Overview of the β Thalassemias: Genetic and Clinical Aspects

There has been much progress in basic studies of the β-thalassemia disorders in recent years, as well as in the practical aspects of prenatal diagnosis and clinical management. Alterations in a single or a few nucleotides account for most of the types of β-thalassemia syndromes that have been characterized, and a variety of deletions have been found associated with β^O thalassemia, δβ thalassemia, γδβ thalassemia, and hereditary persistence of fetal hemoglobin (HPFH). Studies of nondeletional types of HPFH have revealed several single base changes 5′ to the G_γ and A_γ genes, suggesting that these regions may be of major importance in the switchover from fetal to adult hemoglobin synthesis and in the relative production of the G_γ and A_γ globin chains during development. Evaluation of restriction enzyme polymorphisms and the assignment of haplotypes in the β-like globin region of chromosome 11 have allowed delineation of the origin and distribution of thalassemia mutations, and have provided an important means for prenatal diagnosis. These studies have accumulated much new information about the function and expression of eukaryotic genes, and have served as a model for the investigation of human genetic disorders.

The clinical management of patients with Cooley's anemia has benefited greatly from changes in transfusion practice, clear guidelines for splenectomy, and the availability of effective chelation therapy for iron overload. Current basic and clinical studies may lead to new approaches to management, treatment and eventual cures for this disease, including safe bone marrow transplantation, oral chelation treatment, and gene therapy.     

Primary Sj?gren Syndrome in Han Chinese: Clinical and Immunological Characteristics of 483 Patients

The epidemiological characteristics of Sjögren syndrome (SS) are significantly varied in different countries. We conducted the present study to survey the epidemiological characteristics of primary SS in China. We recruited 483 primary SS patients from 16 Chinese medical centers nationwide from January 2009 to November 2011 and assessed salivary and lacrimal gland dysfunction, organ involvement, and autoimmunity in these patients. The cohort included 456 women and 27 men (ratio, 17:1; mean age at onset, 42 ± 11 years; median age at diagnosis, 49 years; range, 41–56 years). Male patients showed a lower frequency of xerophthalmia (37.0% vs 60.7%) and a higher frequency of arthritis (40.7% vs 16.4%). Young-onset patients showed a higher frequency of low C3 levels (57.7% vs 36.3%) and pancytopenia (22.2% vs 8.8%). Patients with systemic involvement had a higher frequency of immunoglobulin A (IgA) (39.4% vs 22.5%) and immunoglobulin M (IgM) (12.4% vs 37.9%). Patients with pulmonary involvement had a higher parotid enlargement (21.4% vs 10.2%), purpura (12.1% vs 5.7%) and higher anti-La/SS-B (61.7% vs 41.8%), immunoglobulin G (IgG) (80.7% vs 64.6%) and IgA (48.9% vs 30.6%) levels. Patients with anti-Ro/SSA antibodies had more frequent exocrine gland symptoms and some extraglandular symptoms and immunological alterations. Compared with previous studies performed in other countries, SS patients in China showed particular clinical manifestation, systemic involvement, and immunological alterations.     

Impact of Ramadan on Clinical and Microbiologic Parameters of Patients Seen at a Diarrheal Hospital in Urban Dhaka,Bangladesh, 1996–2012

Ramadan is a month in the Islamic calendar when Muslims fast during daylight hours. We used data from the surveillance system of the International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka Hospital in Dhaka, Bangladesh, a predominantly Muslim country, to compare the etiology and clinical presentation of patients who presented with diarrhea during Ramadan to that of control periods, defined as the 30 days immediately before Ramadan. The proportion of infecting pathogens was largely the same, although Shigella spp. were less likely to be identified during Ramadan. Clinical presentations during Ramadan among adult Muslim diarrheal patients were also comparable to those admitted during control periods. A subgroup of cholera patients who presented after sunset during Ramadan had a shorter duration of diarrhea and higher prevalence of severe thirst, drowsiness, and severe dehydration. Our findings suggest that Ramadan has few effects on the profile of enteric pathogens and clinical features of adults seeking medical care for diarrhea.     

New Clinical Aspects of Behçet's Disease

Beh?et's disease/syndrome (BD) continues being aloof in his etiopathogenesis and very complex in its clinical manifestations. BD generates a good amount of scientific articles. For example, a simple search in PubMed sample that in the last 5 years has been published 1394 articles, 159 of them revisions. In addition to the basic studies on etiopahtogenesis and disease mechanisms, the diverse clinical manifestations and their treatments, also the own definition of the disease, its classification and the criteria of classification and diagnosis are debate source. In this article we reviewed some aspects in discussin as well as the last therapeutic alternatives and the situation of the EB in Spain.     

