Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only.

BACKGROUND: The detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29years by the National Institutes for Health (NIH) criteria which include ≥6 Café au Lait macules (CAL) as a defining criterion. The discovery of SPRED1 as a cause of Legius syndrome which is manifested by CAL, freckling and learning difficulties has introduced substantial heterogeneity to the NIH criteria. METHODS: We have defined the sensitivity of comprehensive RNA analysis on blood of presumed NF1 patients meeting NIH criteria with at least one nonpigmentary criterion and determined the proportion of children with ≥6 CAL and no family history that has an NF1 or SPRED1 genetic variant. RNA analysis was carried out from 04/2009-12/2015 on 361 NF1 patients. FINDINGS: A presumed causative NF1 mutation was found in 166/171 (97.08%-95% CI 94.56-99.6%) of familial cases and 182/190 (95.8%-95% CI 92.93-98.65%) sporadic de novo cases. Two of thirteen (15%) mutation negative individuals had dysembryoplastic neuroepithelial tumour (DNET) compared to 2/348 (0.6%) with an NF1 variant (p=0.007). No SPRED1 variants were found in the thirteen individuals with no NF1 variant. Of seventy-one individuals with ≥6 CAL and no non-pigmentary criterion aged 0-20years, 47 (66.2%) had an NF1 variant six (8.5%) a SPRED1 variant and 18 (25.3%) no disease causing variant. Using the 95.8% detection rate the likelihood of a child with ≥6 CAL having constitutional NF1 drops from 2/3 to 1/9 after negative RNA analysis. INTERPRETATION: RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥6 CAL that they are unlikely to have NF1.

Fractional Quantum Hall States in a Ge Quantum Well.

Measurements of the Hall and dissipative conductivity of a strained Ge quantum well on a SiGe/(001)Si substrate in the quantum Hall regime are reported. We analyze the results in terms of thermally activated quantum tunneling of carriers from one internal edge state to another across saddle points in the long-range impurity potential. This shows that the gaps for different filling fractions closely follow the dependence predicted by theory. We also find that the estimates of the separation of the edge states at the saddle are in line with the expectations of an electrostatic model in the lowest spin-polarized Landau level (LL), but not in the spin-reversed LL where the density of quasiparticle states is not high enough to accommodate the carriers required.

A descriptive review and discussion of litigation claims against ambulance services.

INTRODUCTION: Litigation claims against the NHS are increasing. Society is less tolerant of mistakes or inadequate service and litigation claims are now becoming increasingly accepted. METHODS: All claims registered with the NHS litigation authority, both closed and still open, were collated from all the ambulance trusts across England in the past 10 years. All incidents notified between 19 December 1995 and 19 April 2005 were included. The data were then analysed according to time, description of the incident, cause of the incident and type of damage incurred. Cases were also described according to the total claim. Potential actions and further work are discussed. RESULTS: Between 19 December 1995 and 19 April 2005 there were 272 cases of litigation conducted through the NHS litigation authority against ambulance services across the United Kingdom. The greatest proportion of claims was as a result of lack of assistance or care, which was alleged in 75 cases. Another significant proportion of cases related to a "failure/delay in treatment" or "diagnosis" accounting for 36 and 34 cases, respectively. The most common type of injury was a fatality in 69 cases and unnecessary pain in a further 56 claims. 17 claims were for sums of over pound 1 million; however, most of these cases were still ongoing. These cases are described in more detail; the type of outcome tended to be brain damage or significant spinal injury rather than a fatality, reflecting the higher cost of continuing long-term care of a chronically injured person. CONCLUSION: This study suggests that the key clinical areas that need to be addressed are obstetric care, spinal injury recognition and the decision not to convey a person to hospital. The first two of these have been addressed in the recent release of the Joint Royal Colleges Ambulance Liaison Committee guidelines. The major areas of organisation relate to reducing delays and providing the safe transfer of patients.

A familial cryptic subtelomeric deletion 12p with variable phenotypic effect.

A 15-year-old-boy and his mother, both carrying a cryptic deletion within 12p13.33, are described. The proband has a mild phenotype with moderate mental retardation and severe behavioural problems. The mother had some learning difficulties at school. Conventional GTL-banded high-resolution chromosome analysis showed normal karyotypes. Subsequent analysis by fluorescence in situ hybridization using a set of probes specific for the subtelomeric regions of all chromosomes, plus a series of probes at 12p13.33 extending from the 12p telomere, showed that both mother and son carry a 1.65 Mb terminal deletion in this region. There are 10 predicted genes within the deleted region. The unanticipated familial nature of the deletion emphasizes the value of family studies in all cases with subtelomeric abnormalities. It also demonstrates the difficulty in making a clinical diagnosis of individuals with this deletion. To the best of the present authors' knowledge, the proband and his mother are the first patients described with a submicroscopic deletion at 12p13.33.

Staphylococcal septicaemia complicating intracavernosal autoinjection therapy for impotence in a man with diabetes.

Intracavernosal injection of vasoactive drugs is a safe, effective, and commonly used treatment for impotence in diabetic men. In prospective studies infection has rarely occurred. We report a case of life-threatening Staphylococcal septicaemia complicating this treatment in a 61-year-old man with Type 2 diabetes, probably due to a combination of an unsterile technique and drug-induced priapism. Infection is a potential risk in diabetic men using intracavernosal injection therapy and those offered it should be informed of the importance of a scrupulous sterile technique and the need to seek urgent medical help for decompression if an erection persists for more than 4-6 h.