Craniofacial screening profile: quick screening for congenital malformations.

The correct identification of syndromes and other congenital malformations at an early age is critical for the child, family and care providers. Most specialists who conduct large screenings of young children are not adequately trained to recognize signs and symptoms that should lead to appropriate referral to the clinical geneticist and/or diagnostic team. A systematic approach for recognizing important signs is presented here; a Craniofacial Screening Profile. Following a brief training program, the Profile was validated by 39 speech-language pathologists in screening 3,539 kindergarten and first grade children. The results were excellent (specificity was 99.6%), demonstrating that with limited training, specialists can effectively screen for important signs and symptoms of a major group of syndromes and other congenital malformations.     

Geometrically based optimization for extracranial radiosurgery

For static beam conformal intracranial radiosurgery, geometry of the beam arrangement dominates overall dose distribution. Maximizing beam separation in three dimensions decreases beam overlap, thus maximizing dose conformality and gradient outside of the target volume. Webb proposed arrangements of isotropically convergent beams that could be used as the starting point for a radiotherapy optimization process. We have developed an extracranial radiosurgery optimization method by extending Webb's isotropic beam arrangements to deliverable beam arrangements. This method uses an arrangement of N maximally separated converging vectors within the space available for beam delivery. Each bouquet of isotropic beam vectors is generated by a random sampling process that iteratively maximizes beam separation. Next, beam arrangement is optimized for critical structure avoidance while maintaining minimal overlap between beam entrance and exit pathways. This geometrically optimized beam set can then be used as a template for either conformal beam or intensity modulated extracranial radiosurgery. Preliminary results suggest that using this technique with conformal beam planning provides high plan conformality, a steep dose gradient outside of the tumour volume and acceptable critical structure avoidance in the majority of clinical cases.     

Future C.E.O.'s in year 2002

Chief Executive Officers of mental health facilities have been interested civil leaders. Many doctors have accepted C.E.O. positions in our history. Today the competitions out to see who will be the future's C.E.O.'s. The rumors run from lawyers to clinicians from many of the hospital's disciplines and from purely administrative side of the hospitals management system. It will not be unusual to see more Ph.D., M.B.A.'s, or M.D., M.P.A. or M.S., M.H.A. degree combinations in year 2002.     

Anti‐C1 domain antibodies that accelerate factor VIII clearance contribute to antibody pathogenicity in a murine hemophilia A model

Essentials

• Inhibitor formation remains a challenging complication of hemophilia A care.
• The Bethesda assay is the primary method used for determining bleeding risk and management.
• Antibodies that block factor VIII binding to von Willebrand factor can increase FVIII clearance.
• Antibodies that increase clearance contribute to antibody pathogenicity.

Summary

Background

The development of neutralizing anti‐factor VIII (FVIII) antibodies remains a challenging complication of modern hemophilia A care. In vitro assays are the primary method used for quantifying inhibitor titers, predicting bleeding risk, and determining bleeding management. However, other mechanisms of inhibition are not accounted for in these assays, which may result in discrepancies between the inhibitor titer and clinical bleeding symptoms.

Objectives

To evaluate FVIII clearance in vivo as a potential mechanism for antibody pathogenicity and to determine whether increased FVIII dosing regimens correct the associated bleeding phenotype.

Methods

FVIII^?/? or FVIII^?/?/von Willebrand factor (VWF)^?/? mice were infused with anti‐FVIII mAbs directed against the FVIII C1, C2 or A2 domains, followed by infusion of FVIII. Blood loss via the tail snip bleeding model, FVIII activity and FVIII antigen levels were subsequently measured.

Results

Pathogenic anti‐C1 mAbs that compete with VWF for FVIII binding increased the clearance of FVIII–mAb complexes in FVIII^?/? mice but not in FVIII^?/?/VWF^?/? mice. Additionally, pathogenic anti‐C2 mAbs that inhibit FVIII binding to VWF increased FVIII clearance in FVIII^?/? mice. Anti‐C1, anti‐C2 and anti‐A2 mAbs that do not inhibit VWF binding did not accelerate FVIII clearance. Infusion of increased doses of FVIII in the presence of anti‐C1 mAbs partially corrected blood loss in FVIII^?/? mice.

