Identification of a mutation in the beta cardiac myosin heavy chain gene in a family with hypertrophic cardiomyopathy.

OBJECTIVE--To investigate the molecular genetic basis of the cause of disease in a family with hypertrophic cardiomyopathy. BACKGROUND--Mutation within the beta cardiac myosin heavy chain gene has been shown to be the pathogenetic mechanism underlying the disease in several families, though clear evidence of heterogeneity has been reported. PATIENTS--A family with a history of hypertrophic cardiomyopathy. RESULTS AND CONCLUSION--This paper reports a mutation at aminoacid position 908 within exon 23 of the beta cardiac myosin heavy chain gene, resulting in a conversion of a leucine to valine. This base substitution was identified in an individual with a confirmed family history but with equivocal symptoms of the disease. Inheritance of the mutation by his symptom free juvenile offspring demonstrates the application of the technique to presymptomatic diagnosis.     

Myocardial beta adrenoceptor density in primary and secondary left ventricular hypertrophy

OBJECTIVES: Myocardial ß-adrenoceptor density has been found tobe reduced in hypertrophic cardiomyopathy, even when systolicfunction is preserved. Our purpose in the current study wasto investigate whether ß-adrenoceptor down-regulationwas unique to hypertrophic cardiomyopathy, or is also presentin secondary myocardial hypertrophy. METHODS: Myocardial ß-adrenoceptor density was measured in11 patients with hypertrophic cardiomyopathy, eight patientswith left ventricular hypertrophy secondary to arterial hypertensionor aortic valve disease and 18 normal control subjects, usingpositron emission tomography with ¹¹C-CGP-12177 as the myocardialß-adrenoceptor ligand. RESULTS: Reflecting the natural incidence of the conditions, the ageof the hypertrophic cardiomyopathy patients was 37 (10) [mean(SD), range 20–51] years and that of the secondary hypertrophypatients 64 (18), [range 26–80] years; P<0.01. Thecontrols' ages were 50 (13), [range 21–65] years; however,since ß-adrenoceptor density is known to be influencedby age, the controls' data was split into groups matched tothe hypertrophic cardiomyopathy and secondary hypertrophy patientsets. For the hypertrophic cardiomyopathy patients, mean leftventricular ß-adrenoceptor was 7.70 (186) pmol . g^–1compared to 10.17 (244) pmol . g^–1 for a matched set of15 controls; P<0.01. In secondary left ventricular hypertrophy,ß-adrenoceptor was 6.35 (1.70) pmol . g^–1 comparedto 9.16 (2.00)pmol . g^–1 for a matched set of 10 controls;P<0.01. Plasma noradrenaline was 5.5 (2.2)nmol . 1^–1in hypertrophic cardiomyopathy and 2.5 (1.0)nmol. 1^–1for the matched controls; P<0.01. The results for adrenalinewere 2.2 (1.1) vs 0.4 (0.3) nmol . 1^–1 respectively; P<0.001.For the secondary hypertrophy patients, the corresponding figureswere 2.5 (1.2) vs 2.5 (1.0) nmol . 1^–1 for noradrenalinefor patients and controls respectively (P=ns); and for adrenaline0.2 (0.1) and 0.3 (0.2) nmol . 1^–1 respectively, P=ns.On multiple regression analysis, no relationships could be demonstratedamongst plasma catecholamines, ß-adrenoceptor, myocardialblood flow and echocardiographic E/A ratio and fractional shortening. CONCLUSION: Myocardial ß-adrenoceptor density appears to be comparablydecreased in both primary and secondary left ventricular hypertrophyin the presence of preserved left ventricular systolic function.     

Outcome of ileorectal anastomosis for Crohn's colitis

One hundred thirty-one patients underwent ileorectal anastomosis (IRA) for Crohn's colitis. Preoperatively, 84 patients (63 percent) were found to have mild or moderate proctitis and 47 (37 percent) had rectal sparing. Sixty-eight (52 percent) had associated small bowel disease, and 20 (15 percent) had perianal disease. Sixty-five IRAs were performed at the time of subtotal colectomy, while 56 were done after previous surgery. Anastomotic leaks occurred in four patients. There were no operative deaths. Thirteen patients (10 percent) with protecting stomas never underwent closure. Among the remaining 118 patients with functioning IRAs, 30 (23 percent) required later proctectomy and 16 (13 percent) required proximal diversion, with the mean period with a functioning IRA in these 46 patients being 4.1 years (range, 6.2 months–12.7 years). An additional 13 patients required preanastomotic resection and neo-IRA, and 11 required proximal small bowel resection. The mean duration of function of all 118 IRAs was 9.2 years. At the time of review, after a mean follow-up of 9.5 years, 72 patients (61 percent) retained a functioning IRA, with 44 being free of disease, while 28 were being treated with steroids or antidiarrheal medication. The mean stool frequency was 4.7 per day. In patients with Crohn's colitis, IRA should be considered as an alternative to proctocolectomy if the rectum is not severely diseased and sphincter function is not compromised.Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, May 12 to 17, 1991.     

