Frontonasal Dysplasia, Severe Neuropsychological Delay, and Midline Central Nervous System Anomalies: Report of 10 Brazilian Male Patients

Here we report on 10 male patients with frontonasal dysplasia, cleft lip/palate, mental retardation, lack of language acquisition, and severe central nervous system involvement. Imaging studies disclosed absence of the corpus callosum, midline cysts, and an abnormally modeled cerebellum. Neuronal heterotopias were present in five patients and parieto-occipital encephalocele in three patients. We suggest that this pattern found exclusively in males, most likely represents a newly recognized syndrome distilled from the group of disorders subsumed under frontonasal dysplasia. (C) 2009 Wiley-Liss, Inc.

Craniometaphyseal Dysplasia With Severe Craniofacial Involvement Shows Homozygosity at 6q21-22.1 Locus

Craniotubular dysplasias (CTD) are a heterogeneous group of genetic disorders of skeletal development, whose clinical and etiological classification is still much debated. One of the most common form is the autosomal dominant craniometaphyseal dysplasia (CMD) which is associated with mutation in the ANKH gene. In the literature a few families are reported with CMD phenotype that suggest an autosomal recessive (AR) pattern of inheritance. A candidate locus at 6q21-22 has been mapped in a large inbred Brazilian family, but the gene of the recessive form is still unknown. Our data on a female patient with CMD phenotype, born from healthy first degree cousins and displaying homozygosity for polymorphic markers at the 6q21-22 locus, further support the existence of an AR CMD, expanding its clinical spectrum to a more severe phenotype. (C) 2011 Wiley-Liss, Inc.

UBE2A Deficiency Syndrome: Mild to Severe Intellectual Disability Accompanied by Seizures, Absent Speech, Urogenital, and Skin Anomalies in Male Patients

We describe three patients with a comparable deletion encompassing SLC25A43, SLC25A5, CXorf56, UBE2A, NKRF, and two non-coding RNA genes, U1 and LOC100303728. Moderate to severe intellectual disability (ID), psychomotor retardation, severely impaired/absent speech, seizures, and urogenital anomalies were present in all three patients. Facial dysmorphisms include ocular hypertelorism, synophrys, and a depressed nasal bridge. These clinical features overlap with those described in two patients from a family with a similar deletion at Xq24 that also includes UBE2A, and in several patients of Brazilian and Polish families with point mutations in UBE2A. Notably, all five patients with an Xq24 deletion have ventricular septal defects that are not present inpatients with a point mutation, which might be attributed to the deletion of SLC25A5. Taken together, the UBE2A deficiency syndrome in male patients with a mutation in or a deletion of UBE2A is characterized by ID, absent speech, seizures, urogenital anomalies, frequently including a small penis, and skin abnormalities, which include generalized hirsutism, low posterior hairline, myxedematous appearance, widely spaced nipples, and hair whorls. Facial dysmorphisms include a wide face, a depressed nasal bridge, a large mouth with downturned corners, thin vermilion, and a short, broad neck. (C) 2010 Wiley-Liss, Inc.

Mandibulofacial Dysostosis, Severe Lower Eyelid Coloboma, Cleft Palate, and Alopecia: A New Distinct Form of Mandibulofacial Dysostosis or a Severe Form of Johnson-McMillin Syndrome?

We describe a patient with a phenotype characterized by mandibulofacial dysostosis with severe lower eyelid coloboma, cleft palate, abnormal ears, alopecia, delayed eruption and crowded teeth, and sensorioneural hearing loss. The karyotype and the screening for mutations in the coding region of TCOF1 gene were normal. The clinical signs of our case overlap the new mandibulofacial dysostosis described by Stevenson et al. [2007] and the case with Johnson-McMillin syndrome described by Cushman et al. [2005]. The similar clinical signs, mainly, the severe facial involvement observed in these cases suggest that they can represent a new distinct form of mandibulofacial dysostosis or the end of the spectrum of Johnson McMillin syndrome. (C) 2010 Wiley-Liss, Inc.

