Impact of a Standardized Titration Protocol with Carvedilol in Heart Failure: Safety,Tolerability, and Efficacy—A Report from the GESICA Registry

Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) studied whether a standardized protocol for the initiation and titration of the β-blocker carvedilol in a multicenter, open-label program would optimize β-blocker use in heart failure (HF) patients. The program included: (1) the carvedilol initiation and titration period, and (2) long-term follow-up at 6 and 12 months. Of 1299 patients in the registry, 504 were excluded due to current therapy; of the remaining 795 eligible patients, 293 were excluded due to contraindications. Of the included patients with follow-up data (n = 316), 93.3% tolerated carvedilol initiation and 47.7% of the patients reached the target dose of 50 mg/day for a mean dose of 39 mg/day. Rates were comparable in the elderly (n = 83), of which 53% achieved a target dose for a mean dose of 43.08 mg/day. This protocol improved therapy rates and achieved target doses quickly (average of 4 visits). Concomitant medications did not have to be adjusted and there were low withdrawal rates (10%) and hospital admissions (7.2%) for HF. Patients were able to maintain carvedilol therapy at 6 and 12 months. These results indicate that a standardized titration protocol, as used in GESICA, for the initiation and titration of β-blockers is well tolerated and may improve β-blocker use in carefully selected heart failure patients.The study authors are members of the GESICA Steering Committee and Subcommittees     

Excision and V–Y plasty reconstruction for giant condyloma acuminatum

Abstract. Background Condyloma acuminata is the most common anorectal lesion in patients infected with human immunodeficiency virus (HIV). Surgical treatment can be challenging in cases where the size and extension into the anal canal make individual excision impossible. These patients require large resections and reconstruction using grafts or local flaps.Methods Six patients were treated for giant perianal condylomas between 1999 and 2001. Four patients were HIV–positive, and were selected for surgical intervention after achieving a T4 count >350 and low viral replication. In 5 cases, the lesions were circularly resected up to the pectinate line and the defect was reconstructed using a bilateral V–Y plasty. In the remaining case, fulguration was possible on one side and a unilateral V–Y plasty was performed.Results There were no infections or healing delays in this series, and the functional and aesthetic results are satisfactory.Conclusion V–Y plasties are a valid method for perianal reconstruction after resection of giant anal condyloma, with good results in selected patients with HIV infection.     

Cutaneous Blood Flow and Peripheral Resistance in Type II Diabetes as Compared to Intermittent Claudication Patients

