A novel mutation of IL1RN in the deficiency of interleukin‐1 receptor antagonist syndrome: Description of two unrelated cases from Brazil

Objective

Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high‐titer autoantibodies or antigen‐specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal‐onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin‐1 (IL‐1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN.

Methods

Two unrelated Brazilian patients were evaluated for the clinical signs and symptoms of these 3 disorders, and peripheral blood samples were assessed for mutations in NLRP3, LPIN2, and IL1RN by DNA resequencing analysis. A mutation in IL1RN that encodes a mutant protein was identified, and the expression and function of this mutant protein were compared to those of the wild‐type protein.

Results

Both patients presented with pustular dermatitis resembling generalized pustular psoriasis, recurrent multifocal aseptic osteomyelitis, and elevation in the levels of acute‐phase reactants, all of which are features most consistent with the DIRA syndrome. Chronic lung disease was observed in 1 of the patients, and jugular venous thrombosis was observed in the other patient. Both patients showed a partial response to corticosteroid therapy, and 1 patient experienced an initial improvement of dermatitis with the use of acitretin. Both patients were homozygous for a novel 15‐bp (in‐frame) deletion on the IL1RN gene. The mutated protein expressed in vitro had no affinity with the IL‐1 receptor, and stimulation of the patients' cells with recombinant human IL‐1α or IL‐1β led to oversecretion of proinflammatory cytokines, similar to the findings obtained in previously reported patients.

Conclusion

The presence of the same homozygous novel mutation in IL1RN in 2 unrelated Brazilian patients suggests that this genetic variant may be a founder mutation that has been introduced in the Brazilian population.

     

Lower extremity physical performance, self-reported mobility difficulty, and use of compensatory strategies for mobility by elderly women

Ganesh SP, Fried LP, Taylor DH Jr, Pieper CF, Hoenig HM. Lower extremity physical performance, self-reported mobility difficulty, and use of compensatory strategies for mobility by elderly women.

Objective

To describe the relationship between lower extremity physical performance, self-reported mobility difficulty, and self-reported use of compensatory strategies (CSs) for mobility inside the home.

Design

Cross-sectional exploratory study.

Setting

Community-dwelling elders.

Participants

Disabled, cognitively intact women 65 years or older (N=1002), from the Women's Health and Aging Study I.

Interventions

Not applicable.

Main Outcome Measures

CS scale: no CS, behavioral modifications (BMs) only, durable medical equipment (DME) with or without use of BMs, and any use of human help (HH); and 3 dichotomous CS measures: any CS (vs none); DME+HH (vs BMs only, among users of any CS); any HH (vs DME only, among users of any DME/HH).

Results

Self-reported mobility difficulty and physical performance were significantly correlated with one another (r=−.57, P<.0001) and with the CS scale ([r=.51, P<.001] and [r=−.54, P<.0001], respectively). Sequential logistic regressions showed self-reported difficulty and physical performance were significant independent predictors of each category of CS. For the any CS and DME+HH models, the odds ratio for self-reported difficulty decreased by approximately 50% when physical performance was included in the model, compared with difficulty alone ([18.0 to 8.6] and [7.3 to 3.8], respectively), but both physical performance and difficulty remained significant predictors (P<.0001). The effects of covariates differed for the various CS categories, with some covariates having independent relationships to CS, and others appearing to have moderating or mediating effects on the relationship of self-reported difficulty or physical performance to CS.

Conclusions

Physical performance, self-reported difficulty, health conditions, and contextual factors have complex effects on the way elders carry out mobility inside the home.     

Five-year outcomes in high-risk participants in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study: a post hoc analysis

OBJECTIVE

To estimate baseline cardiovascular risk of 1,123 participants in the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study and to assess cardiac event rates and the effect of screening on outcomes in these higher-risk participants.

RESEARCH DESIGN AND METHODS

Baseline cardiovascular risk was assessed using four established methods: Framingham score, UK Prospective Diabetes Study (UKPDS) risk engine, criteria of the French-Speaking Association for the Study of Diabetes and Metabolic Diseases, and the presence or absence of metabolic syndrome. Cardiac events (cardiac death or nonfatal myocardial infarction) were assessed during the 4.8-year follow-up in participants with intermediate/high cardiovascular risk.

RESULTS

By various risk-stratification approaches, 53–75% of participants were defined as having intermediate or high cardiovascular risk. The prevalence of inducible ischemia on screening in these individuals ranged from 21 to 24%, similar to lower-risk participants (19–23%). Cardiac event rates were greater in intermediate-/high-risk versus low-risk groups, but this was only significant for the UKPDS risk engine (4.2 vs. 1.2%, P = 0.002). The annual cardiac event rate was <1% in all risk groups, except in the high-risk UKPDS group (∼2% per year). In intermediate-/high-risk participants randomized to screening versus no screening, 4.8-year cardiac event rates were similar (2.5–4.8% vs. 3.1–3.7%).