Bone marrow mononuclear cells attenuate fibrosis development after severe acute kidney injury

One of the early phases that lead to fibrosis progression is inflammation. Once this stage is resolved, fibrosis might be prevented. Bone marrow mononuclear cells (BMMCs) are emerging as a new therapy for several pathologies, including autoimmune diseases, because they enact immunosuppression. In this study we aimed to evaluate the role of BMMC administration in a model of kidney fibrosis induced by an acute injury. C57Bl6 mice were subjected to unilateral severe ischemia by clamping the left renal pedicle for 1 h. BMMCs were isolated from femurs and tibia, and after 6 h of reperfusion, 1 x 10(6) cells were administrated intraperitoneally. At 24 h after surgery, treated animals showed a significant decrease in creatinine and urea levels when compared with untreated animals. Different administration routes were tested. Moreover, interferon (IFN) receptor knockout BMMCs were used, as this receptor is necessary for BMMC activation. Labeled BMMCs were found in ischemic kidney on FACS analysis. This improved outcome was associated with modulation of inflammation in the kidney and systemic modulation, as determined by cytokine expression profiling. Despite non-amelioration of functional parameters, kidney mRNA expression of interleukin (IL)-6 at 6 weeks was lower in BMMC-treated animals, as were levels of collagen 1, connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-beta) and vimentin. Protective molecules, such as IL-10, heme oxygenase 1 (HO-1) and bone morphogenetic 7 (BMP-7), were increased in treated animals after 6 weeks. Moreover, Masson and Picrosirius red staining analyses showed less fibrotic areas in the kidneys of treated animals. Thus, early modulation of inflammation by BMMCs after an ischemic injury leads to reduced fibrosis through modulation of early inflammation.

Toll-Like Receptor 4 Signaling Leads to Severe Fungal Infection Associated with Enhanced Proinflammatory Immunity and Impaired Expansion of Regulatory T Cells

Toll-like receptors (TLRs) present in innate immune cells recognize pathogen molecular patterns and influence immunity to control the host-parasite interaction. The objective of this study was to characterize the involvement of TLR4 in the innate and adaptive immunity to Paracoccidioides brasiliensis, the most important primary fungal pathogen of Latin America. We compared the responses of C3H/HeJ mice, which are naturally defective in TLR4 signaling, with those of C3H/HePas mice, which express functional receptors, after in vitro and in vivo infection with P. brasiliensis. Unexpectedly, we verified that TLR4-defective macrophages infected in vitro with P. brasiliensis presented decreased fungal loads associated with impaired synthesis of nitric oxide, interleukin-12 (IL-12), and macrophage chemotactic protein 1 (MCP-1). After intratracheal infection with 1 million yeasts, TLR4-defective mice developed reduced fungal burdens and decreased levels of pulmonary nitric oxide, proinflammatory cytokines, and antibodies. TLR4-competent mice produced elevated levels of IL-12 and tumor necrosis factor alpha (TNF-alpha), besides cytokines of the Th17 pattern, indicating a proinflammatory role for TLR4 signaling. The more severe infection of TLR4-normal mice resulted in increased influx of activated macrophages and T cells to the lungs and progressive control of fungal burdens but impaired expansion of regulatory T cells (Treg cells). In contrast, TLR4-defective mice were not able to clear their diminished fungal burdens totally, a defect associated with deficient activation of T-cell immunity and enhanced development of Treg cells. These divergent patterns of immunity, however, resulted in equivalent mortality rates, indicating that control of elevated fungal growth mediated by vigorous inflammatory reactions is as deleterious to the hosts as low fungal loads inefficiently controlled by limited inflammatory reactions.