Insulin deficient, type I diabetic patients have reduced skin blood flow reserve. It is not known whether these skin perfusion abnormalities also exist in non-insulin dependent (type II) diabetic patients. An additional open question is whether the reduced skin blood flow is due to increased resistance of the cutaneous microvasculature or to decreased peripheral perfusion pressure due to increased atherosclerosis in the diabetic population. We measured skin blood flow by laser Doppler flowmetry in patients with type II non-insulin treated diabetes. Limb systolic blood pressure was measured distally using a sensitive sonar Doppler device at the finger and toe. The ratio of pressure to flow was computed as an index of peripheral blood flow resistance. To assess the effect of cutaneous blood flow resistance, we elicited maximal vasodilation by increasing local skin temperature directly at the site of the laser Doppler probe. We compared blood flow and pressure in diabetic patients with the values in non-diabetic control patients. As a further control population, we also assessed these same parameters in non-diabetic patients with peripheral vascular disease, which may be expected to decrease large arterial blood flow pressure without directly affecting the microvasculature. There were 68 type II diabetic patients, 18 non-diabetic control subjects, and 25 non-diabetic patients with intermittent claudication. We measured skin blood flow at the dorsal surfaces of the finger and toe, sites with primarily nutritive capillary perfusion, and at the plantar surfaces of the finger and toe, where arteriovenous shunt perfusion predominates. Heat stimulated flow was markedly lower for the diabetic patients at the finger dorsal surface (16.5 ± 1.4 ml/min/100 g vs 29.8 ± 4.4 ml/min/100 g in the non-diabetic group (p < 0.05). The resistance index was 13.2 ± 1.9 in the diabetic patients and 6.8 ± 1.7 in the controls (p < 0.05). At the toe dorsum, basal temperature flow was significantly lower in the diabetic group (0.6 ± 0.1 ml/min/100 g) than in the non diabetic group (1.1 ± 0.2 ml/min/100 gm) with resistance index almost twice as high (379 ± 32) in the diabetic group versus non-diabetic controls (208 ± 36) [p < 0.01 for both comparisons]. With the local application of heat, there was a much larger increase in flow in the non-diabetic subjects than in the diabetic group. The resistance index dropped much more with heat stimulation for the non-diabetic patients (10.8 ± 3.3) than for the diabetic patients (50.6 ± 10.4) [p < 0.01] There was a lesser rise in flow at the toe pulp surface with heat in the diabetic patients (31.3 ± 3.0 ml/min/199 gm) than in the control subjects (45.4 ± 5.9 ml/min/100 gm; p < 0.05) with a higher resistance index (13 ± 4) than in the non-diabetic subjects (4 ± 1) [p < 0.05]. The claudication patients had substantially greater flow at the toe dorsal surface at basal temperature (2.2 ± 0.4 ml/min/100 gm) with significantly lower resistance index (126 ± 24) than the non-diabetic controls (p < 0.05). At 44°C, toe dorsum flow was significantly higher (17.8 ± 3.7 ml/min/100 gm) than in the diabetic patients with lower resistance index (17.0 ± 6.6) [p < 0.05]. Toe pulp flow at basal temperature was significantly higher (10.1 ± 2.0 ml/min/100 gm) than in either the diabetic (3.8 ± 0.6) or non-diabetic control groups (3.5 ± 1.4) [p < 0.05]. Skin blood flow is impaired in diabetes. The reduction is due to increased resistance in the capillary bed rather than to reduced perfusion pressure. The increased resistance was found only in the diabetic patients, not in the non-diabetic patients with peripheral vascular disease. To the contrary, there appeared to be a compensatory decrease in skin flow resistance in the patients with peripheral vascular disease. Thus, there is a small vessel disease which impairs cutaneous perfusion in diabetes, but there is no such effect on skin blood flow in non-diabetic patients with large vessel disease.     

RV Fractional Area Change and TAPSE as Predictors of Severe Right Ventricular Dysfunction in Pulmonary Hypertension: A CMR Study

Background

The right ventricular ejection fraction (RVEF) is a surrogate marker of right ventricular function in pulmonary hypertension (PH), but its measurement is complicated and time consuming. The tricuspid annular plane systolic excursion (TAPSE) measures only the longitudinal component of RV contraction while the right ventricular fractional area change (RVFAC) takes into account both the longitudinal and the transversal components. The aim of our study was to evaluate the relationship between RVEF, RVFAC, and TAPSE according to hemodynamic severity in two groups of patients with PH: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH).

Methods and Results

Fifty-four patients with PAH (n?=?15) and CTEPH (n?=?39) underwent right heart catheterization and cardiac magnetic resonance (CMR). The ventricular volumes and areas, TAPSE, and eccentricity index were measured. The RVFAC was more strongly correlated with the RVEF (r?=?0.81, p?<?0.0001) than the TAPSE (r?=?0.63, p?<?0.0001). RVEF?<?35% was better predicted by the RVFAC than the TAPSE (TAPSE: AUC?=?0.77 and RVFAC: AUC?=?0.91; p?=?0.042). In the group with the worse hemodynamic status, the RVFAC correlated much better with the RVEF than the TAPSE. There were no significant differences in the CMR data analyzed between the groups of PAH and CETPH patients.

Conclusions

The RVFAC is a good index to estimate RVEF in PH patients; even better than the TAPSE in patients with more severe hemodynamic profile, possibly for including the transversal component of right ventricular function in its measurement. Furthermore, RVFAC performance was similar in the two PH groups (PAH and CTEPH).

