Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27

Cerebral cavernous malformation (CCM) is a Mendelian model of stroke, characterized by focal abnormalities in small intracranial blood vessels leading to hemorrhage and consequent strokes and/or seizures. A significant fraction of cases is inherited as an autosomal dominant trait with incomplete penetrance. Among Hispanic Americans, virtually all CCM is attributable to a founder mutation localized to 7q ( CCM1 ). Recent analysis of non-Hispanic Caucasian kindreds, however, has excluded linkage to 7q in some, indicating at least one additional CCM locus. We now report analysis of linkage in 20 non-Hispanic Caucasian kindreds with familial CCM. In addition to linkage to CCM1, analysis of linkage demonstrates linkage to two new loci, CCM2 at 7p13-15 and CCM3 at 3q25.2-27. Multilocus analysis yields a maximum lod score of 14.11, with 40% of kindreds linked to CCM1, 20% linked to CCM2 and 40% linked to CCM3, with highly significant evidence for linkage to three loci (linkage to three loci supported with an odds ratio of 2.6 x 10(5):1 over linkage to two loci and 1.6 x 10(9):1 over linkage to one locus). Multipoint analysis among families with high posterior probabilities of linkage to each locus refines the locations of CCM2 and CCM3 to approximately 22 cM intervals. Linkage to these three loci can account for inheritance of CCM in all kindreds studied. Significant locus- specific differences in penetrance are identified. These findings have implications for genetic testing of this disorder and represent an important step toward identification of the molecular basis of this disease.      

Carcinoma of the tonsil with bilateral breast metastasis: A rare presentation

With increasing local regional control and survival rates, the incidence of distant metastasis is increasing. Head and neck malignancies traditionally metastasize to the lung, liver and bone. We present a case of an elderly woman who was loco‐regionally controlled after radiotherapy for carcinoma of the tonsil, but later presented with breast metastasis. To our knowledge, this metastatic pattern has never been reported in published literature. We also discuss the management of breast metastasis and the need to avoid unnecessary mastectomies in such patients.     

Arsonate-specific murine T cell clones. I. Genetic control and antigen specificity

The antigen-induced proliferative response of lymph node cells (LNC) from mice sensitized to the monofunctional antigen L-tyrosine-p-azobenzenearsonate (ABA-Tyr) was used to monitor genetic control. All strains tested mounted significant responses, but those that were H-2(b) at both the I-A and I-E loci [B10., B6., B10.A(18R), A.BY, and C3H.SW] gave consistently weaker responses than other haplotypes. The F(1) progeny of matings between high and low responder phenotype parents (DBA/2 and B6, respectively) were high responders, establishing the dominance of the responder trait. Proliferative responses of LNC to ABA-Tyr were blocked by the appropriate anti-Ia monoclonal reagents. For example, B10.A(4R) LNCI (I-A(k), I-E(b)) were blocked by anti-I-A(k), whereas B10.A(3R) LNC (I-A(b), I-E(k)) were blocked by anti-I-E(k). Long-term cultures of T cell lines specifically reactive to ABA-Tyr were established from LNC of A/J mice immunized with ABA-Tyr and were cloned by limiting dilution. The proliferative responses to ABA-Tyr of 14 out of 15 clones tested were I-A restricted on the basis of activation by antigen-presenting cells from appropriate recombinant strains and the blocking activity of the monoclonal anti-Ia antibodies. The response of the other clone was I-E restricted. The fine antigen specificity of the clones was studied using structural analogs of the homologous antigen to induce proliferation. The clones could be divided into three types with respect to responsiveness to ABA-histidine (ABA-His). One group responded about equally well to ABA-His and ABA-Tyr. A second set responded less strongly to ABA-His than to ABA-Tyr, while the third showed no response above background to ABA- His. In all instances, the ABA-His-responding clones discriminated exquisitely between the 2-azo and 4-azo histidine isomers, responding only to the 4-azo compound. These T cell clones provide extremely useful tools for studies of T cell specificity, antigen recognition and lymphoid cell interaction systems.     

Prognostic significance of right ventricular diastolic function in thalassaemia major

While left ventricular (LV) restrictive filling pattern is an ominous echocardiographic finding in thalassaemia major (TM), the prognostic significance of right ventricular (RV) diastolic function in patients with TM has not been thoroughly investigated. We studied 45 TM asymptomatic transfusion-dependent patients with normal LV systolic function by Doppler echocardiography. The 15-year cumulative survival rate was 34% in patients with RV restrictive filling pattern (RFP) and 82% in patients with RV non-RFP (log-rank = 10.41, p = 0.0013). Doppler estimation of RV filling pattern is very important in evaluating the prognosis of TM patients and should be performed routinely and using a standardised followup protocol.     

