypriot pedigrees with three such mutations. A total of 236 at-risk family members were genetically studied, and 127 (53.8) carried a heterozygous mutation. Clinico-pathological correlations were available in all of these patients. Renal biopsies in 21 of these patients all showed various stages of focal, segmental glomerulosclerosis (FSGS). Thirteen of these biopsies were also studied with EM and showed thinning of the glomerular basement membrane.Results. Mutation G1334E (COL4A3) was found in six pedigrees, mutation G871C (COL4A3) in four and mutation 3854delG (COL4A4) in one pedigree. Clinical and laboratory correlations in all 127 mutation carriers (MC) showed that microscopic haematuria was the only urinary finding in patients under age 30. The prevalence of 'haematuria alone' fell to 66 between 31 and 50 years, to 30 between 51 and 70 and to 23 over age 71. Proteinuria with CRF developed on top of haematuria in 8 of all MC between 31 and 50 years, to 25 between 51 and 70 years and to 50 over 71 years. Altogether 18 of these 127 MC (14) developed ESRD at a mean age of 60 years. Two members with different mutations married, and two of their children inherited both mutations and developed adolescent, autosomal recessive Alport syndrome (ATS), confirming that these mutations are pathogenic.Conclusions. Our data confirm for the first time a definite association of heterozygous COL4A3COL4A4 mutations with familial microscopic haematuria, thin basement membrane nephropathy and the late development of familial proteinuria, CRF, and ESRD, due to FSGS, indicating that the term 'benign familial haematuria' is a misnomer, at least in this cohort. A strong hypothesis for a causal relationship between these mutations and FSGS is also made. Benign familial haematuria may not be so benign as commonly thought. 24 2721 2729 Cited By :47

