Development of predictive nomograms for clinical use to quantify the risk of isolating resistance prone organisms in patients with infected foot ulcers.

Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) have been considered prevalent pathogens in foot infections. However, whether empiric therapy directed against these organisms is necessary, and in whom to consider treatment, is rather unclear. The aim of this study was to develop predictive algorithms for forecasting the probability of isolating these organisms in the infected wounds of patients in a population where the prevalence of resistant pathogens is low. This was a retrospective study of regression model-based risk factor analysis that included 140 patients who presented with infected, culture positive foot ulcers to two urban hospitals. A total of 307 bacteria were identified, most frequently MRSA (11.1%). P. aeruginosa prevalence was 6.5%. In the multivariable analysis, amputation (odds ratio (OR) 5.75, 95% confidence interval (CI) 1.48-27.63), renal disease (OR 5.46, 95% CI 1.43-25.16) and gangrene (OR 2.78, 95% CI 0.82-9.59) were identified as risk factors associated with higher while diabetes (OR 0.07, 95% CI 0.01-0.34) and Infectious Diseases Society of America infection severity >3 (OR 0.18, 95% CI 0.03-0.65) were associated with lower odds of P. aeruginosa isolation (C statistic 0.81). Similar analysis for MRSA showed that amputation was associated with significantly lower (OR 0.29, 95% CI 0.09-0.79) risk, while history of MRSA infection (OR 5.63, 95% CI 1.56-20.63) and osteomyelitis (OR 2.523, 95% CI 1.00-6.79) was associated with higher odds of isolation (C statistic 0.69). We developed two predictive nomograms with reasonable to strong ability to discriminate between patients who were likely of being infected with P. aeruginosa or MRSA and those who were not. These analyses confirm the association of some, but also question the significance of other frequently described risk factors in predicting the isolation of these organisms.

Successful treatment of Old World cutaneous leishmaniasis caused by Leishmania infantum with posaconazole.

Old World cutaneous leishmaniasis is a widespread and potentially disfiguring protozoal infection that is endemic in the Mediterranean basin, Africa, and parts of Asia. Human infection is caused by several species of Leishmania parasites, such as Leishmania infantum. Available systemic and topical treatments vary in efficacy and are often unjustified due to their toxicity. We report on a case that was treated with posaconazole, a drug typically considered an antifungal agent but which also targets specific metabolic pathways of the parasite.

The immunomodulatory effect of leflunomide in rat cardiac allotransplantation.

Leflunomide, a novel immunosuppressant, has been the subject of recent preclinical studies using solid organ allo- and xenotransplantation models. The objectives of this study were to evaluate the efficacy and toxicity of leflunomide using a rat cardiac allotransplant model in two different strain combinations (DA x PVG and DA x Lew). Leflunomide, at doses ranging between 5 and 30 mg/kg, prolonged graft survival in both strain combinations as effectively as CsA and FK506 1 mg/kg (P < 0.05). A dose-dependent effect was seen only after a longer treatment course. When ongoing rejection was intercepted early (postoperative day 2), 5 mg/kg was as effective as 1 mg/kg FK506 (P > 0.05) but was inferior to CsA in the DA x PVG combination (P < 0.05). However, in the DA x Lew combination, leflunomide was equally as efficacious as 15 mg/kg CsA and 1 mg/kg FK506 (P > 0.05). If ongoing rejection was treated at postoperative day 4, 10 mg/kg leflunomide was not only as effective as 15 mg/kg CsA and 1 mg/kg FK506, but demonstrated a dose-dependent increase in graft survival in both strain combinations. The toxicity of leflunomide at doses of especially 5-20 mg/kg was minimal in comparison to therapeutic doses of CsA and FK506 using body weight and biochemical parameters of renal and liver function. These in vivo observations convincingly show leflunomide to be equally as potent an immunosuppressant as CsA and FK506 in transplant rejection. It is also well tolerated on long-term administration and, by virtue of this fact, is a potentially suitable candidate for clinical transplantation.

Association of MICA gene and HLA-B*5101 with Behçet's disease in Greece.

PURPOSE: Behçet's disease (BD) is known to be associated with HLA-B51 in many different ethnic groups. Recently MICA, a member of a novel family of the human major histocompatibility complex (MHC) class I genes termed MIC (MHC class I chain-related genes), was identified near the HLA-B gene, and a triplet repeat microsatellite polymorphism was found in the transmembrane (TM) region. Because a strong association with BD of one particular MICA-TM allele, A6, was shown in a Japanese population, the present study was conducted to investigate microsatellite polymorphism in Greek patients with BD to know whether this association is generally observed in BD occurring in other populations. METHODS: Thirty-eight Greek patients with BD and 40 ethnically matched control subjects were examined for MICA microsatellite polymorphism using polymerase chain reaction (PCR) and subsequent automated fragment detection by fluorescent-based technology. RESULTS: Similar to the Japanese patients with BD, the phenotype frequency of the MICA-TM A6 allele was significantly increased in the Greek patients with BD (50.0% in control subjects versus 86.8% in BD cases), with an odds ratio (OR) of 6.60 (P = 0.0012). The MICA-A6 allele was found in a high frequency both in males and females (weighted OR = 6.68; P = 0.0017). No association was found between the A6 allele and several disease features. A strong association exists between the MICA-TM A6 allele and the B*5101 allele in both the control subjects and patients with BD (weighted OR = 44.39; P = 0.0000023). CONCLUSIONS: This study revealed in Greek patients a strong association of BD with a particular MICA-TM allele, MICA-A6, providing insight into the molecular mechanism underlying the development of BD.