     

Expression of matrix metalloproteinases in vasculitic neuropathy

The aim of this study was to investigate the expression pattern and cellular source of matrix metalloproteinases (MMP) in vasculitic neuropathy. Matrix metalloproteinases are endopeptidases degrading components of extracellular matrix proteins, and they have been implicated in the pathogenesis of inflammatory demyelination. They are induced by cytokines, secreted by inflammatory cells, and enhance T cell migration. Vasculitic neuropathy occurs as a component of systemic vasculitis or as an isolated angiitis of the peripheral nervous system, and T cell-mediated inflammation is detected in its pathogenesis. Nerve biopsy sections of eight patients with nonsystemic vasculitic neuropathy (NSVN) and four with systemic vasculitic neuropathy were examined for the presence of CD4+, CD8+, and CD68+ cells and immunohistochemically for MMP-2 and MMP-9 expression. Nerve biopsies of eight patients with noninflammatory neuropathy were used as a control group. Semiquantitative polymerase chain reaction analysis was performed to detect MMP-2 and MMP-9 mRNA. The predominant cells were CD8+ and CD68+ T cells. Expression of MMP-9, but not MMP-2, was increased in perivascular inflammatory infiltrate in nerve tissues of vasculitic neuropathy patients. This MMP-9 expression correlated positively with immunostaining of CD8+ T cells. No difference was detected between immunostaining patterns of nonsystemic and systemic vasculitic neuropathies with the antibodies used, except in MMP-9 immunostaining, which was found to be enhanced in NSVN group. Polymerase chain reaction analysis revealed elevated mRNA levels of MMP-9 and MMP-2 compared with controls, but this did not reach statistical significance. Our results imply a pathogenic role for MMP-9 secreted from CD8+ cells in vasculitic neuropathy.     

Alkaptonuric ochronosis: a case with multiple joint replacement arthroplasties

Alkaptonuria is an extremely rare hereditary disorder of metabolism which may affect various systems. Degeneration of the articular surfaces in major joints leads to complications, which may further necessitate joint replacements. In this report, a case of advanced alkaptonuria with multiple joint replacements is presented and musculoskeletal system involvement in this disorder is reviewed.Abbreviations HGA Homogentisic acid     

Ulcerogenicity devoid novel non-steroidal anti-inflammatory agents (NSAIDS): syntheses,computational studies,and activity of 5-aryliden-2-imino-4-thiazolidinones

A series of new 5-aryliden-2-imino-4-thiazolidinones (5a–e and 6a–e) were synthesized via a three-step reaction and characterized by physicochemical and spectral data. The uniqueness of the derivatives lies in the fact that none of them had an acidic group, like conventional NSAIDS, but exhibited significant in vivo activity in acute inflammation models. In particular, 5-(3-chlorobenzyliden)-2-(pyridin-2-yl-imino)-4-thiazolidinone(5a) and 5-(3-chlorobenzyliden)-2-(5-methylisoxazol-3-yl-imino)-4-thiazolidinone (6a) showed remarkable paw oedema inhibition (67.76 and 74.47 % oedema inhibition, respectively, after 3 h) comparable to that of Ibuprofen (74.56 % oedema inhibition, after 3 h) at half of the dose of the standard drug. Also, compounds 5a (72.86 %) and 6a (80.20 %) were found to possess significant inhibition of albumin denaturation when screened for in vitro anti-inflammatory activity. In addition, these compounds were docked into the known active site of COX-2 protein using Glide XP and QPLD algorithms, and the binding-free energy was calculated using Prime MM/GBSA simulation methods. The combined use of molecular docking and MM/GBSA methods gave a good correlation between the predicted binding-free energy and experimentally determined biological activities. It was also evident from the docking results that 2-methylisoxazolylimino or 2-(pyridin-2-yl-imino substitution and 3-chloro moiety on 5-benzylidin nucleus of these 4-thiazolidinone derivatives can easily occupy the COX-2 binding pocket, considered as the critical interaction for COX-2 inhibition. Moreover, pharmacokinetic properties of all the synthesized compounds were predicted, with good results. Further, the synthesized derivatives showed neither acute toxicity nor symptoms of gastric ulceration, at extended doses, owing to the absence of an acidic group.     