Background Asthma is the most common respiratory disorder complicating pregnancy, and is associated with a range of adverse maternal and perinatal outcomes. There is strong evidence however, that the adequate control of asthma can improve health outcomes for mothers and their babies. Despite known risks of poorly controlled asthma during pregnancy, a large proportion of women have sub-optimal asthma control, due to concerns surrounding risks of pharmacological agents, and uncertainties regarding the effectiveness and safety of different management strategies. Objectives To assess the effects of interventions (pharmacologic and non-pharmacologic) for managing women's asthma in pregnancy on maternal and fetal/infant outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (2 June 2014) and the Cochrane Airways Group's Trials Register (4 June 2014). Selection criteria Randomised and quasi-randomised controlled trials comparing any intervention used to manage asthma in pregnancy, with placebo, no intervention, or an alternative intervention. We included pharmacological and non-pharmacological interventions (including combined interventions). Cluster-randomised trials were eligible for inclusion (but none were identified). Cross-over trials were not eligible for inclusion. We included multi-armed trials along with two-armed trials. We also included studies published as abstracts only. Data collection and analysis At least two review authors independently assessed trial eligibility and quality and extracted data. Data were checked for accuracy. Main results We included eight trials in this review, involving 1181 women and their babies. Overall we judged two trials to be at low risk of bias, two to be of unclear risk of bias, and four to be at moderate risk of bias. Five trials assessed pharmacological agents, including inhaled corticosteroids (beclomethasone or budesonide), inhaled magnesium sulphate, intravenous theophylline, and inhaled beclomethasone verus oral theophylline. Three trials assessed non-pharmacological interventions, including a fractional exhaled nitric oxide (FENO)-based algorithm versus a clinical guideline-based algorithm to adjust inhaled corticosteroid therapy, a pharmacist-led multi-disciplinary approach to management versus standard care, and progressive muscle relaxation (PMR) versus sham training. The eight included trials were assessed under seven separate comparisons. Pharmacological interventions Primary outcomes: one trial suggested that inhaled magnesium sulphate in addition to usual treatment could reduce exacerbation frequency in acute asthma (mean difference (MD) -2.80; 95% confidence interval (CI) -3.21 to -2.39; 60 women). One trial assessing the addition of intravenous theophylline to standard care in acute asthma did not report on exacerbations (65 women). No clear difference was shown in the risk of exacerbations with the use of inhaled beclomethasone in addition to usual treatment for maintenance therapy in one trial (risk ratio (RR) 0.36; 95% CI 0.13 to 1.05; 60 women); a second trial also showed no difference, however data were not clearly reported to allow inclusion in a meta-analysis. No difference was shown when inhaled beclomethasone was compared with oral theophylline for maintenance therapy (RR 0.88; 95% CI 0.59 to 1.33; one trial, 385 women). None of these trials reported on neonatal intensive care admissions. Secondary outcomes: inhaled magnesium sulphate in acute asthma was shown to improve lung function measures (one trial, 60 women); intravenous theophylline in acute asthma was not associated with benefits (one trial, 65 women). No clear differences were seen with the addition of inhaled corticosteroids to routine treatment in three trials (374 women). While inhaled beclomethasone, compared with oral theophylline, significantly reduced treatment discontinuation due to adverse effects in one trial (384 women), no other differences were observed, except for higher treatment adherence with theophylline. Four of the five trials did not report on adverse effects. Non-pharmacological interventions Primary outcomes: in one trial, the use of a FENO-based algorithm was shown to significantly reduce asthma exacerbations (RR 0.61; 95% CI 0.41 to 0.90; 220 women); and a trend towards fewer neonatal hospitalisations was observed (RR 0.46; 95% CI 0.21 to 1.02; 214 infants). No exacerbations occurred in one trial assessing pharmacist-led management; this approach did not reduce neonatal intensive care admissions (RR 1.50; 95% CI 0.27 to 8.32; 58 infants). One trial (64 women) assessing PMR did not report on exacerbations or neonatal intensive care admissions. Secondary outcomes: the use of a FENO-based algorithm to adjust therapy led to some improvements in quality of life scores, as well as more frequent use of inhaled corticosteroids and long-acting β-agonists, and less frequent use of short-acting β-agonists (one trial, 220 women). The FENO-based algorithm was associated with fewer infants with recurrent episodes of bronchiolitis in their first year of life, and a trend towards fewer episodes of croup for infants. Pharmacist-led management improved asthma control scores at six months (one trial, 60 women); PMR improved lung function and quality of life measures (one trial, 64 women). No other differences between comparisons were observed. Authors' conclusions Based on eight included trials, of moderate quality overall, no firm conclusions about optimal interventions for managing asthma in pregnancy can be made. Five trials assessing pharmacological interventions did not provide clear evidence of benefits or harms to support or refute current practice. While inhaled magnesium sulphate for acute asthma was shown to reduce exacerbations, this was in one small trial of unclear quality, and thus this finding should be interpreted with caution. Three trials assessing non-pharmacological interventions provided some support for the use of such strategies, however were not powered to detect differences in important maternal and infant outcomes. While a FENO-based algorithm reduced exacerbations, the effects on perinatal outcomes were less certain, and thus widespread implementation is not yet appropriate. Similarly, though positive effects on asthma control were shown with PMR and pharmacist-led management, the evidence to date is insufficient to draw definitive conclusions. In view of the limited evidence base, further randomised trials are required to determine the most effective and safe interventions for asthma in pregnancy. Future trials must be sufficiently powered, and well-designed, to allow differences in important outcomes for mothers and babies to be detected. The impact on health services requires evaluation. Any further trials assessing pharmacological interventions should assess novel agents or those used in current practice. Encouragingly, at least five trials have been identified as planned or underway.