HLA-B*5101 in Greek patients with Behçet's disease.

Behçet's disease (BD) is a recurrent systemic vasculitis of unknown etiology. Genetic factors and infectious agents seem to be related to the etiology and pathogenesis of the disease. BD is strongly associated with HLA-B51 antigen in many ethnic groups. As there are differences in HLA profile in different ethnic groups, we designed this case-control study to examine the association of HLA-B51 alleles and BD as well as to investigate the influence of sex, age at development of the International Study Group (ISG) for Behçet's Disease criteria and certain features of disease severity on the strength of this association. The study includes 62 Greek BD patients who fulfill the ISG criteria for Behçet's disease and 87 controls. Serological HLA Class-I typing was performed by standard microlymphocytotoxicity technique. HLA-DNA typing for the B5 group was performed in all B51 subjects and controls by PCR-SSO. Allele B*5101 was found in 80% of BD patients and in 26% of controls (odds ratio (OR) 10.48, p < 10[-6]). Males who carry this allele have a higher risk than females for BD (OR 16.97 and 5.74 respectively). B*5101 predisposes to BD at a younger age in both sexes and to the development of erythema nodosum (OR = 11, p = 0.004). This was confirmed by multiple logistic regression analysis. A weak but not significant association was found between B*5101 and uveitis (OR = 2). No association was found between B*5101 and vasculitis or skin lesions in either sex. It was concluded that in the Greek population allele B*5101 is a predisposing marker for BD, as in most ethnic groups, and that this allele predisposes to the development of the disease at a younger age in both sexes and to the development of erythema nodosum.

Overview analysis of adjuvant therapies for melanoma--a special reference to results from vaccinia melanoma oncolysate adjuvant therapy trials.

A phase III, randomized, double-blind, multi-institutional vaccinia melanoma oncolysate (VMO) trial was performed for patients with stage III (AJCC) melanoma. When compared with the control vaccinia virus (V) therapy, VMO therapy did not show clinical efficacy in the final analysis of data from this trial. However, the data did allude to significant therapeutic efficacy with VMO therapy if it had been compared with an observation arm. Therefore, a comparative overview statistical analysis was performed to identify the therapeutic efficacy of VMO. This review compares VMO results with data from the treatment and observation arms of other prominent randomized anti-melanoma biologic trials (i.e., ECOG EST 1684; SWOG, IFN-gamma (J. Natl. Cancer Inst. 87 (1995) 1710); WHO IFN-alfa-2a (ASCO 14 (1995) 410); Mayo IFN-alfa-2a (J. Clin. Oncol. 13 (1995) 2776); French IFN-alfa-2a (ASCO 15 (1996) 437). The analysis was carried out comparing the disease-free interval (DFI) and overall survival (OS). The analysis shows that the VMO results are fairly comparable to the results of the treatment arms from the ECOG and Mayo trials at the 5-year mark; percent DFI 0.37, 0.37, and 0.4, percent OS 0.48, 0.46, 0.47, respectively. In some cases, VMO DFI is superior to the observation arms from other studies; ECOG, Mayo, and WHO; 0.37 versus 0.26, 0.3, 0.27 (4 years), respectively. These comparative results suggest that the vaccinia arm is not a true observation arm in the VMO trial, and the VMO could have shown an enhanced efficacy had the trial included a no-treatment observation control arm.

Fibrocystic disease of the breast and HLA antigens.

One hundred and ten patients with fibrocystic disease of the breast and 200 controls were HLA typed with a panel of 100 antisera for A and B locus. The main finding was the decreased frequency of BW35 antigen among patients compared to the controls. The difference remained significant in patients with the fibrous type of the disease and in patients of the nulliparous group. In addition the last group of patients showed a significant increase of All antigen.

Right ventricular echocardiographic, vectorcardiographic and electrocardiographic study in cor pulmonale.

An echocardiographic (echo), vectorcardiographic (VCG) and electrocardiographic (ECG) study of the right ventricle was carried out in 27 patients with chronic obstructive pulmonary disease and cor pulmonale. The subxiphoid echocardiographic approach was applied in all patients. The right ventricular internal diameter index (RVIDd), anterior right ventricular wall thickness (RVWT) and the ratio (R) intraventricular septum thickness/anterior right ventricular wall thickness were statistically different in the 27 patients compared to the 33 normals. All 27 patients had a RVIDd greater than 1.33 cm while in only 17 (63%, P less than 0.01) of these was right ventricular hypertrophy (RVH) detected with VCG or ECg criteria. In 20 patients the RVWT was measured and in 19 of these the RVWT was greater than 0.56 cm. In only one patient was the RVWT less than 0.56 cm. VCG or ECG criteria showed RVH in only 14 (70%) of these patients. The R was measured in 18 patients. All patients had R less than 1.99 and in only 12 (67%, P less than 0.01) of these was RVH diagnosed with VCG or ECG criteria. It seems that the RVIDd, the RVWT and the R are useful indexes for the detection of right ventricular dilatation and hypertrophy. Therefore echocardiography is superior to the conventional ECG and VCG in the recognition of right ventricular hypertrophy and dilatation.

