Germline mutations of the CDKN2 gene in UK melanoma families

Germline mutations in CDKN2 on chromosome 9p21, which codes for the cyclin D kinase inhibitor p16, and more rarely, mutations in the gene coding for CDK4, the protein to which p16 binds, underlie susceptibility in some melanoma families. We have sequenced all exons of CDKN2 and analysed the CDK4 gene for mutations in 27 UK families showing evidence of predisposition to melanoma. Five different germline mutations in CDKN2 were found in six families. Three of the mutations (Met53Ile, Arg24Pro and 23ins24) have been reported previously. We have identified two novel CDKN2 mutations (88delG and Ala118Thr) which are likely to be associated with the development of melanoma, because of their co-segregation with the disease and their likely functional effect on the CDKN2 protein. In binding assays the protein expressed from the previously described mutation, Met53Ile, did not bind to CDK4/CDK6, confirming its role as a causal mutation in the development of melanoma. Ala118Thr appeared to be functional in this assay. Arg24Pro appeared to bind to CDK6, but not to CDK4. No mutations were detected in exon 2 of CDK4, suggesting that causal mutations in this gene are uncommon. The penetrance of these mutant CDKN2 genes is not yet established, nor is the risk of non-melanoma cancer to gene carriers.      

IMPORTANCE OF DONOR SELECTION IN RENAL TRANSPLANTATION

Renal transplantation has become a treatment of choice for patients with end stage renal disease. A successful transplant is the result of a combination of several factors acting synergistically, such as the degree of HLA compatibility between donor and the recipient, pretransplant blood transfusions, the recipient''s state of immunoreactivity and sensitization, immunosuppressive therapy given in post operative period etc. Donor selection appears to be the most critical factor for the long term success of the organ graft. In this brief review, some of the important parameters of donor selection in renal transplantation are highlighted.KEY WORDS: Histocompatibility (HLA) matching, Cross match, Sensitization     

Proteus syndrome

Abstract: This female Asian (Malay) baby had clinical features of Proteus syndrome. She had a large right facial lipolymphangioma with hyperpigmentation of the overlying skin. There was a smaller lymphangioma over the left side of her neck with excess nuchal folds, macrodactyly and bilateral talipes equinovarus. Despite the extensive hemifacial swelling, there was no evidence of upper respiratory tract obstruction. Generalized seizures developed on the sixth day of life which were controlled with phenobarbital. The lymphangiomas were excised without recurrence.     

ANTIBIOTIC RESISTANCE PATTERN OF ISOLATES FROM WOUND AND SOFT TISSUE INFECTIONS

Two-hundred and eighty bacterial isolates from wound and soft tissue infections were studied for species identification and antibiotic resistance pattern. Amongst them 122 isolates were from community acquired infection and 158 were from nosocomial infections. The common community acquired pathogens were Staphylococcus aureus (67.8%) and Streptococcus pyogenes (10.7%), whereas Staphylococcus aureus (60.1%) and E. Coli (8.9%) were common in nosocomial infection. Only two anaerobes (Cl perfringens) were isolated. Penicillin resistance was found to be 87% and 92% for Staphylococccus aureus in community acquired and noscomial infections respectively. 85% of Proteus isolates were resistant to ampicillin. There was relatively lower level of resistance by all isolates to cefotaxime. Gentamicin showed higher rate of resistance than netilmicin and amikacin. Resistance of E. coli isolates to fluoroquinolones being 79% for norfloxacin, 81% for ciprofloxacin and 60% for ofloxacin. The study showed a higher resistance of methicillin resistant Staphylococcus aureus (MRSA) to other antibiotics. Amikacin and ofloxacin were the best recommended drugs for empirical therapy for all organisms, the susceptibility rate being 80.7% and 80.4%.KEY WORDS: Antibiotic resistance, Soft tissue infections, Wound infections     

Application of the vena contracta method for the calculation of the mitral valve area in mitral stenosis