CONCLUSIONS

A substantial portion of the DIAD population was defined as having intermediate/high baseline cardiovascular risk. Nevertheless, their annual cardiac event rate was low and not altered by routine screening for inducible ischemia.In the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, 1,123 asymptomatic individuals with type 2 diabetes were randomized to either screening with stress myocardial perfusion imaging (MPI) or no screening. The prevalence of inducible ischemia was assessed and the hypothesis that screening would have a favorable effect on outcome was tested. The results of the DIAD study have been published (1–3). The prevalence of abnormal MPI was not only lower than anticipated at 22% of participants, but, in addition, only 6% of participants had clinically significant inducible ischemia and another 6% had adenosine-induced ischemic electrocardiogram changes (1). The cumulative 4.8-year cardiac event rate (cardiac death and nonfatal myocardial infarction) was low (2.9% overall or 0.6% per year) (3). Moreover, there was no significant difference in cardiac outcomes between participants who were randomized to screening versus no screening. These favorable outcomes were unexpected when compared with historical outcomes data in patients with type 2 diabetes (4,5). One possible explanation for these findings could be that the DIAD population was at relatively low baseline cardiovascular risk and therefore not representative of the general type 2 diabetic population.To place the DIAD cohort into clear perspective, a post hoc analysis of baseline cardiovascular risk was performed using four well-known risk-stratification approaches, including the Framingham risk score (6), the UK Prospective Diabetes Study (UKPDS) risk engine (7), high-risk criteria as defined by the French-Speaking Association for the Study of Diabetes and Metabolic Diseases (ALFEDIAM) and the French Society of Cardiology (SFC) (8), and the presence of metabolic syndrome as defined by the International Diabetes Federation Taskforce (9). The prevalence of abnormal screening, cardiac event rates and the effect of screening on outcomes were analyzed in participants stratified as having intermediate/high cardiovascular risk (Fig. 1).Open in a separate windowFigure 1Flow diagram of the post hoc analysis of the DIAD data. Cardiac outcomes were reanalyzed in the not-low-risk participants who were randomized to no screening versus screening.     

Ferritin level at diagnosis is not correlated with poorer survival in non RBC transfusion dependent lower risk de novo MDS

We evaluated the prognostic value of serum ferritin (SF) level at diagnosis in 318 newly diagnosed IPSS low and int 1 (lower) risk MDS patients included in the French MDS registry, who did not require RBC transfusions and had baseline SF level determination. Increased baseline SF level (>300 ng/ml) was correlated with male gender, more pronounced anaemia, and diagnosis of RARS but had no negative impact on progression to AML or survival.     

Normative Data for Anthropometric Parameters Used in Delineation of Dysmorphic Features in North Indian Children

Objective  

To provide normative data for a set of anthropometric parameters which are commonly used in delineation of dysmorphic features.     

A pilot study to assess the feasibility,safety and cost of robotic assisted total hysterectomy and bilateral salpingo-oophorectomy

The aim of this study was to evaluate the safety, feasibility and cost-effectiveness of robotic assisted total hysterectomy and bilateral salpingo-oophorectomy (RATHBSO). Sixteen women underwent this new procedure for a variety of gynaecological indications. Outcome measures included operating time, estimated blood loss, length of hospital stay and cost. No intra-operative complications were recorded. Fifteen patients were discharged on day 1 following the procedure, and one patient stayed an extra day for pain relief. The cost of the procedure compared favourably with other surgical hysterectomy techniques. We conclude that RATHBSO is a feasible and safe surgical technique with all the advantages of minimal access surgery and equivalent cost.     

Radicular Stud Attachment: An Alternative to Improved Retention and Esthetics

With the increasing demand and popularity of dental implants, the use of removable partial dentures in replacing missing teeth has become less popular. One of the obvious limitations of RPD is the unsightly view of metal used for the retentive clasp and the difficulty in obtaining a good fit. This case report describes the use of a radicular stud attachment as an alternative method to obtain improved retention and esthetics.     

Perinatal hypophosphatasia presenting as neonatal epileptic encephalopathy with abnormal neurotransmitter metabolism secondary to reduced co-factor pyridoxal-5′-phosphate availability

We describe two neonates presenting with perinatal hypophosphatasia and severe epileptic encephalopathy resulting in death. Both had increased levels of urinary vanillactate, indicating functional deficiency of aromatic amino acid decarboxylase, a pyridoxal-5-phosphate (PLP)-dependent enzyme required for dopamine and serotonin biosynthesis. Clinical findings and results of subsequent metabolic investigations were consistent with secondary pyridoxine-deficient encephalopathy. These patients highlight the importance of tissue non-specific alkaline phosphatase in the neuronal PLP-dependent metabolism of neurotransmitters. In addition, the disturbance of PLP metabolism appears to underlie the predominant neurological presentation in our patients. We recommend the measurement of serum alkaline phosphatase (ALP) during the assessment of perinatal seizures.     

Prevention of sexually transmitted HIV infections through the President's Emergency Plan for AIDS Relief: a history of achievements and lessons learned

HIV prevention in the President's Emergency Plan for AIDS Relief (PEPFAR) began when both data on HIV prevalence and the toolbox of interventions for prevention of sexual transmission were relatively limited. PEPFAR's early focus was on scaling-up information, education, and communication programs that included messaging on abstinence for youth and faithfulness primarily through nongovernmental organizations, including faith-based organizations. Additional activities included condom promotion, distribution, and social marketing. In epidemics concentrated within key populations, PEPFAR's prevention efforts focused on a minimum package of services including outreach, information, education, and communication programs, STI treatment (where appropriate), and condom promotion and distribution. As more epidemiological data became available and with experience gleaned in these early efforts, the need for tailored and flexible approaches became evident. The next iteration of prevention efforts still emphasized behavioral interventions, but incorporated a sharper focus on key epidemic drivers, especially multiple partners; a data-driven emphasis on high transmission areas and populations, including prevention with people living with HIV; and a more strategic and coordinated approach at the national level. Recently, the paradigm for prevention efforts has shifted yet again. Evidence that biomedical interventions such as male circumcision, treatment for prevention of vertical and horizontal transmission, and treatment itself could lead to declines in incidence has refocused PEPFAR's prevention portfolio. New guidance on sexually transmitted HIV focuses on combination prevention, emphasizing biomedical, behavioral and structural approaches. Landmark speeches by the President and the Secretary of State and new ambitious targets for PEPFAR point toward a new goal: an AIDS-free generation.