Prolonged fever of unknown origin and hemophagocytosis evolving into acute lymphoblastic leukemia

Hemophagocytic syndrome (HPS) is an unusual acute syndrome presenting with fever, hepatosplenomegaly, and cytopenias. The hallmark of HPS is the accumulation of activated macrophages that engulf hematopoietic cells in the reticuloendothelial system. Most cases of HPS in adults are secondary to infection or malignancy, and thus investigation of the underlying disease is necessary. We describe a patient with prolonged fever, HPS, and chromosomal abnormalities in the bone marrow who underwent thorough evaluation for the cause of his symptoms. A final diagnosis of acute lymphoblastic leukemia (ALL) was established in a fourth, repeated bone marrow biopsy performed more than 2 months after the first presenting symptom appeared. This unusual case demonstrates the importance of cytogenetic abnormalities found in cases of HPS and the importance of repeated testing when an underlying disease is suspected.     

Atherosclerotic pattern of coronary myocardial bridging assessed with CT coronary angiography

The aim of our study was to evaluate the atherosclerotic pattern of patients with coronary myocardial bridging (MB) by means of CT Coronary Angiography (CT-CA). 254 consecutive patients (166 male, mean age 58.6 ± 10.3) who underwent 64-slice CT-CA according to current clinical indications were reviewed for the presence of MB and concomitant segmental atherosclerotic pattern. Coronary plaques were assessed in all patients enrolled. 73 patients (29%) presented single (90%) or multiple (10%) MB, frequently (93%) localized in the mid-distal left anterior descending artery. The MB segment was always free of atherosclerosis. Segments proximal to the MB presented: no atherosclerotic disease (n = 37), positive remodeling (n = 23), <50% (n = 14), or >50% stenoses (n = 7). Distal segments presented a different atherosclerosis pattern (P < 0.0001): absence of disease (n = 73), no significant lesions (n = 8). No significant differences were found between segments proximal to MB and proximal coronary segments apart from left main trunk. Pattern of atherosclerotic lesions located in segments 6 and 7 significantly differs between patients with MB and patients without MB (P < 0.05). CT-CA is a reliable method to non-invasively demonstrate MB and related atherosclerotic pattern. CT-CA provides new insight regarding atherosclerosis distribution in segments close to MB.     

Epidemiology of Crohn's disease in Israel: a survey of Israeli kibbutz settlements

OBJECTIVE: The prevalence of Crohn's disease ranges from 10 to 70 cases per 100,000 population, and is 3-8 times more common among Jews. However, this excess risk is not evident in the Jewish population of Israel. Recently we have described a significant increase in the prevalence and incidence of Crohn's disease in the south of Israel. The aim of this study was to confirm this trend in a stable population found in communal (kibbutz) settlements. METHODS: We repeated a community-based survey in 124,400 kibbutz residents, 10 yr after our first study. This population represents 5% of the Jewish population of Israel. All Crohn's disease patients were located by contacting the kibbutz clinics of the 269 kibbutz settlements (100% compliance). Data was updated to December 31st, 1997, which was designated the point prevalence date, and included information on gender, age, origin, education, profession, extent of the inflammatory process, clinical spectrum of the disease, therapy, complications of the disease, and treatment. The average annual incidence for the 10 yr was calculated from the prevalence data. Only cases with a definite diagnosis of Crohn's disease made in a recognized gastroenterology unit were accepted into the study. RESULTS: There were 81 confirmed cases of Crohn's disease and the prevalence rate rose from 25.5/100,000 in 1987 to 65.1/100,000 in 1997 (p < 0.001). The mean annual incidence rate for this period (1987-1997) is 5.0/100,000/yr. Prevalence rates were higher in women than men, and in those born in Israel or Europe/America than in Asia/Africa. The mean age at presentation of the disease was lower in 1997 than in 1987, 37.4 +/- 17.0 and 45.0 +/- 17.0 yr, respectively (p = 0.041). Prevalence was highest in men with > 16 yr of education, and in women with 11-12 yr education, 119.7 and 100.3/100,000, respectively. CONCLUSIONS: During the decade 1987-1997, the prevalence of Crohn's disease has increased in Israel and is approaching the rates in Europe and America.     