Primary Cytomegalovirus Infection in an Outpatient Setting—Laboratory Markers and Clinical Aspects

Abstract. Background: Occasionally, primary cytomegalovirus (CMV) infection may give rise to more or less severe clinical illness in immunocompetent adults. We retrospectively analyzed cases of acute CMV infection in medical outpatients. Patients and Methods: Over a 6-year period, we identified 22 patients with a febrile illness and hepatitis suffering from primary CMV infection. This was diagnosed on the basis of a strongly positive CMV IgM antibody test result and/or CMV IgG seroconversion. Clinical features as well as relevant laboratory results were analyzed. We also tested available samples for CMV glycoprotein B-specific antibodies and CMV IgG avidity and analyzed results of Epstein-Barr virus (EBV)-specific antibody assays. In addition, current age-specific CMV IgG seroprevalence rates were determined using 9,870 routine patient samples. Results: At presentation, all patients complained of malaise and fever higher than 38 °C, and many also complained of cephalgia. Most patients who underwent abdominal ultrasonography had an enlargement of the spleen. Most patients had a relative lymphocytosis but only three had a mild leukocytosis. C-reactive protein was only slightly elevated in 13 patients; all 22 patients had elevated levels of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH). Half the patients reported travel to areas outside western Europe, mostly to tropical and subtropical areas, within 3 weeks before onset of illness. Primary CMV infection was confirmed by negative anti-gB antibody test results and the absence of high-avidity CMV antibodies. In contrast, despite past EBV infection demonstrated by positive anti-EBNA-1 results, 15 out of 21 patients tested for EBV markers had positive or nonspecific IgM test results. The overall CMV IgG seroprevalence rate in the routine samples was 64.4%, with marked age-dependent increases. Conclusion: CMV is a relevant differential diagnosis in feverish illnesses accompanied by hepatitis in otherwise healthy adults, about 40% of whom are CMV-naïve. Half our patients seem to have acquired their CMV infection abroad, so that a diagnosis of CMV infection needs to be taken into account in travelers, in addition to infectious illnesses more commonly considered in this context, such as dengue or hepatitis A. For diagnosis, both CMV and EBV antibody studies should be performed and the inclusion of assays able to demonstrate past infection is helpful for achieving a definite diagnosis.     

Clinical Expression of ‘Silent’ Hepatitis B Virus Infection in a Patient with Visceral Leishmaniasis

A 69-year-old male was hospitalized in January 1999 because of viszeral leishmaniasis. He had also suffered from anti-hepatitis C virus (HCV)-positive chronic hepatitis for years. All serum hepatitis B virus (HBV) antigens and antibodies were negative except for anti-HBc. The patient was treated with amphotericin B cholesteryl sulfate (2 mg/kg twice a day for 7 days, iv). Fever disappeared on the 3rd day of treatment, the clinical condition improved rapidly and the patient recovered. In May 1999 the patient developed iteric HBsAg-negative acute hepatitis (aspartate aminotransferase 722 U/l; alanine aminotransferase 988 U/l). Anti-HBc IgM was positive and HBV-DNA was detected in serum by PCR. Anti-HAV IgM was negative. A serum sample obtained on presentation and stored at −80°C was retrospectively tested and found positive for HBV-DNA. In July 1999, complete remission of acute hepatitis and seroconversion to anti-HBs was observed. We suppose that a moderate depression of the immune system, probably associated with leishmaniasis, may have enhanced HBV replication in the patient who had an HBsAg-negative ‘silent’ HBV infection. Restoration of the immune system after successful antiprotozoan therapy might have induced cell-mediated necrosis of the HBV-infected hepatocytes and seroconversion to anti-HBs. Received: June 6, 2000 · Revision accepted: February 16, 2001     

Clinical–Morphological Features and Outcomes of Lupus Podocytopathy

Background and objectives

Lupus podocytopathy, which is characterized by diffuse foot process effacement without peripheral capillary wall immune deposits and glomerular proliferation, has been described in SLE patients with nephrotic syndrome in case reports and small series. This study aimed to better characterize the incidence, clinical–morphologic features, and outcomes of such patients from a large Chinese cohort.

