Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma.

Background: Hereditary C1q deficiency is associated with early-onset autoimmunity causing SLE or SLE-like disease as well as increased risk for infections with encapsulated bacteria. It is a rare genetic condition inherited in an autosomal recessive manner, caused by mutations in C1q genes. Treatment and management of this rare disease are very complex and include prophylactic vaccination, antibiotics, and immunosuppressive drugs. There are two possible modalities for the replacement of the missing protein: regular fresh frozen plasma (FFP) administration and allogeneic hematopoietic stem cell transplant because the protein is derived from monocytes. Replacing C1q with FFP is being attempted in some patients with success in controlling the disease and in avoiding flare. Case Report: We report a case of sixteen-month-old girl with ulcerations in her mouth, skin erythema, and elevated liver enzymes. ANAs were positive, antibodies against dsDNA were negative, but she had positive anti-Smith antibodies. Complement complements C3 and C4 levels were normal. Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency. The girl has pathogenic homozygous nonsense mutation in C1qC gene, Arg69Ter (c205>T). The initial response to corticosteroid therapy was good. Regular fresh frozen plasma infusions keep her disease under control, and we were able to reduce the dose of corticosteroids. Conclusion: Young patients with cutaneous lesions resembling SLE, early onset of autoimmunity, with normal C3, C4, elevated ANAs, and negative anti-dsDNA, C1q deficiency should be suspected and complement screening tests should be done. It is important to exclude secondary C1q deficiency. FFP in our patient seems to be well tolerated, without any side effects, able to control the disease.

Electrochemical characterization and estimation of DNA-binding capacity of a series of novel ferrocene derivatives.

The synthesis of a series of methyl 2-alkyl-5-aryl-4-ferrocenoylpyrrolidine-2-carboxylates has been achieved by [3 + 2] dipolar cycloaddition of azomethine ylides to acryloylferrocene. The electrochemical properties of novel products were examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). These techniques revealed the quasi-reversible one-electron oxidation process. The DNA-binding capacity of all the products was also studied using CV and DPV, and significant interactions between synthesized compounds and nucleic acid, mostly of the electrostatic type, were disclosed. DFT calculations and molecular docking tests were carried out to gain a more exhaustive insight into the interactions of the obtained products with nucleic acid. A detailed characterization of the new compounds was performed by IR, NMR and elemental analyses, followed by single-crystal X-ray diffraction experiments for two representatives.

Design and synthesis of novel ferrocene-quinoline conjugates and evaluation of their electrochemical and antiplasmodium properties.

The tropical disease malaria is responsible for more than 400,000 deaths annually, especially in Southeast Asia and Africa. Although the number of malaria cases is declining, there still is an urgent need for novel antimalarial agents. The emergence of hybrid antimalarial agents and the precedence set by the antimalarial drug ferroquine (FQ) prompted us to design new ferrocene-containing quinoline structures. Herein, we report the efficient synthesis of three different series of ferrocene-quinoline conjugates and a class of ferrocene-containing heterotricycles in good to high yields. For all twenty novel ferrocenyl derivatives, electrochemical properties were investigated using cyclic voltammetry and antiplasmodium evaluation against a chloroquine-susceptible NF54 strain of the human malaria parasite Plasmodium falciparum was conducted, pointing to three compounds showing submicromolar potency. Subsequently, cytotoxicity assays against a Chinese Hamster Ovarian cell line and evaluation against a chloroquine-resistant strain of Plasmodium falciparum for these three compounds revealed selective and promising antiplasmodium activity.

Ferrier rearrangement promoted by an electrochemically generated zirconium catalyst.

In situ generated zirconium catalyst from a sacrificial zirconium anode was successfully applied to promote Ferrier rearrangement of 3,4,5-tri-O-acetyl-D-glucal and 6-deoxy-3,4-di-O-acetyl-L-glucal (3,4-di-O-acetyl-L-rhamnal) in the presence of three thiols and eleven thiophenols as nucleophiles. A simple constant current electrolysis (20 mA, 0.4 F mol(-1)) of an acetonitrile solution of lithium perchlorate (0.1 M) containing the corresponding glycal and S-nucleophiles, using a zirconium anode and a platinum cathode resulted in the successful synthesis of the corresponding 2,3-unsaturated peracetylated thioglycosides (with an average anomer ratio α/ß=4.129 in the case of peracetylated D-glucal and 8.740 in the case of L-rhamnal). The same procedure proved to be appropriate in synthesizing dihydropyran derivatives ('C-glycosides') using allyltrimethylsilane as the nucleophile (only 'α-anomers' were obtained). All new compounds were fully characterized by spectral data, whereas single-crystal X-ray analysis was performed for two thioglycosides.

