Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy characterized by a highly variable course and outcome. The disease is believed to be driven by B-cell receptor (BCR) signals generated by external antigens and/or cell-autonomous BCR interactions, but direct in vivo evidence for this is still lacking. To further define the role of the BCR pathway in the development and progression of CLL, we evaluated the capacity of different types of antigen/BCR interactions to induce leukemia in the Eμ-TCL1 transgenic mouse model. We show that cell autonomous signaling capacity is a uniform characteristic of the leukemia-derived BCRs and represents a prerequisite for CLL development. Low-affinity BCR interactions with autoantigens generated during apoptosis are also positively selected, suggesting that they contribute to the pathogenesis of the disease. In contrast, high-affinity BCR interactions are not selected, regardless of antigen form or presentation. We also show that the capacity of the leukemic cells to respond to cognate antigen correlates inversely with time to leukemia development, suggesting that signals induced by external antigen increase the aggressiveness of the disease. Collectively, these findings provide in vivo evidence that the BCR pathway drives the development and can influence the clinical course of CLL.

Between January 2014 and the beginning of February 2015, the Federal Institute of Public Health in the Federation of Bosnia and Herzegovina has reported 3,804 measles cases. Notable transmission has been observed in three Central Bosnia Canton municipalities: Bugojno, Fojnica and Travnik. Most cases were unvaccinated 2,680 (70%) or of unknown vaccination status 755 (20%). Health authorities have been checking vaccination records and performing necessary prevention measures. The epidemic is still ongoing.

BackgroundPol III-related leukodystrophies, including 4H leukodystrophy, are recently recognized disorders that comprise hypomyelination and various neurologic and non-neurologic clinical manifestations. We report the unique neurologic presentation of the micturition dysfunction in Pol III-related leukodystrophy and describe the novel endocrine abnormalities in this entity.Case presentationA 32-year-old Caucasian female exhibited chronic urinary incontinence that commenced at the age of 7 years and remained the unexplained symptom more than two decades before the onset of progressive neurologic decline. A transient growth failure and absent sexual development with hypoprolactinemia appeared in the meanwhile. Neurologic, endocrine, neuroradiologic, and genetic evaluation performed only in the patient’s thirties, confirmed the diagnosis of 4H leukodystrophy as the only cause of the micturition disturbance.ConclusionThe report shows for the first time that an unexplained chronic bladder dysfunction should be evaluated also as a possible 4H leukodystrophy, thus alerting to the unexpected neurologic and endocrine features in 4H leukodystrophy.

PFAPA syndrome is the most common autoinflammatory disorder in childhood with unknown etiology. The aim of our study was clinical evaluation of PFAPA patients from a single tertiary care center and to determine whether variations of AIM2, MEFV, NLRP3, and MVK genes are involved in PFAPA pathogenesis. Clinical and laboratory data of consecutive patients with PFAPA syndrome followed up at the University Children's Hospital, Ljubljana, were collected from 2008 to 2014. All four genes were PCR amplified and directly sequenced. Eighty-one patients fulfilled criteria for PFAPA syndrome, 50 (63%) boys and 31 (37%) girls, with mean age at disease onset of 2.1 ± 1.5 years. Adenitis, pharyngitis, and aphthae were present in 94%, 98%, and 56%, respectively. Family history of recurrent fevers in childhood was positive in 78%. Nineteen variants were found in 17/62 (27%) patients, 4 different variants in NLRP3 gene in 13 patients, and 6 different variants in MEFV gene in 5 patients, and 2 patients had 2 different variants. No variants of clinical significance were found in MVK and AIM2 genes. Our data suggest that PFAPA could be the result of multiple low-penetrant variants in different genes in combination with epigenetic and environmental factors leading to uniform clinical picture.