Design, setting, participants, & measurements

Lupus podocytopathy was identified from 3750 biopsies of SLE patients obtained from 2000 to 2013 that showed mild glomerular histology in patients with a clinical sign of nephrotic syndrome. The biopsy results were divided into three groups: glomerular minimal change, mesangial proliferation, and FSGS.

Results

Fifty (1.33%) cases were identified as lupus podocytopathy and included minimal change in 13 cases, mesangial proliferation in 28 cases, and FSGS in nine cases. Extensive foot process effacement appeared in all the biopsies and mesangial electron-dense deposits were present in 47 biopsies. All patients demonstrated nephrotic syndrome, and the median proteinuria was 5.72 g/24 h (interquartile range [IQR], 3.82, 6.92). Seventeen (34%) cases presented with AKI. Forty-seven (94%) patients achieved remission after immunosuppressive therapy for a median time of 4 weeks (IQR, 2, 8). Compared with the patients with minimal change and mesangial proliferation, patients with FSGS showed significantly higher incidence of AKI and severe tubule–interstitial injury and a much lower complete remission rate. During follow-up of a median of 62 (IQR, 36, 84) months, renal relapses occurred in 28 (59.6%) patients. No patient died or developed ESRD.

Conclusions

The findings from this cohort study suggest that lupus podocytopathy may represent a special entity of lupus nephritis with distinct clinical–morphologic features. The differences in AKI incidence, tubular injury severity, and response to treatment between the patients with minimal change/mesangial proliferation and those with FSGS patterns indicate two different subtypes of lupus podocytopathy.     

Survey of Wild Mammal Hosts of Cutaneous Leishmaniasis Parasites in Panamá and Costa Rica

The eco-epidemiology of American cutaneous leishmaniasis (ACL) is driven by animal reservoir species that are a source of infection for sand flies that serve as vectors infecting humans with Leishmania spp parasites. The emergence and re-emergence of this disease across Latin America calls for further studies to identify reservoir species associated with enzootic transmission. Here, we present results from a survey of 52 individuals from 13 wild mammal species at endemic sites in Costa Rica and Panama where ACL mammal hosts have not been previously studied. For Leishmania spp. diagnostics we employed a novel PCR technique using blood samples collected on filter paper. We only found Leishmania spp parasites in one host, the two-toed sloth, Choloepus hoffmanni. Our findings add further support to the role of two-toed sloths as an important ACL reservoir in Central America.     

Clinical and Serological Aspects of Patients with Anti-Jo-1 Antibodies – an Evolving Spectrum of Disease Manifestations

The aim of this study was to compare ELISA, immunodiffusion and immunoblot for the detection of anti-Jo-1 antibodies, and to investigate the association of the results with clinical manifestations. In two medical centres for rheumatology and one for pulmonology, all patients with suspected connective tissue disease were screened over a 5-year period for anti-Jo-1 antibodies by ELISA. Positive sera were controlled in another laboratory by immunodiffusion. If immunodiffusion was negative, sera were controlled again by ELISA. ELISA-positive immunodiffusion-negative sera were tested by immunoblotting. The patients were characterised clinically, and their clinical signs and symptoms were compared with those of 257 patients with anti-Jo-1 antibodies published in 15 case series and 30 case reports. Twenty-five patients had a positive ELISA test. Fifteen sera were positive by ELISA and immunodiffusion (group 1). Three sera showed high titres in both ELISA tests with negative immunodiffusion and immunoblot (group 2). Seven sera showed low titres in both ELISA tests. The results were negative in the other tests (group 3). Patients in groups 1 and 2 could be classified as Jo-1 syndrome patients. Of these 18 patients, 15 had arthritis, 14 had myositis and 14 had interstitial lung disease. Only four patients had myositis at disease onset. We describe four unusual patients with Jo-1 syndrome in detail: 1. Long history of seronegative rheumatoid arthritis; 2. Sjo¨gren’s syndrome with Ro- and La-antibodies; 3. Scleroderma and bronchial carcinoma with centromere antibodies; 4. Corticoid-sensitive psychosis. Patients with suspected connective tissue disease may be screened for anti-Jo-1 antibodies by ELISA. It detects some patients that are missed by immunodiffusion. Especially lower ELISA titres should be controlled by another method because of the low specificity of the test. The clinical picture is variable. Most patients have features other than myositis at disease onset. Received: 19 July 1999 / Accepted: 10 December 1999     