OBJECTIVES: The vena contracta is the narrowest region of the regurgitant or stenotic jet just downstream the orifice and reflects the size of that orifice. This study was performed to assess the accuracy of the vena contracta width (VCW) in evaluating the severity of mitral stenosis (MS) and to compare the mitral valve area (MVA) determined by VCW with MVAs obtained by other more traditional echocardiographic methods. METHODS: We studied 59 patients (43 females, 42 +/- 14 years) with MS. VCW was measured in the apical four chamber view by Doppler color flow mapping. The largest diameter of the VCW during diastole was measured for at least three cardiac cycles and averaged. MVA was calculated from the following equation: pir(2), where r = VCW/2. MVA was also determined by planimetry, the pressure half-time method, and by the Gorlin formula. RESULTS: In this study, the width of the vena contracta ranged from 0.89 to 1.73 cm (mean 1.30 +/- 0.21). MVA, calculated based on the VCW, ranged from 0.63 to 2.35 cm(2) (mean 1.36 +/- 0.41). MVA by VCW (1.36 +/- 0.41 cm(2)) showed good correlations with three comparative techniques: (1) the cross-sectional area by planimetry (1.35 +/- 0.36 cm(2), mean difference = 0.21 +/- 0.16 cm(2), y = 0.91x + 0.14, r = 0.79, SEE = 0.26 cm(2), p < 0.001); (2) the area derived from the Doppler pressure half-time (1.27 +/- 0.32 cm(2), mean difference = 0.22 +/- 0.19 cm(2), y = 0.97x + 0.13, r = 0.76, SEE = 0.27 cm(2), p < 0.001), and (3) the area derived from the Gorlin equation in the 18 patients who underwent catheterization (1.27 +/- 0.35 cm(2), mean difference = 0.19 +/- 0.16, y = 0.98x + 0.05, r = 0.81, SEE = 0.26 cm(2), p < 0.001). CONCLUSIONS: These findings suggest that Doppler color flow imaging of the MS jet in the vena contracta can provide an accurate estimation of MVA and appears to be potentially applicable in the assessment of the severity of MS.     

Is the Change of Late Potential Over Time Related to Enzyme Levels?Ichemic Burden in Acute Myocardial Infarction

Background: The ventricular late potential (VLP) detected using the technique of signal average electrocardiography (SAECG) interacts with several factors, primarily time. Method: In this study, we examined the interaction, over time, of VLP with the initial ischemic burden and enzyme levels in acute myocardial infarction. Patients diagnosed as having acute myocardial infarction were included in the study. On the first day, the patients underwent enzyme analysis and electrocardiography (ECG) follow‐up every 6 hours. A 24‐hour ambulatory ECG was performed on the seventh day in order to determine the ischemic burden. SAECG findings (TQRS, RMS, LAS were obtained on the seventh day, in the first and third months. The study was continued with the patients who did not require angioplasty as decided with angiographic evaluation in the first month. Results: The study included 30 patients with acute myocardial infarction (mean age 51 ± 12, 28 males and 2 females). The initial mean CK‐MB levels and the mean ischemic burden were 98 ± 31 U/L and 44 ± 96 minutes. The TQRS (ms), LAS (ms), and RMS (μV) values (mean ± SD) obtained at day 7, month 1, and month 3 are 97 ± 12, 96 ± 9, 103 ± 11, P = 0.01; 31 ± 10, 31 ± 11, 32 ± 10, P = 0.46; 43 ± 28, 41 ± 26, 33 ± 25, P = 0.01, respectively. We observed that the TQRS and RMS values changed significantly with time, but these levels of significance disappeared when adjusted for the initial ischemic burden and CK‐MB levels (P = 0.06; P = 0.53). The VLP frequency was 33% at day 7 and 23% at month 3. Unlike the CK‐MB level, the initial ischemic burden was significantly different between the patients with and without VLP at month 3 (150.85 ± 149.28, 12.34 ± 26.48, P = 0.001). When tested together with age and gender, it was found that the high initial ischemic burden increased the possibility of VLP (OR: 24, Cl: 2.09–279.52, P = 0.01) at month 3. Conclusion: SAECG findings in patients with myocardial infarction changed with time; however, this change occurred depending on the initial ischemic burden and CK‐MB levels. Of these, only the initial ischemic burden, especially in high levels, was a determinant for the presence of VLP in the late period of myocardial infarction. A.N.E. 2002;7(3):242–246     