Learning Point for Clinicians Myocardial infarction in the young can be related to cocaine and anabolic steroid use. This case reminds us that although an uncommon cause, anabolic steroids should not be forgotten. Furthermore, this case teaches us the utility of repeating the clinical history, particularly when a ‘diagnostic dead end’ is reached or there is high clinical suspicion of something a patient may be reluctant to disclose. A 30-year-old male, presented with chest pain at rest. His electrocardiogram …

Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies. © 2014 Papazachariou et al. 9 12 Cited By :13

Background: Homozygous familial hypercholesterolemia (FH) is a rare disease with an incidence of 1 in 1 million births. It is characterized by blood cholesterol levels over 600 mg/dl and the development of extensive cutaneous xanthomata before the age of 5. Severe premature coronary artery disease results in fatal myocardial infarctions within the first two decades of life. The absence of LDL receptors makes homozygous FH resistant to treatment with most HMG-CoA reductase inhibitors, and alternative methods of removing cholesterol have been employed. Methods: We used the ASAHI plasauto-IQ double filtration cascade plasmapheresis to treat 2 young brothers aged 14 and 11 years and 6 months for 5 years and 1 month and 3 years and 10 months, respectively. The elder brother has received 136 double filtration treatments at 2-week intervals and the younger brother 100 such treatments without complications. Results: During the period of treatment the average pretreatment total serum cholesterol level for patient 1 was 442 mg/dl. The average posttreatment value was 163 mg/dl. The average fall in total serum cholesterol with each treatment was 63.2%. The mean total serum cholesterol for all the periods of treatment was calculated at 303 mg/dl. For the 2nd patient, the average pretreatment value of total serum cholesterol was 435 mg/dl. The posttreatment value was 124 mg/dl and the average fall 71.5%. The calculated mean total serum cholesterol for all periods of treatment was 280 mg/dl. Conclusions: Double filtration cascade plasmapheresis at 2-week intervals provides an effective and safe long-term treatment for patients with homozygous FH. The achieved reduction in serum cholesterol allows complete resolution of cutaneous xanthomata, arrests previous atherosclerosis, and prolongs normal life.

A detailed morphometric analysis of glomerular basement membrane (GBM) thickness was carried out on biopsies from 16 patients exhibiting normal histology and unremarkable immunofluorescence. Eleven of these patients presented with proteinuria, 8 in the nephrotic syndrome range, while 5 had hematuria as well. The remaining 5 patients presented with hematuria only. Eight patients had an initial diagnosis of minimal change disease, 4 were diagnosed as thin-membrane nephropathy, 2 had Alport syndrome, and the remaining 2 had hypertensive nephropathy. Quantitative morphometric analysis of GBM identified 3 subsets of patients. The first subset consisted of 6 patients: 5 adults, with an average GBM width of 361 +/- 34 nm, and 1 child. The second subset included 8 patients with thin GBMs and a mean thickness of 253 +/- 15 nm. The last subset comprised 2 patients with Alport syndrome showing marked variability in GBM thickness. This study has confirmed the presence of thin GBMs in hematurics, but has also revealed GBM thinning in 50% of patients with a diagnosis of minimal change disease.

acute renal failure; pregnancy; partial lipo- towards the end of the gestation period, between 34dystrophy; low C3; membranoproliferative nephritis and 38 weeks, and it is invariably the result of pre-eclampsia and its complications or the result of severeblood loss [5–7]. Occasionally post-infectious glom-erulonephritis may occur during pregnancy and can be

We describe a large Cypriot family with an interstitial type of nephropathy, inherited as an autosomal dominant trait that led to end stage renal failure between 51 to 78 years of age (mean 62.2 years). Twenty-three people are known to be affected, but several younger relatives with normal renal function may remain undiagnosed because of the absence of precise clinical and laboratory diagnostic criteria. This nephropathy is associated with medullary renal cysts, hypertension, hyperuricemia, and gout. Several relatives have typical medullary cystic disease (MCD), while in the others the findings are compatible with this diagnosis. Due to the similarity of clinical and pathologic findings, earlier reports had suggested that MCD may be allelic to autosomal recessive familial juvenile nephronophthisis, which was mapped recently to chromosome band 2q13. Linkage analysis of the present family with a closely linked marker excluded linkage to the above locus. Linkage was also excluded to the PKD1 locus of adult polycystic kidney disease type 1, and up to 5 cM on either side, on chromosome 16. We suggest that because of the element of hyperuricemia and gout found in this family, although with reduced penetrance, it may represent a variant of autosomal dominant MCD of the adult type. This variability may be the result of allelic or locus heterogeneity. Molecular genetic approaches including linkage analysis on appropriate families will certainly assist in classifying such related genetically heterogeneous disorders.