The microbiology and pathogenesis of infective endocarditis

Some details of 544 episodes of infective endocarditis occurring in 541 patients during 1981 and 1982 are reported. The mean age of patients was 51.6 years and there was a greater proportion of males (2:1). Of the 544 episodes 347 (63%) were due to streptococci, 19% to staphylococci, and 14% to bowel organisms. A wide variety of other organisms were responsible for a few cases, and 10% were culture negative. In 60% the portal of entry of the infection could not be ascertained: 19% were probably of dental origin: 16% arose from the alimentary, genitourinary, or respiratory tracts or from the skin or in association with drug addiction, fractures, or pregnancy; the remaining 5% were related to cardiac or other vascular surgery, cardiac catheterisation, haemodialysis, or other procedures involving the blood stream. Seventy-four (14%) of the 541 patients (mean age 59.0 years) died; the mortality was 30% in staphylococcal cases, 14% in infections due to bowel organisms, and 6% in other streptococcal infections. One hundred and seventy-one (32%) of the patients appeared to have had normal hearts before the onset of illness and another 59 (11%) had cardiac lesions not previously recognised. The aortic valve was the most common site of infection. Ninety (17%) of the patients had prosthetic valves or had undergone other cardiac surgery while 34 (6%) had had a previous episode of infective endocarditis. Nine (1.6%) episodes were not diagnosed until necropsy or operation and 34 (6.3%) required urgent valve replacement.     

The microbiology and pathogenesis of infective endocarditis.

Some details of 544 episodes of infective endocarditis occurring in 541 patients during 1981 and 1982 are reported. The mean age of patients was 51.6 years and there was a greater proportion of males (2:1). Of the 544 episodes 347 (63%) were due to streptococci, 19% to staphylococci, and 14% to bowel organisms. A wide variety of other organisms were responsible for a few cases, and 10% were culture negative. In 60% the portal of entry of the infection could not be ascertained: 19% were probably of dental origin: 16% arose from the alimentary, genitourinary, or respiratory tracts or from the skin or in association with drug addiction, fractures, or pregnancy; the remaining 5% were related to cardiac or other vascular surgery, cardiac catheterisation, haemodialysis, or other procedures involving the blood stream. Seventy-four (14%) of the 541 patients (mean age 59.0 years) died; the mortality was 30% in staphylococcal cases, 14% in infections due to bowel organisms, and 6% in other streptococcal infections. One hundred and seventy-one (32%) of the patients appeared to have had normal hearts before the onset of illness and another 59 (11%) had cardiac lesions not previously recognised. The aortic valve was the most common site of infection. Ninety (17%) of the patients had prosthetic valves or had undergone other cardiac surgery while 34 (6%) had had a previous episode of infective endocarditis. Nine (1.6%) episodes were not diagnosed until necropsy or operation and 34 (6.3%) required urgent valve replacement.     

A new finite element approach for near real‐time simulation of light propagation in locally advanced head and neck tumors

Background and Objectives

Several clinical studies suggest that interstitial photodynamic therapy (I‐PDT) may benefit patients with locally advanced head and neck cancer (LAHNC). For I‐PDT, the therapeutic light is delivered through optical fibers inserted into the target tumor. The complex anatomy of the head and neck requires careful planning of fiber insertions. Often the fibers' location and tumor optical properties may vary from the original plan therefore pretreatment planning needs near real‐time updating to account for any changes. The purpose of this work was to develop a finite element analysis (FEA) approach for near real‐time simulation of light propagation in LAHNC.

Methods

Our previously developed FEA for modeling light propagation in skin tissue was modified to simulate light propagation from interstitial optical fibers. The modified model was validated by comparing the calculations with measurements in a phantom mimicking tumor optical properties. We investigated the impact of mesh element size and growth rate on the computation time, and defined optimal settings for the FEA. We demonstrated how the optimized FEA can be used for simulating light propagation in two cases of LAHNC amenable to I‐PDT, as proof‐of‐concept.

Results

The modified FEA was in agreement with the measurements (P = 0.0271). The optimal maximum mesh size and growth rate were 0.005–0.02 m and 2–2.5 m/m, respectively. Using these settings the computation time for simulating light propagation in LAHNC was reduced from 25.9 to 3.7 minutes in one case, and 10.1 to 4 minutes in another case. There were minor differences (1.62%, 1.13%) between the radiant exposures calculated with either mesh in both cases.

Conclusions

Our FEA approach can be used to model light propagation from diffused optical fibers in complex heterogeneous geometries representing LAHNC. There is a range of maximum element size (MES) and maximum element growth rate (MEGR) that can be used to minimize the computation time of the FEA to 4 minutes. Lasers Surg. Med. 47:60–67, 2015. © 2015 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.     

Tumor necrosis factor-alpha polymorphism, bone strength phenotypes, and the risk of fracture in older women

TNFalpha is a proinflammatory cytokine that promotes osteoclastic bone resorption. We evaluated the association between a G-308A polymorphism (rs1800629) at the TNFA locus and osteoporosis phenotypes in 4306 older women participating in the Study of Osteoporotic Fractures. Femoral neck bone mineral density (BMD) and structural geometry were measured using dual-energy x-ray absorptiometry and hip structural analysis. Incident fractures were confirmed by physician adjudication of radiology reports. Despite similar femoral neck BMD, women with the A/A genotype had greater subperiosteal width (P = 0.01) and endocortical diameter (P = 0.03) than those with the G/G genotype. The net result of these structural differences was that there was a greater distribution of bone mass away from the neutral axis of the femoral neck in women with the A/A genotype, resulting in greater indices of bone bending strength (cross-sectional moment of inertia: P = 0.004; section modulus: P = 0.003). Among 376 incident hip fractures during 12.1 yr of follow-up, a 22% decrease in the risk of hip fracture was seen per copy of the A allele (relative risk 0.78; 95% confidence interval 0.63, 0.96), which was not influenced by adjustments for potential confounding factors, BMD, or bone strength indices. The G-308A polymorphism was not associated with a reduced risk of other fractures. These results suggest a potential role of genetic variation in TNFalpha in the etiology of osteoporosis.