Biochemical and Molecular Aspects of β-Thalassemia Types in Northern Sardinia

Forty-three patients with β-thalassemia from Northern Sardinia (31 severe and polytransfused, six follow-up babies, five adults with mild thalassemia who were not transfusion dependent, and a young transfused patient was also affected by a disease of intermediate severity) were studied in order to establish the fetal hemoglobin composition, restriction fragment 1ength polymorphisin haplotypes at the β-globin gene cluster, and the type(s) of mutation. Haplotype II was prevalent, [56/86 chromosomes (65%)], haplotype I was also fairly common, [22/86 chromosomes (25%)], while other types were relatively rare. The nonsense mutation at codon 39 was nearly exclusive, [76/80 chromosomes (95%)]. Other β-thalassemia mutations occurred on chromosomes with haplotypes 111, IX, X, and perhaps V, and a new type related to II. The mutated A_γT gene was associated with type type II, X, and the new type. Type IX was linked to a βd` gene and to an Xmn I site 5′ to the G<sub>γ</sub> gene, to a high G<sub>γ</sub> globin level, and to a disease of mild severity. Type I11 was associated with a β<sup>+</sup>+-thalassemic gene. The d`39 mutation linked to type I1 was associated with thalassemia intermedia in three patients.     

False positivity of circumsporozoite protein (CSP)–ELISA in zoophilic anophelines in Bangladesh

Circumsporozoite protein enzyme-linked immunosorbent assays (CSP–ELISAs) are widely used for malaria vector identification throughout the world. However, several studies have reported false-positive results when using this method. The present study was conducted to estimate the frequency of false positives among anopheline species in malaria endemic areas of Bangladesh. In total, 4724 Anopheles females belonging to 25 species were collected and tested for Plasmodium falciparum, Plasmodium vivax-210, and P. vivax-247 CSP. Initially, 144 samples tested positive using routine CSP–ELISA, but the number of positive results declined to 85 (59%) when the samples were tested after heating at 100° C for 10 min to remove false-positive specimens. Ten species, Anopheles annularis, Anopheles baimaii, Anopheles barbirostris, Anopheles jeyporiensis, Anopheles karwari, Anopheles kochi, Anopheles minimus s.l., Anopheles peditaeniatus, Anopheles philippinensis, and Anopheles vagus were CSP-positive. The highest and lowest infection rates were found in An. baimaii (4/25, 16.0%) and An. jeyporiensis (1/139, 0.67%), respectively. A significant correlation was found (regression analysis, R² = 0.49, F = 8.25, P < 0.05) between human blood index results and the true CSP-positive ratios in 15 Anopheles species. We confirmed that false-positive reactions occurred more frequently in zoophilic species. The relatively high proportion of false positives (40%) that was found in this study should warn malaria epidemiologists working in the field to be cautious when interpreting ELISA results.     

Clinical Efficacy of L-Ornithine–L-Aspartate in the Management of Hepatic Encephalopathy

The clinical efficacy of both oral and parenteral L-ornithine–L-aspartate (OA) was confirmed by randomized, placebo-controlled, double-blind studies in patients with manifest hepatic encephalopathy and hyperammonemia. The drug was able to reduce high blood ammonia levels induced either by ammonium chloride or protein ingestion or existing as a clinical complication of cirrhosis per se. Furthermore, OA improved performance in Number Connection Test-A as well as mental state gradation. In contrast to the positive effects observed in patients with more advanced hepatic encephalopathy, oral OA does not seem to affect minimal hepatic encephalopathy. In a recent trial, OA decreased protein breakdown and stimulated protein synthesis in muscle. The therapy had little side effects, increasing with higher intravenously administered dosages, and was well tolerated after oral and parenteral administration.     

The Important Role of Inflammatory Biomarkers Pre and Post Bare–Metal and Drug–Eluting Stent Implantation

In-stent restenosis and stent thrombosis are major complications after percutaneous coronary intervention and coronary stent placement. The inflammatory status of an individual, as reflected by biomarkers and genetic polymorphisms, is a strong predictor of the risk of in-stent restenosis and stent thrombosis. Identifying biomarkers and studying their values are crucial for a more efficient personalized intervention. General inflammatory biomarkers, evidence of inflammation, and the difference between inflammatory biomarkers after bare-metal stent and drug-eluting stent placement are discussed. Clinical implications and the use of antiplatelet and anti-inflammatory medications, as well as future directions in coronary intervention, in reducing the occurrence of these complications, are also discussed.     