Balanoposthitis caused by Pseudomonas aeruginosa co-producing metallo-beta-lactamase and 16S rRNA methylase in children with hematological malignancies

Balanoposthitis is defined as the inflammation of the glans penis and its foreskin. In the presence of other underlying medical conditions, this localized infection may spread systemically, serving as a source of fever and bacteremia in neutropenic males. Two rare cases of balanoposthitis caused by a clonally related Pseudomonas aeruginosa isolate co-producing the SPM-1 metallo-beta-lactamase and the novel 16S rRNA methylase RmtD are described. Four multidrug-resistant (MDR) P. aeruginosa isolates were successively recovered from glans/foreskin swabs and urine cultures from two uncircumcised pediatric patients, one with Burkitt`s non-Hodgkin`s lymphoma and one with acute lymphoblastic leukemia. Clinically, preputial colonization by MDR P. aeruginosa evolved to severe balanoposthitis with glans/foreskin lesions as a source of fever. Combination therapy of ciprofloxacin and/or aztreonam (systemic) plus polymyxin B (topical) was effective once reversion of the neutropenic condition was achieved. Although P. aeruginosa remains an unusual cause of balanoposthitis, these cases should alert the physician to the potential pathogenicity of this bacterium. Furthermore, co-production of metallo-beta-lactamase and 16S rRNA methylase has a potential impact on the empirical management of complicated infections caused by P. aeruginosa. Crown Copyright (C) 2009 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. All rights reserved.

Heme Impairs Prostaglandin E(2) and TGF-beta Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

In many hemolytic disorders, such as malaria, the release of free heme has been involved in the triggering of oxidative stress and tissue damage. Patients presenting with severe forms of malaria commonly have impaired regulatory responses. Although intriguing, there is scarce data about the involvement of heme on the regulation of immune responses. In this study, we investigated the relation of free heme and the suppression of anti-inflammatory mediators such as PGE(2) and TGF-beta in human vivax malaria. Patients with severe disease presented higher hemolysis and higher plasma concentrations of Cu/Zn superoxide dismutase (SOD-1) and lower concentrations of PGE(2) and TGF-beta than those with mild disease. In addition, there was a positive correlation between SOD-1 concentrations and plasma levels of TNF-alpha. During antimalaria treatment, the concentrations of plasma SOD-1 reduced whereas PGE(2) and TGF-beta increased in the individuals severely ill. Using an in vitro model with human mononuclear cells, we demonstrated that the heme effect on the impairment of the production of PGE(2) and TGF-beta partially involves heme binding to CD14 and depends on the production of SOD-1. Aside from furthering the current knowledge about the pathogenesis of vivax malaria, the present results may represent a general mechanism for hemolytic diseases and could be useful for future studies of therapeutic approaches. The Journal of Immunology, 2010, 185: 1196-1204.

Fonsecaea pedrosoi infection induces differential modulation of costimulatory molecules and cytokines in monocytes from patients with severe and mild forms of chromoblastomycosis

The host defense mechanism in chromoblastomycosis has not been thoroughly investigated. It has been suggested that cell- mediated immunity in patients with long- standing chromoblastomycosis is somehow impaired. As a result, these individuals became unable to develop an efficient immune reaction. Many studies have shown that monocyte- derived macrophages exhibit critical activities in immunity to microorganisms. Moreover, the ability of cells from the monocytic lineage to process and present antigens, to produce cytokines, and to provide costimulatory signals confirms their pivotal role in the initiation of specific immune responses. In the present study, it was observed that monocytes from patients with a severe form of disease had a higher production of IL- 10 and a lower expression of HLA- DR and costimulatory molecules when stimulated with specific antigen or LPS. Immune modulation with recombinant IL- 12 or anti- IL- 10 can restore the antigen- specific Th1- type immune response in chromoblastomycosis patients by up- regulating HLA- DR and costimulatory molecules in monocytes. Therefore, our data show that monocytes from patients with different clinical forms of chromoblastomycosis present distinct phenotypic and functional profiles. This observation suggests possible mechanisms that control the T cell response and influence their role in the development of pathology.