Severe combined immunodeficiency in Serbia and Montenegro between years 1986 and 2010: a single-center experience.

Severe combined immunodeficiency (SCID), including the 'variant' Omenn syndrome (OS), represent a heterogeneous group of monogenic disorders characterized by defect in differentiation of T- and/or B lymphocytes and susceptibility to infections since birth. In the period of 25 years, between January 1986 and December 2010, a total of 21 patients (15 SCID, 6 OS) were diagnosed in Mother & Child Health Institute of Serbia, a tertiary-care teaching University hospital and a national referral center for patients affected with primary immunodeficiency (PID). The diagnoses were based on anamnestic data, clinical findings, and immunological and genetic analysis. The median age at the onset of the first infection was the 2nd month of life. Seven (33 %) patients had positive family history for SCID. Out of five male infants with T-B+NK- SCID phenotype, mutation analysis revealed interleukin-2 (common) gamma-chain receptor (IL2RG) mutations in 3 with positive X-linked family history, and Janus-kinase (JAK)-3 gene defects in the other two. Six patients had T-B-NK+ SCID phenotype and further 6 features of OS, 11 of which had recombinase-activating gene (RAG1or RAG2) and 1 Artemis gene mutations. One child with T+B+NK+ SCID phenotype as well had proven RAG mutation. One child each with T-B+NK+ SCID phenotype, CD8 lymphopenia and unknown phenotype remained without known underlying genetic defect. Of the eight patients who underwent hematopoetic stem cell transplant (HSCT) 5 survived, the other 13 died between 2 days and 12 months after diagnosis was made. Early diagnosis of SCID, before onset of severe infections, offers possibility for HSCT and cure. Education of primary-care pediatricians, in particular including awareness of the risk of using live vaccines and non-irradiated blood products, should improve prognosis of SCID in our setting.

Disseminated crusted papules in a newborn.

BACKGROUND: Congenital self-healing Langerhans cell histiocytosis (Hashimoto-Pritzker disease) is the rarest form of Langerhans cell histiocytosis, usually confined to the skin and/or mucous membranes. Cutaneous eruption is mostly generalized, papular, nodular or vesicular. Despite impressive clinical presentation in a newborn it infrequently spreads to internal organs (which then portends a grave prognosis, indistinguishable from Letterer-Siwe disease). CASE REPORT: We presented a full-term newborn, female, 3.3 kg who had a multitude of erythematous and crusted papules, nodules and pseudovesicles distributed all over the body, except for the mucous membranes. A biopsy and haematoxylin--eosin stain revealed dermal infiltration of pleomorphic histiocytes with eosinophilic ground-glass cytoplasm and round to bean-shaped nuclei. Over the next six weeks the eruption gradually subsided leaving no residues, or a few atrophic scars. CONCLUSION: There is no need for specific treatment of congenital self-healing Langerhans cell-histiocytosis in the absence of multiorgan involvement. However, a close and regular follow-up is necessary to evaluate the children for systemic symptoms and signs.

Fever of unknown origin in 185 paediatric patients: a single-centre experience.