Twelve years of biennial Japanese–German Workshops 'on Molecular and Cellular Aspects of Carcinogenesis

This report describes and comments upon the 12-year-long history of a successful joint activity of leading Japanese and German scientists in the field of basic cancer research, the Essen Series of Biennial Japanese-German Workshops on Molecular and Cellular Aspects of Carcinogenesis.     

Mutation Spectrum of β-Thalassemia and Other Hemoglobinopathies in Chittagong,Southeast Bangladesh

Abstract

Thalassemia is one of the most common autosomal recessive blood disorders in the world. It shows a variety of clinical expression, starting from asymptomatic to severe blood transfusion dependence. More than 500 alleles have been characterized in or around the β-globin region. Moreover, most geographical regions have their own characteristics, frequency and availability of these alleles, predominantly circulating within the communities present in that particular region. In this study, we explored the spectrum of β-thalassemia (β-thal) alleles present in Chittagong, Southeast Bangladesh. This study comprises β-thal and Hb E (HBB: c.79?G?>?A) patients from in and around the area of Chittagong. Not only exploring the complete β-globin mutation spectrum of the area, but we also tried to look at the origin of the mutated alleles. The β-thal mutations of Bangladesh show a relatively wide spectrum of alleles, which further demonstrates the heterogeneity of the disease in this country. Although our study showed that the majority of the mutations have their origin in neighboring countries such as India, countries of Southeast Asia, Pakistan, etc., some unusual alleles do not originate in neighboring countries and put a little more diversity in the overall spectrum of β-thal-specific alleles. Overall, this study demonstrates the mutation spectrum related to β-thal in Chittagong, Southeast Bangladesh.     

Clinical Outcomes of Dialysis Catheter–Related Candidemia in Hemodialysis Patients

Background and objectives: Candidemia is a rare complication in catheter-dependent hemodialysis patients. As a result, there is uncertainty about its optimal medical management. The goal of this retrospective study was to compare the clinical outcomes of catheter-related candidemia managed with two different strategies: Guidewire exchange of the infected catheter versus removal with delayed replacement.Design, setting, participants, & measurements: We retrospectively queried a prospective, computerized vascular access database to identify 40 hemodialysis patients with catheter-related candidemia. All patients underwent treatment with antifungal medications for 2 wk, in conjunction with guidewire catheter exchange or catheter removal with delayed replacement. The primary outcomes were major complications, recurrent candidemia, and patient survival.Results: Candidemia represented approximately 2% of all cases of catheter-related bloodstream infections. Of the 40 patients with candidemia, 27 underwent guidewire catheter exchange and 13 had prompt catheter removal with delayed replacement. The two treatment groups were similar in demographic, clinical, and catheter characteristics. Only 1 (2.5%) patient developed a serious complication (endophthalmitis). Recurrence of candidemia within 3 mo was observed in 15% of each treatment group. Patient survival at 6 mo was similar in both groups.Conclusions: Catheter-related candidemia is rare in hemodialysis patients and has a low complication rate. Catheter exchange over a guidewire in conjunction with antifungal therapy is an effective and safe treatment regimen.Candidemia is a widely recognized nosocomial infection in non-neutropenic hospitalized patients with intravascular catheters (1,2). It can be complicated by osteomyelitis, septic arthritis, endocarditis, central nervous system candidiasis, and endophthalmitis (3). Systemic antifungal agents do not eradicate the Candida catheter biofilm (4), suggesting that the central vein catheter should be removed in patients with catheter-related candidemia. Several large, prospective studies observed a shorter duration of candidemia, better clinical outcomes, and lower mortality when the central vein catheter was removed or replaced (1,2,5–7). These observations form the basis of the current guidelines, which recommend removing the intravascular catheter to eradicate the source of candidemia (3).Candidemia is a relatively uncommon complication of hemodialysis catheters; therefore, there are no large series describing its frequency, complications, or optimal medical management. Dialysis catheter–related candidemia is typically treated with an antifungal drug in conjunction with catheter removal and delayed placement of a new, tunneled dialysis catheter. This strategy creates hardship in managing the patient''s dialysis, because it requires placement of a temporary dialysis catheter. In patients with dialysis catheter–related bacteremia, exchange of the infected tunneled catheter for a new one over a guidewire can achieve a high cure rate while simplifying access management (8–12). It is unknown whether this strategy is effective and safe for management of dialysis catheter–related candidemia.The goal of this study was to evaluate the frequency and medical complications of dialysis catheter–related candidemia. In addition, we evaluated whether guidewire exchange of the infected tunneled catheter is a viable alternative to catheter removal with delayed replacement.