The effects of 12 months of growth hormone replacement therapy on cardiac autonomic tone in adults with growth hormone deficiency

OBJECTIVES: Growth hormone deficiency (GHD) in adults is associated with a cluster of cardiovascular risk factors. Some abnormalities of cardiac structure and function have been reported in adult patients with GHD, but there are few data related to cardiac autonomic tone. Non-invasive assessment of cardiac autonomic status can be achieved by heart rate variability (HRV), which can be measured by using time-domain or frequency-domain variables. To our knowledge, short-term (6 months) effects of GH replacement therapy (GHRT) on HRV in a limited number of patients have been evaluated prospectively in only two previous studies. The present study was therefore designed to investigate the effects of GHD and 12 months of GHRT on cardiac autonomic tone in a larger number of adult patients with severe GHD. PATIENTS AND METHODS: HRV measurement, by using time-domain variables, was performed in 22 patients with GHD (eight men, 14 women; mean age 45.4 +/- 2.4 years) and 22 healthy controls (nine men, 13 women; mean age 40.8 +/- 1.8 years) at baseline. The time-domain variables (sympathetically influenced parameters SDNN and SDANN and parasympathetically influenced parameters RMSSD and PNN50) were derived from 24-h electrocardiogram (ECG) recordings. In the patient group, cardiac autonomic tone was re-evaluated after 6 and 12 months of GHRT. RESULTS: Mean baseline values of SDNN and SDANN were significantly higher (higher values mean lower sympathetic activity) in GHD patients than in healthy controls (P < 0.05), but mean baseline values of RMSSD and PNN50 did not differ significantly in healthy controls and patients. After 6 and 12 months of GHRT, mean SDNN and SDANN were decreased significantly when compared with the baseline values before GHRT (P < 0.05). However, mean RMSSD and PNN50 did not differ significantly from baseline. When SDNN and SDANN measurements were evaluated individually for each patient, after 12 months of GHRT both of the sympathetically influenced parameters decreased in 90% of the patients. CONCLUSIONS: These data indicate that sympathetic tone is decreased in adult patients with severe GHD. Additionally, an increment in sympathetic activity and normalization of sympathovagal balance have been demonstrated after 6 and 12 months of GHRT. This result suggests that, at least at the doses used in this study, GHRT improves sympathetic tone, without an obvious arrhythmogenic effect.     

Factor V deficiency in Philadelphia-positive chronic myelogenous leukemia

Factor V deficiency has been identified in 8 of 8 patients 7--20 yr of age, with Philadelphia-positive (Ph1+) chronic myelogenous leukemia (CML). In these 8 patients, factor V deficiency was not due to hepatic dysfunction, factor V inhibitors, or disseminated intravascular coagulation. In 3 patients, factor V activity rose 10%--12% (0.10--0.12 U/ml) after the infusion of 28--31 ml/kg body weight of fresh frozen plasma (FFP). The rise persisted less than 14 hr. The mean measured postinfusion rise in factor V was 18% of the expected rise calculated from the volume of FFP infused in the patients' plasma volume. In 4 patients, a small transient rise in factor V activity occurred after splenectomy or plateletpheresis. Factor V deficiency was completely corrected after a marked reduction in bone marrow cellularity in 2 patients with Ph1+ CML treated with extensive chemotherapy, total body irradiation, and bone marrow transplantation. Factor V deficiency was retrospectively observed in 6 of 20 patients, ages 20--80 yr, with Ph1+ CML and 3 of 6 patients with other myeloproliferative disorders. The factor V deficiency appears to be associated with the large myeloid- megakaryocytic cell mass characteristic of CML and other myeloproliferative disorders.