AIM: We conducted a prospective study to evaluate the causes and outcome in children with fever of unknown origin (FUO). METHODS: From 1990 to 1999, 185 children with FUO were evaluated. Initial evaluation included routine haematological analysis, Epstein-Barr virus (EBV) serology, urine, stool or blood cultures, chest X-ray and tuberculin probe. RESULTS: In 131 (70%) patients diagnosis was established, and 70 (37.8%) had infectious disease. EBV infection was the most common infection followed by visceral leishmaniasis (VL), urinary tract infection (UTI) and tuberculosis. Autoimmune disorders were diagnosed in 24 (12.9%), Kawasaki disease in 12 (6.4%), malignant diseases in 12 (6.4%) and miscellaneous conditions in 15 (8.1%) patients. In the remaining 54 (30%) patients, diagnosis was not established and most of them had self-limited disease. During the investigation, 26 (14%) patients developed serious organ dysfunction and five patients (two with virus-associated haemophagocytic syndrome, one with VL and two unknown) died. CONCLUSION: The most important infectious causes of FUO in our study were EBV infection and VL. Kawasaki disease represented a significant cause of FUO at the beginning of our study because it was not recognized by primary-care physicians. We report myelodysplastic syndrome as another emerging cause of paediatric FUO. Repeated clinical examination and careful use of specific laboratory examinations, invasive diagnostic procedures or imaging are crucial in approaching paediatric FUO.

Idiopathic CD4+ lymphocytopenia and juvenile laryngeal papillomatosis.

We report on an association of idiopathic CD4+ lymphocytopenia (ICL) and juvenile laryngeal papillomatosis (JLP) in a pediatric-aged patient. Because of a past medical history of recurrent lung infections and severe chickenpox in infancy, immunologic investigations were done at age 6 years. On several occasions, a CD4+lymphocyte count of <300 cells/mm3 was detected, supporting the diagnosis of ICL. During follow-up, both medical (interferon-alpha) and surgical treatments of JLP were only partially efficient. Our patient developed disseminated infection with Mycobacterium avium and died at 10 years of age. Human papillomavirus is an important pathogen in pediatric and adult patients with ICL. In pediatric patients with JLP who develop other unusually severe viral or opportunistic infections, immunological investigations should be considered.

Lupus nephritis in childhood: a review of 53 patients followed at a single center.

We retrospectively evaluated the clinical and histopathological features, treatment modalities, and outcome of 53 children and adolescents with biopsy-proven lupus nephritis (LN), followed between September 1983 and September 2001. The mean age (+/-SD) at the time of diagnosis of systemic lupus erythematosus (SLE) was 12.9+/-2.6 years and the mean follow-up from the time of biopsy was 4.8+/-3.4 years. At the time of biopsy, all 53 patients had proteinuria, 21 (40%) had nephrotic syndrome, and 14 (26%) had impaired renal function. Class IV nephritis, observed in 34 (64%) patients, was the most frequent histopathology on initial renal biopsy. The patients with class IV LN had a significant tendency to develop hypertension ( P=0.04) and nephrotic syndrome ( P=0.027), and a lower mean glomerular filtration rate ( P=0.000). Based on the renal histopathology and clinical presentation, patients were treated with corticosteroids alone or combined with azathioprine or with intravenous cyclophosphamide. Plasmapheresis or cyclosporine was used in 4 and 1 patient, respectively. Follow-up biopsies, performed in 13 patients, showed no change in 6 patients, were progressive in 4, and regressive in 3. On final clinical evaluation, renal disease was in complete or partial remission in 42 of 53 patients (80%), 4 had clinically active disease but with normal renal function, and 7 (13%), all with WHO class IV LN, were classified as having an adverse outcome, i.e., either preterminal (2) or terminal (4) renal failure or death (1). Five-year kidney and patient survival rates from the time of biopsy to the endpoints of terminal renal failure or death were 88.6% and 98.1%, respectively, in the whole group, and 82.4% and 97.1%, respectively, in the WHO class IV group. Nephrotic syndrome and class IV nephritis at initial biopsy were the only parameters significantly associated with adverse outcome in our study group. There was no association with gender, age, hypertension, impaired renal function, anemia, increased morphological index scores, and treatment modalities. We conclude that clinical and histopathological features of LN and treatment regimens in our study do not differ markedly from those in most pediatric series. However, the 5-year kidney and patient survival rates are among the best reported in recent pediatric series. The prognosis of LN is primarily dependent on the histopathological lesions.

Long-term follow-up and prognosis of chronic granulomatous disease in Yugoslavia: is there a role for early bone marrow transplantation?