Summary Background: Oxidized low density lipoprotein (ox-LDL) and high-sensitive C-reactive protein (hs-CRP) are elevated in diabetes mellitus (DM) and associated with accelerated atherosclerosis. Little is known about their dynamics in the acute phase of ST segment elevation myocardial infarction (STEMI), especially in relation to the presence of DM and pre-diabetes (pre-DM). This study aimed to analyze timedependent changes in ox-LDL and hs-CRP regarding the presence of pre-DM and DM in STEMI patients treated by primary percutaneous coronary intervention (pPCI). Methods: In 103 consecutive patients with the first anterior STEMI ox-LDL and hs-CRP were measured before pPCI, on day 2 and day 7 after pPCI. Results: Patients were classified into: non-diabetics, pre-diabetics and diabetics. In each group the maximal ox-LDL concentration was found on admission, decreased on day 2 and reached the lowest values on day 7 (p<0.001). Diabetics had the highest ox-LDL concentrations compared to pre-diabetics and non-diabetics (on admission: p=0.028, on day 2: p=0.056, on day 7: p=0.004). hs-CRP concentration rose from admission, reached its peak on day 2 and decreased on day 7, in each group (p<0.001). Significant differences in hs-CRP concentrations were found between non-diabetics and pre-diabetics on admission (p=0.018) and day 2 (p=0.026). In a multivariate analysis DM was an independent determinant of high ox-LDL concentrations. Both ox-LDL and hs-CRP significantly correlated with Killip class, left ventricular ejection fraction, NT-proBNP and peak troponin I. Conclusions: In patients with the first STEMI treated by pPCI there were significant differences in ox-LDL and hs-CRP concentrations between non-diabetics, pre-diabetics and diabetics. Ox-LDL and hs-CRP concentrations were related to heart failure parameters. Kratak sadržaj Uvod: Oksidovani lipoprotein niske gustine (ox-LDL) i vi- sokosenzitivni C-reaktivni protein (hs-CRP) povišeni su u dijabetes melitusu (DM) i povezani sa ubrzanom atero- sklerozom. Malo je poznata njihova dinamika u akutnoj fazi infarkta miokarda sa elevacijom ST segmenta (STEMI), na- ročito uzavisnosti od prisustva DM ili predijabetesa (pre-DM). Ova studija je analizirala promenu koncentracija ox-LDL i hs-CRP u akutnoj fazi STEMI u odnosu na prisustvo pre- DM i DM kod bolesnika lečenih primarnom perkutanom koronarnom intervencijom (pPKI). Metode: Kod 103 konsekutivna bolesnika sa prvim pred- njim STEMI, hs-CRP i ox-LDL mereni su pre pPCI, drugog i sedmog dana nakon pPKI. Rezultati: Bolesnici su podeljeni u tri grupe: nedijabetičari, predijabetičari i dijabetičari. U svakoj grupi maksimalna koncentracija ox-LDL bila je na prijemu, smanjivala se drugog dana i postizala najniže vrednosti sedmog dana (p<0,001). Dijabetičari su uvek imali najviše vrednosti ох- LDL u poređenju sa predijabetičarima i nedijabetičarima (na prijemu: p=0,028, drugog dana: p=0,056 i sedmog dana: p=0,004). Koncentracija hs-CRP je u svakoj grupi rasla od prijema, postizala maksimalne vrednosti drugog dana i smanjivala se sedmog dana (p<0,001). Značajna razlika u koncentraciji hs-CRP između nedijabetičara i predijabetičara registrovana je na prijemu (p=0,018) i dru- gog dana (p=0,026). U multivarijantnoj analizi DM je bio nezavisan prediktor visokih koncentracija ox-LDL. I ox-LDL i hs-CRP su značajno korelisali sa Killip klasom, ejekcionom frakcijom leve komore, koncentracijom NT-proBNP i mak- simalnom vrednošču troponina I. Zaključak: Kod bolesnika sa prvim STEMI lečenim pPKI postojale su značajne razlike u koncentraciji ox-LDL i hs- CRP između nedijabetičara, predijabetičara i dijabetičara. Koncentracije ox-LDL i hs-CRP značajno su korelisale sa parametrima srčane insuficijencije.