Renal involvement in paroxysmal nocturnal hemoglobinuria: an update on clinical features,pathophysiology and treatment

Objectives: The present review summarizes the available knowledge regarding acute and chronic kidney dysfunction in patients with paroxysmal nocturnal hemoglobinuria (PNH) focusing on its clinical features, pathophysiology and treatment.

Methods: A thorough PubMed search was performed using as main keywords: ‘paroxysmal nocturnal hemoglobinuria’, ‘acute kidney injury’, ‘chronic kidney disease’ and ‘eculizumab’.

Results: PNH’s etiopathogenesis is based on acquired mutations that lead to the reduction or absence of CD55 and CD59 complement regulators, which are responsible for some of the disease’s major clinical features, like intravascular hemolysis, cytopenias and thrombosis. PNH is often underdiagnosed, mainly due to its occasional mild manifestations and to its ability to mimic other severe clinical conditions. Various mechanisms have been proposed for the kidney damage attributed to the release of cell-free heme and free iron, including inflammatory response, oxidative stress, nitric oxide depletion, renal ischemia, membrane damage and apoptosis. Eculizumab, a terminal complement inhibitor, provides a safe and effective treatment option, especially when it is initiated early in the presence of kidney damage.

Discussion: Kidney injury is a poorly investigated clinical feature of PNH that affects a significant portion of patients. Increased awareness is needed by physicians to recognize the early signs and symptoms of acute and chronic renal insufficiency, so as to initiate the necessary therapy. It is also important to re-evaluation of PNH-specific treatments during the course of the disease.

Conclusion: Understanding the difficult but at the same time impressive mechanisms behind PNH remains a challenge for treating physicians.     

Phantom cytomegalovirus infection in vasculitis patients: what it means and what to do

We report our experience and hypothesis on the diagnosis and treatment of patients with vasculitis who are simultaneously diagnosed with serum-positive cytomegalovirus (CMV) immunoglobulin (Ig)M antibodies and negative CMV DNA polymerase chain reaction (PCR). It remains unknown how to treat this kind of phantom CMV infection. In a patient diagnosed with Henoch-Schönlein vasculitis, CMV IgM titers were increased while angiitis and renal function deteriorated. Empiric treatment of phantom CMV infection with ganciclovir in this CMV IgM-positive and PCR-negative patient resulted in complete vasculitis remission, serum CMV antibody seroconversion, and renal function improvement. These results imply something more than coincidence.     

The Boston Naming Test in Greek: Normative data and the effects of age and education on naming

Background: The Boston Naming Test (BNT) is widely used as a clinical assessment of language and cognitive deficits. It has been adapted and translated for use in other languages and cultures.

Aims: This study translated and adapted the test for use in Greece. Normative data were collected on the test for healthy Greek speakers of different ages and educational backgrounds.

Methods and Procedures: Participants in four different age ranges and with three levels of educational achievement were tested. They were screened for cognitive decline using a Greek version of the mini mental state examination.

Outcomes and Results: Strong effects of age and education were found on naming. The former replicates previous results. Results on the latter have been less consistent and their occurrence here reflects the greater inequality in educational opportunity that has existed in Greece until comparatively recent times. Significant interactions between age, education, and gender are interpreted as reflecting changing social and gender roles in Greek society. A reordering of items reflecting their difficulty for this Greek sample is presented for clinical use.

Conclusions: This study provides norms for a Greek version of the BNT. These highlight the effects of age and education on naming. Scores for many older and less‐educated participants might be taken to indicate pathology despite their lack of neurological or cognitive problems. This illustrates the need for norms that reflect local circumstances and the need to update norms as social and educational changes occur.     

Endothelin‐1 Acutely Reduces the Permeability of Visceral Sheep Peritoneum In Vitro Through Both Endothelin‐A and Endothelin‐B Receptors

Mesothelium is an important part of the peritoneal barrier for water and ion transport, essential for effective peritoneal dialysis (PD). Peritoneal fibrosis has been associated with PD treatment failure. Endothelin‐1 (ET‐1) is a potent vasoactive peptide, involved in pathologic fibrotic processes. Its action is mediated mainly by endothelin type A (ET_A) and type B (ET_B) receptors. The aim of this study was to investigate, by Ussing chamber experiments, the effect of ET‐1 on the transmesothelial electrical resistance (R_TM) of the isolated visceral sheep peritoneum. Intact sheets of visceral peritoneum were obtained from 40 adult sheep and mounted in Ussing‐type chambers. ET‐1 (10^?7 M), BQ‐123 (ET_A receptor antagonist; 10^?6 M), BQ‐788 (ET_B receptor antagonist; 10^?6 M), and their combinations were added on the apical and the basolateral side of the peritoneum. R_TM was measured before and serially after addition of the substances, and changes were registered as percentage (ΔR_TM %). R_TM increased within 1 min after addition of ET‐1 apically (ΔR_TM 65.03 ± 15.87%; P < 0.05) or basolaterally (ΔR_TM 85.5 ± 20.86%; P < 0.05). BQ‐123 and BQ‐788 and their combination significantly reduced (P < 0.05) the effect of ET‐1 to a similar degree in all cases. These results clearly indicate that ET‐1 reduces ionic permeability of the visceral sheep peritoneum in vitro. Additionally, it is obvious that this inhibitory effect is mediated through both ET_A and ET_B receptors.     