Severe novel influenza A (H1N1) infection in cancer patients

Patients and methods: Clinical data from all patients admitted with acute respiratory failure due to novel viral H1N1 infection were reviewed. Lung tissue was submitted for viral and bacteriological analyses by real-time RT-PCR, and autopsy was conducted on all patients who died. Results: Eight patients were admitted, with ages ranging from 55 to 65 years old. There were five patients with solid organ tumors (62.5%) and three with hematological malignancies (37.5%). Five patients required mechanical ventilation and all died. Four patients had bacterial bronchopneumonia. All deaths occurred due to multiple organ failure. A milder form of lung disease was present in the three cases who survived. Lung tissue analysis was performed in all patients and showed diffuse alveolar damage in most patients. Other lung findings were necrotizing bronchiolitis or extensive hemorrhage. Conclusions: H1N1 viral infection in patients with cancer can cause severe illness, resulting in acute respiratory distress syndrome and death. More data are needed to identify predictors of unfavorable evolution in these patients.

The most severe parkinsonian patients are most improved with duodenal levodopa infusion

Objectives:To find variables correlated to improvement with intraduodenal levodopa/carbidopa infusion (Duodopa) in order to identify potential candidates for this treatment. Two clinical studies comparing Duodopa with oral treatments in patients with advanced Parkinson’s disease have shown significant improvement in percent on-time on a global treatment response scale (TRS) based on hourly and half-hourly clinical ratings and in median UPDRS scores.Methods:Data from study 1 comparing infusion with Sinemet CR (12 patients, Nyholm et al, Clin Neuropharmacol 2003; 26(3): 156-163) and study 2 comparing infusion with individually optimised conventional combination therapies (18 patients, Nyholm et al, Neurology, in press) were used. Measures of severity were defined as total UPDRS score and scores for sections II and III, percent functional on-time and mean squared error of ratings on the TRS and as mean of diary questions about mobility and satisfaction (only study 2). Absolute improvement was defined as difference in severity, and relative improvement was defined as percent absolute improvement/severity on oral treatment. Pearson correlation coefficients between measures of improvement and other variables were calculated.Results:Correlations (r2>0.28, p<0.05) between severity during oral treatment and absolute improvement on infusion were found for: Total UPDRS, UPDRS III and TRS ratings (studies 1 and 2) and for diary question 1 (mobility) and UPDRS II (study 2). Correlation to relative improvement was found for total UPDRS (study 2, r2=0.47). Figure 1 illustrates absolute improvement in total UPDRS vs. total UPDRS during oral treatment (study 2).Conclusion:Correlating different measures of severity and improvement revealed that patients with more severe symptoms were most improved and that the relation between severity and improvement was linear within the studied groups. The result, which was reproducible between two clinical studies, could be useful when deciding candidates for the treatment.

Humming as a mean of communicating during meal time situations : A Single Case study involving a women with severe dementia and her caregiver

Objective: ‘Music Therapeutic Caregiving’, when caregivers sing for or together with persons with dementia during morning care situations, has been shown to increase verbal and nonverbal communication between persons with dementia and their caregivers, as well as enhance positive and decrease negative emotions in persons with dementia. No studies about singing during mealtimes have been conducted, and this pilot project was designed to elucidate this. However, since previous studies have shown that there is a risk that persons with dementia will start to sing along with the caregiver, the caregiver in this study hummed such that the person with dementia did not sing instead of eat. The aim of this pilot project was threefold: to describe expressed emotions in a woman with severe dementia, and describe communication between her and her caregivers without and with the caregiver humming. The aim was also to measure food and liquid intake without and with humming. Method: The study was constructed as a Single Case ABA design in which the ordinary mealtime constituted a baseline which comprised a woman with severe dementia being fed by her caregivers in the usual way. The intervention included the same woman being fed by the same caregiver who hummed while feeding her. Data comprised video observations that were collected once per week over 5 consecutive weeks. The Verbal and Nonverbal Interaction Scale and Observed Emotion Rating Scale were used to analyze the recorded interactions. Results: A slightly positive influence of communication was shown for the woman with dementia, as well as for the caregiver. Further, the women with dementia showed a slight increase in expressions of positive emotions, and she ate more during the intervention. Conclusion: Based on this pilot study no general conclusions can be drawn. It can be concluded, however, that humming while feeding persons with dementia might slightly enhance communication, and positive expressed emotions in persons with dementia. To confirm this, more studies on group levels are needed. Because previous studies have found that caregiver singing during caring situations influences persons with dementia positively it might be desirable to test the same during mealtime.