A Research Note on Statistical Methods Used to Create Indices of Child Well-Being

Growing numbers of researchers are combining individual indicators of child well-being into overall indices. This research note examines five different methodologies that have been used to construct an overall index of child well-being. All five methods are applied to four datasets and the results are examined in terms of consistency of results across methods. The datasets reflect child well-being indicators at the country, state, county, and neighborhood levels. The results show that all five of the approaches to index construction examined here produce very similar results. This is reflected in very high correlation coefficients with index values and rankings across geographic units. The findings suggest that rankings of geographic units on child well-being indices are likely to be robust regardless of the particular index methodology used.     

Accuracy of cardiac CT in evaluating severity of left atrial appendage spontaneous echo contrast: comparison with transesophageal echocardiography

To investigate the capacity of biphasic cardiac CT (CCT) for qualitative and quantitative evaluation of different grades of left atrial appendage spontaneous echo contrast (LAASEC). The study included 267 inpatients with confirmed atrial fibrillation who underwent both CCT and transesophageal echocardiography (TEE). CT numbers for LAA, ascending aorta (AA), and left atrium (LA) were identified, and ROC curves for LAA, LAA/AA, and LAA/LA were plotted. With TEE as the standard, the sensitivity, specificity, PPV, NPV, and accuracy of CCT for LAASEC grade?≥?1 were 60.3, 92.9, 92.4, 64.8, and 75.7%; and for grade?≥?2 were 100.0, 84.4, 71.4, 100.0, and 88.8% respectively. The values of LAA, LAA/AA, and LAA/LA were significantly larger in LAASEC grade 0 versus 1 and in grade 1 versus 2, but were similar in grades 2 and 3 or in grades 3 and 4. The values of LAA/AA were larger in grade 2 versus 4. When the cutoff value for LAA/AA?=?0.897, sensitivity, specificity, PPV, NPV, and accuracy of CCT for LAASEC grade?≥?1 was 89.6, 83.2, 87.9, 85.5, and 86.9% and with a cutoff for LAA/AA of 0.524, the sensitivity, specificity, PPV, NPV, and accuracy for LAASEC grade?≥?2 was 98.7, 92.7, 84.1, 99.4, and 94.4%. Although CCT showed limited diagnostic accuracy for grade 1 LAASEC, grade?≥?2 LAASEC could be excluded when there was no LAA filling defect on first-phase CCT, and TEE can be avoided. CCT has an excellent accuracy in diagnosing LAASEC, and quantitative analysis (in particular LAA/AA) is superior.     

Social–Emotional Aspects of Male Escorting: Experiences of Men Working for an Agency

Social situations and emotional correlates associated with male sex work have not been well documented. Most of the research in this area focuses on sexual activity with little mention of other aspects of the job. Yet, research with female sex workers finds significant social and emotional components to sex work. The current study focused on how male sex workers (MSWs) perceived and adapted to the social–emotional aspects of their job. As part of a larger project examining MSWs working for a single escort agency, 40 men (M age, 22.3 years, 75 % Caucasian) located in the mid-Atlantic U.S. participated in semi-structured interviews. The agency owner was also interviewed. Participants reported a range of social and emotional factors regarding sex work and employed a variety of strategies to provide good customer service and adapt to negative experiences. For most, social support was inhibited due to fear of stigmatization that might result if participants disclosed sex work to significant others outside the agency. Instead, interactions within the agency provided core work-related social support for most MSWs. Emotional and relational tasks inherent to escort work grew easier with experience and negativity about the job declined. Our data suggested that socially connected individuals seemed to be more satisfied with sex work. Social and emotional requirements represented a significant but unanticipated component of male sex work to which escorts actively adapted. Escorting may be similar to other service occupations in terms of the social–emotional situations and skills involved.