Chronic cholecystitis in elderly patients. Correlation of the severity of inflammation with the number and size of the stones

BACKGROUND: [corrected] The present study focused on cholecystectomized elderly patients and aimed to investigate whether inflammation in the gallbladder wall was associated with the number and size of gallstones, as well as the patients' age. PATIENTS AND METHODS: The present study included 306 cholecystectomized patients aged over 65 years. From the specimens derived from cholecystectomy, the gallstone number, the largest gallstone diameter and gallbladder wall thickness were determined. According to the histopathological examination, chronic inflammation was subdivided into mild-moderate and severe. Univariable analysis and multivariable logistic regression followed. RESULTS: Mild-moderate inflammation characterized 63.4% of the cases and severe inflammation 366%. Solitary gallstones were found in 13.1% of the cases, while multiple gallstones were found in 86.9% of the cases. The largest gallstone diameter was less than 1 cm in the majority of cases (73.2%). The gallbladder wall thickness was associated with the degree of inflammation (p < 0.001, Chi-square). In the univariable analysis, inflammation was positively associated with the diameter of the largest gallstone (p = 0.032, Chi-square), but negatively associated with the number of gallstones (p < 0.001, Chi-square) and patients' age (p = 0.008, logistic regression). The number of gallstones was negatively associated with the diameter of gallstones and positively associated with the patients' age. The diameter of the largest gallstone was negatively associated with the patients' age. In the multivariable logistic regression, the effect of age (OR = 0.95, 95% CI: 0.91-0.99) and solitary gallstones (OR = 2.66, 95% CI: 1.02-6.93) on inflammation persisted, but that of the largest gallstone diameter vanished. CONCLUSION: The elderly population presented mainly with multiple and small gallstones. Solitary gallstones and younger age were the most important predictors for severe inflammation.     

Rare copy number variants identified in prune belly syndrome

Prune belly syndrome (PBS), also known as Eagle-Barrett syndrome, is a rare congenital disorder characterized by absence or hypoplasia of the abdominal wall musculature, urinary tract anomalies, and cryptorchidism in males. The etiology of PBS is largely unresolved, but genetic factors are implicated given its recurrence in families. We examined cases of PBS to identify novel pathogenic copy number variants (CNVs). A total of 34 cases (30 males and 4 females) with PBS identified from all live births in New York State (1998–2005) were genotyped using Illumina HumanOmni2.5 microarrays. CNVs were prioritized if they were absent from in-house controls, encompassed ≥10 consecutive probes, were ≥20 Kb in size, had ≤20% overlap with common variants in population reference controls, and had ≤20% overlap with any variant previously detected in other birth defect phenotypes screened in our laboratory. We identified 17 candidate autosomal CNVs; 10 cases each had one CNV and four cases each had two CNVs. The CNVs included a 158 Kb duplication at 4q22 that overlaps the BMPR1B gene; duplications of different sizes carried by two cases in the intron of STIM1 gene; a 67 Kb duplication 202 Kb downstream of the NOG gene, and a 1.34 Mb deletion including the MYOCD gene. The identified rare CNVs spanned genes involved in mesodermal, muscle, and urinary tract development and differentiation, which might help in elucidating the genetic contribution to PBS. We did not have parental DNA and cannot identify whether these CNVs were de novo or inherited. Further research on these CNVs, particularly BMP signaling is warranted to elucidate the pathogenesis of PBS.     

Contribution of BRCA1 and BRCA2 germline mutations to the incidence of early-onset breast cancer in Cyprus

In Cyprus, the prevalence of breast cancer associated with BRCA1 and BRCA2 mutations in young women is unknown. In this study, we present the results of mutational analysis of the BRCA1 and BRCA2 genes in 26 Cypriot women diagnosed with breast cancer by the age of 40. The entire coding regions, including splice sites, of the BRCA1 and BRCA2 genes were sequenced using cycle sequencing. We identified four pathogenic mutations: two in BRCA1 [c.1840A>T (K614X), c.5310delG (5429delG)] and two in BRCA2 [c.3531-3534delCAGC (3758del4), c.8755delG (8984delG)] in six of 26 unrelated patients. The BRCA2 mutation c.3531-3534delCAGC (3758del4) is novel and the BRCA1 mutation c.1840A>T (K614X) is reported for the first time in Cypriot patients. The BRCA2 Cypriot founder mutation c.8755delG (8984delG) was detected in three unrelated patients. Additionally, we identified one novel BRCA1 missense mutation, two novel polymorphisms and three novel intronic variants of which BRCA1 c.4185+3A>G (IVS12+3A>G) may be pathogenic. Of the six BRCA1/2 mutation carriers, only four had a family history. These results show that the prevalence of BRCA1 and BRCA2 mutations in Cypriot women diagnosed with early-onset breast cancer is high. We conclude that Cypriot women with early-onset breast cancer should be offered BRCA1/2 testing irrespective of their family history.