We report the long-term follow-up of 12 pediatric-aged patients with chronic granulomatous disease (CGD). The mean age at the onset of infections was 5 months with a median delay in diagnosis of 2.5 years. Bacille Calmette-Guérin lymphadenitis was the most common presenting infection (6) followed by suppurative lymphadenitis (4), liver abscess (1), or Salmonella sepsis (1). Prophylaxis with cotrimoxazole was recommended to all patients. During the mean follow-up of 10 years (range, 4-23 years) pneumonitis was the most prevalent infection (91%) followed by lymphadenitis (83%), aphtous stomatitis (58%), and liver abscesses (25%). Seven (58%) patients developed chronic lung disease due to grossly delayed diagnosis (3) or poor compliance with antimicrobial prophylaxis (4). Five (41%) patients died during the second decade of life of aspergillosis (3) or chronic lung disease (2). Probability of survival into the third decade of life was estimated to be only 19%. We argue that HLA-identical bone marrow transplantation (BMT), if possible, should be attempted at early age because of significant morbidity and mortality in adolescence. BMT also should be considered in patients who suffer severe infections despite antimicrobial prophylaxis or patients with evidence of chronic lung disease. Possibility of elective BMT from unrelated donors remains to be carefully evaluated.

[Lupus nephritis in children and adolescents: clinical and morphologic aspects and clinico-morphologic correlations]. / Lupusni nefritis kod dece i adolescenata: klinicke i morfoloske odlike i klinicko-morfoloska korelacija.

In 53 children and adolescents (47 males, 6 females) with lupus nephritis, clinical features at the time of renal biopsy were analyzed and correlated with pathohistological findings. The mean age at the time of diagnosis of systemic lupus was 12.9 +/- 2.6 (SD) years; the mean ages at the time of diagnosis of lupus nephritis and renal biopsy were 13.5 +/- 2.6 and 13.6 +/- 2.5 years, respectively. The most frequent clinical and laboratory features of lupus nephritis at the time of biopsy were proteinuria (100% of patients), haematuria (88%), nephrotic syndrome (38%), hypertension (32%), and decreased glomerular filtration rate (26%). On initial biopsy, the most frequent finding was diffuse proliferative glomerulonephritis (in 64.1%), followed by "mesangiopathy" (20.8%), minimal changes (7.5%), membranous nephropathy (5.8%), and focal proliferative nephritis (1.9%). Nephrotic syndrome, hypertension, decreased glomerular filtration rate, and haematuria were significantly associated with WHO classes IV and III of lupus nephritis.

[Lupus nephritis in children and adolescents: therapy, clinical course and prognosis]. / Lupusni nefritis kod dece i adolescenata: terapija, klinicki tok i prognoza bolesti.

In 53 children and adolescents (47 males, 6 females) with lupus nephritis, clinical features at the time of renal biopsy were analyzed and correlated with pathohistological findings. Therapeutic regimens used and the renal status at the end of follow-up are presented, and factors significantly associated with adverse outcome are analyzed. The mean age at the time of diagnosis of systemic lupus was 12.9 +/- 2.6 (SD) years, the mean ages at the time of diagnosis of lupus nephritis and renal biopsy were 13.5 +/- 2.6 and 13.6 +/- 2.5 years, respectively. The patients having WHO classes I and II of lupus nephritis were treated with prednisone and/or azathioprine; those with WHO classes IV and III were treated with cyclophosphamide (25) or with corticosteroids (5) or with corticosteroids and azathioprine (4), five of them were also treated with plasmapheresis; the patients with WHO class V were treated with prednisone and azathioprine or cyclosporine. Repeated renal biopsies were performed in 12 patients: worsening of morphological lesions was found in four patients, improvement in two and no change was observed in six patients (all with WHO class IV). At the end of follow-up lasting from 0.1 to 14.6 years (mean 4.8 +/- 3.2 years) 80% of patients were in complete (49%) or partial (30%) remission, in 8% of patients the renal disease was clinically active, and in 13% of patients the adverse outcome was noted: one patient died in the first month after diagnosis from extrarenal complications, two patients were in preterminal and the other four in terminal renal failure. Adverse outcome was significantly associated with the presence of nephrotic syndrome at the time of biopsy and with class IV nephritis. The five-year patient's survival rate was 98.1%. The five-year kidney survival rate was 88.6% and 82.4% for the whole group and for the subgroup of patients having classes III and IV nephritis, respectively.