Análise clínica e epidemiológica do transplante de medula óssea no Serviço de Oncologia Pediátrica do Hospital de Clínicas de Porto Alegre

Objetivos: Descrever o perfil e as complicações agudas mais importantes das crianças que receberam transplante de medula óssea (TMO) em nosso Serviço. Casuística e métodos: Análise retrospectiva de 41 pacientes menores de 21 anos transplantados entre Agosto de 1997 até Junho de 2002. Deste total 20 receberam transplante alogênico e 21 receberam transplante autogênico. Resultados: No TMO alogênico a média de idade foi de 8,9 + 5,4 anos, sendo 12 pacientes do sexo masculino. As fontes de células foram: medula óssea (MO) 12, sangue periférico (SP) 5, sangue de cordão umbilical não aparentado (SCU) 3. As doenças tratadas foram leucemia linfóide aguda (LLA) 7 pacientes, leucemia linfóide crônica (LMC) 2; leucemia mielóide aguda (LMA) 4; Síndrome mielodisplásica 2; Linfoma de Burkitt 1, Anemia aplástica grave 1; Anemia de Fanconi 1; Síndrome Chediak Higashi 1; Imunodeficiência congênita combinada grave 1. Um paciente desenvolveu doença do enxerto contra hospedeiro (DECH) aguda grau 2 e três DECH grau 4. Três pacientes desenvolveram DECH crônica. Todos haviam recebido SP como fonte de células. A sobrevida global foi de 70,0 + 10,3%. A principal causa do óbito foi DECH em 3 pacientes e sépse em outros 3. Todos os óbitos ocorreram antes do dia 100. Um dos pacientes que recebeu SCU está vivo em bom estado e sem uso de medicações 3 anos e 6 meses pós TMO. No TMO autogênico, a média de idade foi de 8,7 + 4,3 anos, sendo 11 pacientes do sexo masculino. As fontes de células foram SP 16, MO 3, SP + MO 2. As doenças tratadas foram: tumor de Wilms 5; tumores da família do sarcoma de Ewing 4; neuroblastomas 3; linfomas de Hodgkin 3; rabdomiossarcomas 2, tumor neuroectodérmico primitivo do SNC 2; Linfoma não Hodgkin 1; LMA 1. A sobrevida global está em 59,4 + 11,7 %. Cinco óbitos tiveram como causa a progressão da doença de base, um óbito ocorreu devido à infecção 20 meses pós TMO e dois óbitos foram precoces por sépse. As toxicidades mais comuns em ambos os grupos foram vômitos, mucosite, diarréia e dor abdominal. Infecções foram documentadas em 58,5% dos pacientes e 46,9% tiveram no mínimo um agente isolado na hemocultura. Os tempos de enxertia de neutrófilos e plaquetas correlacionaram-se com o número de células progenitoras infundidas. Conclusão: A sobrevida de nossos pacientes é semelhante à encontrada na literatura de outros serviços nacionais e internacionais. Não encontramos diferença entre os dois tipos de transplante com relação às toxicidades agudas e ás infecções.

Nutrição parenteral como fator de risco para infecção relacionada a cateter venoso central

O uso de cateteres venosos centrais (CVC) para fins diagnósticos e terapêuticos está incorporado à prática médica diária. Complicações sérias, com elevada morbidade e mortalidade, como a sepse, estão associadas a este procedimento. O diagnóstico das infecções relacionadas a cateter é fundamentado em sinais clínicos e laboratoriais. Os fatores de risco para infecção devem ser considerados por ocasião da utilização de CVC e estão relacionados ao paciente, ao cateter, ao tipo de solução administrada, ao profissional que manipula o cateter e ao agente etiológico. A identificação destes fatores permite a intervenção precoce sobre os mesmos e o manejo adequado do CVC e das complicações clínicas relacionadas.