Distribution of treated mental illness in the neighborhoods of Jerusalem

The authors compared the rates of treated mental illness among ethnically advantaged Ashkenazic Jews and ethnically disadvantaged Sephardic Jews in four areas of Jerusalem defined by socioeconomic status. They found that the rates of illness were higher in areas of lower socioeconomic status, that the Ashkenazim had higher rates of illness than the Sephardim in the areas of lower status, and that there was a comparatively high rate of illness among the Ashkenazim in the very religious Jewish neighborhoods. They interpret these findings on the basis of the theories of social causation and social selection, including genetic transmission.     

Salmonella diskitis in a 2-year old immunocompetent child

Spine infections are uncommon in paediatrics and are generally caused by Staphylococcus aureus. Salmonella spp. are a rare cause of spine infections, usually affecting children with sickle-cell anaemia. We present a case of group C1 Salmonella diskitis in a previously healty 2-y-old child, and review the relevant literature.     

Prolonged pyrexia and lung metastases. A rare presentation of an occult epithelioid sarcoma

A 31-year-old patient presenting with fever of unknown origin, night sweats and weight loss, associated later with pulmonary nodules, is described. Multiple invasive diagnostic procedures, including exploratory laparotomy and open-lung biopsy, suggested a benign inflammatory granulomatous disease. Metastatic epithelioid sarcoma was ultimately diagnosed after biopsy of an enlarging groin mass. Epithelioid sarcoma should be considered in the differential diagnosis of prolonged fever, associated with granulomas of obscure etiology.     

Atomic structure and hierarchical assembly of a cross-β amyloid fibril

The cross-β amyloid form of peptides and proteins represents an archetypal and widely accessible structure consisting of ordered arrays of β-sheet filaments. These complex aggregates have remarkable chemical and physical properties, and the conversion of normally soluble functional forms of proteins into amyloid structures is linked to many debilitating human diseases, including several common forms of age-related dementia. Despite their importance, however, cross-β amyloid fibrils have proved to be recalcitrant to detailed structural analysis. By combining structural constraints from a series of experimental techniques spanning five orders of magnitude in length scale—including magic angle spinning nuclear magnetic resonance spectroscopy, X-ray fiber diffraction, cryoelectron microscopy, scanning transmission electron microscopy, and atomic force microscopy—we report the atomic-resolution (0.5 Å) structures of three amyloid polymorphs formed by an 11-residue peptide. These structures reveal the details of the packing interactions by which the constituent β-strands are assembled hierarchically into protofilaments, filaments, and mature fibrils.It is well established that a wide variety of peptides or proteins without any evident sequence similarity can self-assemble into amyloid fibrils (1, 2). These structures have many common characteristics, typically being 100–200 Å in diameter and containing a universal “cross-β” core structure composed of arrays of β-sheets running parallel to the long axis of the fibrils (3). These fibrillar states are highly ordered, with persistence lengths of the order of microns (4) and mechanical properties comparable to those of steel and dragline silk, and much greater than those typical of biological filaments such as actin and microtubules (5). Amyloid fibrils can also possess very high kinetic and thermodynamic stabilities, often exceeding those of the functional folded states of proteins (6), as well as a greater resistance to degradation by chemical or biological means (7). Several functional forms of proteins that exploit these properties have been observed in biological systems (8). More generally, however, the conversion of normally soluble functional proteins into the amyloid state is associated with many debilitating human disorders, ranging from Alzheimer’s disease to type II diabetes (1, 9). Our understanding of the nature of this type of filamentous aggregate has greatly improved in recent years (3, 10–19), particularly through the structural determination of their elementary β-strand building blocks (20) and the characterization of their assembly into cross-β steric zippers (21, 22). However, a thorough understanding of the hierarchical assembly of these individual structural elements into fully-formed fibrils, which display polymorphism but possess a range of generic features (23), has so far been limited by the absence of a complete atomic-resolution cross-β amyloid structures (2).We report here the simultaneous determination of the atomic-resolution structures of a cross-β amyloid fibril and two polymorphic variants, formed by an 11-residue fragment of the protein transthyretin, TTR(105–115) (20). These fibrils have the classic amyloid morphology, being 100–200 Å in diameter and typically 1–3 µm in length (SI Appendix, Fig. S1). We have achieved this objective by bringing together a set of complementary biophysical techniques to provide atomic structures of these complex aggregates. Specifically, we have combined interatomic structural restraints from magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy with high-resolution electron density maps from cryoelectron microscopy (cryo-EM), together with data from X-ray fiber diffraction, scanning transmission electron microscopy (STEM), and atomic force microscopy (AFM) measurements. Our results reveal the molecular basis of the stability and polymorphism of these amyloid fibrils by defining at high resolution the variety of structural elements in their hierarchical self-assembly.