Mycobacterial infections are rare in developed countries. Isolated involvement of the liver and biliary tree by mycobacterial infection is extremely rare. We report a case of a 45-year-old Caucasian female presenting with obstructive jaundice with a common bile duct stricture and multiple hypodense liver lesions raising suspicion of a metastatic cholangiocarcinoma. Percutaneous core biopsies of the liver lesions however suggested granulomatous process and histology at surgical excision confirmed this finding. Atypical mycobacteria (M. abcessus) sensitive to Amikacin were cultured from the surgical specimen proving the diagnosis. With the resurgence of tubercular and atypical mycobacterial infections in the developed world, it is important not to overlook these in differential diagnosis of various malignancies.

Familial hematuria (FH) is explained by at least four different genes (see below). About 50% of patients develop late proteinuria and chronic kidney disease (CKD). We hypothesized that MYH9/APOL1, two closely linked genes associated with CKD, may be associated with adverse progression in FH. Our study included 102 thin basement membrane nephropathy (TBMN) patients with three known COL4A3/COL4A4 mutations (cohort A), 83 CFHR5/C3 glomerulopathy patients (cohort B) with a single CFHR5 mutation and 15 Alport syndrome patients (cohort C) with two known COL4A5 mild mutations, who were categorized as "Mild" (controls) or "Severe" (cases), based on renal manifestations. E1 and S1 MYH9 haplotypes and variant rs11089788 were analyzed for association with disease phenotype. Evidence for association with "Severe" progression in CFHR5 nephropathy was found with MYH9 variant rs11089788 and was confirmed in an independent FH cohort, D (cumulative p value = 0.001, odds ratio = 3.06, recessive model). No association was found with APOL1 gene. Quantitative Real time PCR did not reveal any functional significance for the rs11089788 risk allele. Our results derive additional evidence supporting previous reports according to which MYH9 is an important gene per se, predisposing to CKD, suggesting its usefulness as a prognostic marker for young hematuric patients. © 2013 Voskarides et al. 8 Cited By :3

Microscopic haematuria is the presenting symptom of several conditions, either heritable or acquired. A well-recognized familial condition is Alport syndrome, either of X-linked or autosomal recessive inheritance, as well as thin basement membrane nephropathy (TBMN) because of heterozygous collagen IV mutations. Even though microscopic haematuria of TBMN was long considered as a benign disease with excellent prognosis, more recent data suggest that development of chronic kidney disease (CKD) and even end-stage kidney disease (ESKD) is not a rare finding, perhaps owing to the cofounding role of modifier genes and other factors. Recent investigations in London and Cyprus culminated in the identification of another autosomal dominant condition that presents with microscopic haematuria because of heterozygous mutations in the CFHR5 gene, which apparently plays a pivotal role in the regulation of the alterative pathway of complement system, which constitutes a significant part of innate immunity in humans. Histologically, the hallmark observation is the isolated glomerular deposition of C3 complement in the absence of immune complexes. It is considered one of the C3 glomerulopathies, and it may or may not be accompanied by mild membranoproliferative glomerulonephritis. Interestingly, a single mutation has been identified so far, a duplication of exons 2-3 of the CFHR5 gene, and it has been described in patients of Greek-Cypriot descend only, perhaps originating on the Troodos mountains of Cyprus. Thus far, no patient with a mutation in this gene has been diagnosed in any other population. In Cyprus, it has been found in clusters of families in neighbouring villages in a total of 136 patients, and it constitutes a strong founder phenomenon. About 50% of patients over 50 years have progressed to CKD, and 14% of all patients progressed to ESKD. It is not quite well understood why males run a much higher risk to progress to CKD, compared to women.