Conclusions

A subset of antibodies that inhibit VWF binding to FVIII increase the clearance of FVIII–mAb complexes, which contributes to antibody pathogenicity. This may explain differences in the bleeding phenotype observed despite factor replacement in some patients with hemophilia A and low‐titer inhibitors.

     

Clinical similarities among bradykinin-mediated and mast cell-mediated subtypes of non-hereditary angioedema: a retrospective study

Background

Non-hereditary angioedema (non-HAE) is characterized by local swelling due to self-limiting, subcutaneous or submucosal extravasation of fluid, and can be divided into three subtypes. These subtypes are believed to have different pathophysiological backgrounds and are referred to in recent guidelines as bradykinin-mediated (e.g. caused by angiotensin-converting-enzyme-inhibitors), mast cell-mediated (e.g. angioedema with wheals) or idiopathic (cause unknown). Bradykinin-mediated subtypes are more closely related to hereditary angioedema than the other forms. Because clinical features of these non-HAE subtypes have not been studied in detail, we have looked at the clinical characteristics of symptoms and potential differences in clinical presentation of bradykinin-mediated and mast cell-mediated angioedema (AE) subtypes.

Methods

A questionnaire was sent to patients presenting with AE at our tertiary outpatient clinic to document clinical characteristics, potential triggers and location of AE. The severity of AE attacks was analysed using visual analogue scales (VAS).

Results

The questionnaire was returned by 106 patients, of which 104 were included in the analysis. AE with wheals, idiopathic AE, and drug-associated AE occurred in 64 (62%), 25 (24%) and 15 patients (14%) respectively. Most patients (62%) reported prodromal symptoms while 63% reported multiple locations for an attack. Face and oropharynx were the main locations of AE attacks of any subtype while swelling was the symptom most frequently reported as severe. Overall severity of the last attack was indicated as severe by 68% of the patients. There were no differences between the subgroups.

Conclusion

This similarity in clinical presentation raises the possibility that ACEi-induced, mast cell-mediated and idiopathic AE share common pathways.

Electronic supplementary material

The online version of this article (doi:10.1186/s13601-015-0049-8) contains supplementary material, which is available to authorized users.     

Medical radiation exposure in children with bleeding disorders: an institutional experience

Patients with bleeding disorders may be exposed to ionizing radiation during medical care. We hypothesized that children with severe haemophilia may have higher radiation exposure than those with mild bleeding disorders (MBDs). To compare medical radiation exposure rates between children with severe haemophilia and MBDs. Charts of 35 pediatric patients with severe haemophilia were randomly selected from a database of active male patients followed in our bleeding disorders clinic from 2000 to 2010. Case patients were age and sex matched with two control patients with MBDs [Type 1 von Willebrand disease (VWD) or mild platelet function defect (PFD)]. By retrospective review, data on radiation exposure in millisieverts (mSv) was collected from radiological studies performed within Emory/CHOA. The rates of exposure between cohorts were compared using the Mann–Whitney Test. Case patients had a mean of 11.3 (median 8, IQR = 29) radiographic studies compared with 1.8 (median 1, IQR = 11) for controls (P < 0.001). The mean effective dose of radiation per patient per year of study was two mSv for case patients (median 0.4, IQR = 3) and 0.4 mSv for control patients (median 0.01, IQR = 0.3) (P < 0.001). Overall, 1.4% of controls and 31.4% of cases accumulated high to very high levels of exposure ( > 20 mSv). Case patients with severe hemophilia accumulated significantly more medical radiation exposure than controls. While the use of ionizing radiation is often necessary for management of these patients, avoidance of unnecessary exposure along with exploration of alternative imaging techniques and low dose protocols should be considered whenever possible.