Hypertrophic cardiomyopathy in 2013: Current speculations and future perspectives

Hypertrophic cardiomyopathy (HCM), the most variable cardiac disease in terms of phenotypic presentation and clinical outcome, represents the most common inherited cardiomyopathic process with an autosomal dominant trait of inheritance. To date, more than 1400 mutations of myofilament proteins associated with the disease have been identified, most of them “private” ones. This striking allelic and locus heterogeneity of the disease certainly complicates the establishment of phenotype-genotype correlations. Additionally, topics pertaining to patients’ everyday lives, such as sudden cardiac death (SCD) risk stratification and prevention, along with disease prognosis, are grossly related to the genetic variation of HCM. This review incorporates contemporary research findings and addresses major aspects of HCM, including preclinical diagnosis, genetic analysis, left ventricular outflow tract obstruction and SCD. More specifically, the spectrum of genetic analysis, the selection of the best method for obstruction alleviation and the need for a unique and accurate factor for SCD risk stratification are only some of the controversial HCM issues discussed. Additionally, future perspectives concerning HCM and myocardial ischemia, as well as atrial fibrillation, are discussed. Rather than enumerating clinical studies and guidelines, challenging problems concerning the disease are critically appraised by this review, highlighting current speculations and recommending future directions.     

Hospitalization affects the anticoagulation patterns of patients with atrial fibrillation

Journal of Thrombosis and Thrombolysis - Scarce data are available on the effects of hospitalization on oral anticoagulation (OAC) patterns in patients with atrial fibrillation (AF). This study...     

Brain natriuretic peptide and the athlete’s heart: a pilot study

Background: The role of brain natriuretic peptide (BNP) in differentiating the athlete’s heart from maladaptive cardiac hypertrophy is unclear. Methods: To address this issue, an integrated M mode, two‐dimensional B mode and Doppler echocardiographical study were performed and plasma BNP levels were measured in 25 strength athletes, 25 patients with established hypertrophic cardiomyopathy (HCM) and 25 healthy volunteers. Results: Among athletes, BNP levels correlated negatively with the total training time (r = ?0.79, p = 0.002) and positively with ejection fraction (r = 0.58, p = 0.049) and fractional shortening (r = 0.57, p = 0.049). A BNP cut‐off value of 11.8 pg/ml had 88% specificity and 74% negative predictive value for the exclusion of HCM. Conclusions: Brain natriuretic peptide might be useful as a preparticipation screening test in athletes.     

Malignant atrophic papulosis (Degos' disease): clinicopathological correlations

Malignant atrophic papulosis (MAP) is a rare disease characterized by pathognomonic cutaneous lesions and frequently fatal systemic involvement. Dermatologists should have a high index of suspicion for systemic complications in a patient presenting with MAP. We report a case of malignant atrophic papulosis to highlight the clinicopathological features and review this important dermatological diagnosis.     

Ritual Circumcision: No Longer a Problem for Health Services in the British Isles

INTRODUCTION

Primary care trust (PCT) funding of a ritual circumcision service has recently been withdrawn from our unit, raising concerns that this may result in greater morbidity from community circumcision. The aims of this study were to document our circumcision practice before and after the withdrawal of PCT funding and to determine its effect on the morbidity from circumcision. In addition, we wanted to survey all paediatric surgical centres in the British Isles to ascertain how many still offer a ritual circumcision service.

PATIENTS AND METHODS

We retrospectively reviewed our circumcision practice for 1 year prior to the removal of UK Government funding, and then performed a prospective audit of our practice for the 12 months following funding withdrawal. An e-mail survey was also performed of all paediatric surgical units to determine the ritual circumcision service provision throughout the British Isles.

RESULTS

A total of 213 boys underwent circumcision during the 12 months prior to the withdrawal of funding, of which 106 cases (50%) were ritual circumcisions. After funding withdrawal, 99 boys underwent circumcision, of which 98 cases (99%) were for medical reasons. A similar number of boys were re-admitted after a hospital circumcision during the two review periods (5 versus 4 patients), whereas the number admitted following a community circumcision rose after funding withdrawal (6 versus 11 patients). Only a third of British paediatric surgical centres offer a ritual circumcision service, and a significant proportion of these were either providing the service without PCT funding, or were reconsidering their decision to continue.

CONCLUSIONS

PCT funding withdrawal for ritual circumcision had an impact on our unit''s procedural case volume. This represented a cost saving to the trust, despite a higher rate of admissions for postoperative complications. There is an inequality in healthcare provision throughout the British Isles for ritual circumcision, and we feel it is vital to offer support and training to medical and non-medical practitioners who are being asked to perform a greater number of circumcisions in the community.