Most Alport cases, 85%, are caused by mutations in the X-linked gene, COL4A5 that encodes the α5 chain of type IV collagen, the most abundant structural protein in the glomerular basement membrane (GBM). The remaining 15% of cases are caused by autosomal recessive mutations in the genes that encode the α3 and α4 chains of the type IV collagen, COL4A3/COL4A4 1,2. Thin basement membrane nephropathy (TBMN) is reportedly also a genetically heterogeneous condition, caused by heterozygous COL4A3/COL4A4 mutations in about 40-50% of the cases. No other responsible genes have been identified as yet. Collagen type IV, as all collagens, is a trimer formed by combinations of three of the six alpha chains, α1-α6. Genes COL4A1 and COL4A2 map to chromosome 13q34, COL4A3 and COL4A4 map to chromosome 2q36–q37 and COL4A5 and COL4A6 map to Xq22-23. All six genes are encoded in nearly 50 exons and close to 1600 aminoacids, and consist of an Nterminal 7S domain, a C-terminal non-collagenous (NC1) domain and a large collagenous domain in between, containing the characteristic Gly-X-Y repeat, common to all collagens. All six alpha chains contain 22-26 natural interruptions of the Gly-X-Y repeats, spread throughout their central collagenous domain. These are presumably regions of specific function and/or ligand binding sequences, of significance to its structural role in the basement membrane. Although there are many possible combinations among the six alpha chains, only three are biologically compatible and found in basement membranes. These are composed of α1α1α2, α3α4α5 and α5α5α6. Type IV collagen participates in forming networks interacting with additional important components of the basement membranes, such as laminin and nidogen 3,4. As a component of the glomerular filtration barrier, along

Background Chronic groin pain after mesh repair of inguinal hernia has been attributed to the presence of sutures. Methods This randomized clinical trial compared inguinal hernia repair using a self-fixating composite mesh or a sutured lightweight mesh, with pain at 1 year as primary outcome. Patients completed a self-evaluation questionnaire at 2 weeks and were examined after 1 year. Results Some 198 patients received self-fixating mesh and 196 sutured mesh. There were no differences between the groups in mean pain scores measured on a visual analogue scale during 2 weeks of immediate convalescence or at 1 year. Chronic pain and discomfort was experienced by 36·3 per cent of patients in the self-fixating and 34·1 per cent in the sutured mesh group (P = 0·658), affecting the everyday life of 1·1 and 2·8 per cent respectively (P = 0·448). Conclusion Open inguinal hernia repair with a composite self-fixating mesh resulted in similar pain in the early postoperative convalescence period and at 1 year as repair with a sutured lightweight mesh. Registration number: NCT01026935 (http://www.clinicaltrials.gov).

Background Long-term sequelae in open inguinal hernia repair with either a bilayer mesh (Prolene Hernia System [PHS]) or an onlay mesh (Lichtenstein patch) were compared. Methods Questionnaires, phone calls, and clinical evaluation were applied as follow-up at 2 and 5 years postoperatively. Results Five percent of patients in the PHS group and 14% in the Lichtenstein group ( P = .022) reported sensory dysfunction of the skin in the operated groin at 5 years. Chronic postoperative pain decreased over time and was reported by 11% of all patients at 5 years. Discomfort in the operated groin was found in 25% of all patients 5 years after the operation. The cumulative recurrence rate at 5 years was .8% for the PHS and 1.7% for the Lichtenstein procedure ( P = .620). Conclusions The 2 approaches resulted in comparable rates of recurrence and long-term chronic postoperative pain. The Lichtenstein patch caused significantly more often long-term sensory dysfunction of the skin in the operated groin.