Effects of sho-saiko-to on production of prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and superoxide from peripheral monocytes and polymorphonuclear cells isolated from HIV infected individuals.

The effects of Sho-saiko-to (SST), a traditional Chinese medicine, on the production of PGE2 from monocytes, LTB4 and superoxide from polymorphonuclear cells (PMNC) in HIV infected individuals were studied. SST inhibited the production of PGE2 from monocytes stimulated by opsonized zymosan in all groups including the healthy control group and also inhibited the production of superoxide from PMNC after stimulation with FMLP. On the other hand, SST enhanced the production of LTB4 when PMNC were stimulated by the calcium ionophore A23187. These results suggest that SST has different effects on the production of prostanoids or superoxide from monocytes and PMNC. Furthermore, our data indicates that inhibition of PGE2 or superoxide production will lead to indirect suppression of HIV, and enhancement of LTB4 will contribute to the upregulation of the immune reaction in HIV infected individuals.

The distribution of HLA antigens and genes in the Greek population.

200 Greeks were typed by lymphocytotoxicity for 14 HLA-A and 18 HLA-B antigens with 120 sera. A high frequency of Bw35 and B5 antigen was apparent. The most remarkable disequilibria found were those between A2-B5 and A9-B18.

Left ventricular function in patients with chronic obstructive pulmonary disease.

We assessed the left ventricle function in 24 patients with severe (forced expiratory volume in 1 sec less than 50% of predicted) chronic obstructive pulmonary disease (COPD) and in 21 normal people. We measured the left ventricular systolic time intervals (STI) and echocardiographic left ventricular diameters, volumes, cardiac index, stroke volume index, echo ejection fraction and functional mean rate of circumferential fiber shortening (Vcf). In 13 of the 24 patients with COPD the mean pulmonary artery pressure and pulmonary artery wedge pressure were recorded. The STI in the patients with COPD were found abnormal while the echocardiographic parameters and pulmonary wedge pressure were normal. 1 patient had a high pulmonary arterial wedge pressure and a low Vcf. 2 patients had an ejection fraction less than 60%, but in only 1 of these the Vcf was low. No patient had all three parameters abnormal. We conclude that in patients with COPD the increased right ventricular afterload and the interaction between left and right ventricles are responsible for the abnormal left ventricular STI, while the left ventricular function is normal.

[Frequency of HLA antigens in Greek patients with open-angle glaucoma]. / Häufigkeit der HLA-Antigene bei griechischen Patienten mit Offenwinkel-Glaukom.

50 Greek patients with primary open-angle glaucoma were tissue-typed for a total of 29 HLA antigens (groups A and B). The results were compared with those of 200 control persons. A statistically significant difference at the level of p less than 0.05 was noted only with regard to the A2 antigen. These findings are in accordance with those of other authors who found no correlation between glaucoma simplex and the frequency of HLA antigens.

Respiratory drive in patients with chronic obstructive pulmonary disease.

Respiratory drive (deltaP 0.1/deltaPCO2) and ventilatory response (deltaVE/deltaPCO2) to CO2 has been estimated in 20 normal subjects and 28 patients with chronic obstructive pulmonary disease (COPD). In patients with COPD, drive and ventilatory response to CO2 were diminished, but no statistical correlation with FEV1, MBC, TLC, FRC, RV/TLC was found. A statistically negative correlation was found between blood bicarbonate and drive or ventilatory response to CO2. Patients with emphysema and normal PaCO2 demonstrated normal deltaP 0.1/deltaPCO2. In contrast, patients with chronic bronchitis with the same pulmonary function abnormalities and hypercapnia had significant diminution of the deltaP 0.1/deltaPCO2. Therefore, we feel that pulmonary function abnormalities alone cannot explain the deltaP 0.1/deltaPCO2 decrease; in most cases there sould coexist a diminished respiratory sensitivity.

Systolic time intervals in chronic obstructive pulmonary disease.

The systolic time intervals (STI) were used to study the left ventricular performance in 51 patients with chronic obstructive pulmonary disease (COPD), in 24 normal subjects and in 13 patients with both COPD and coronary heart disease (CHD). Our study shows that resting spine STI are abnormal in patients with COPD and that the STI in the sitting position and after exercise in these patients are changing in a similar way to those of normal subjects. In patients with both COPD and CHD we found the resting supine STI and the postexercise left ventricular ejection time index (LVETI) to differ from both normals and patients with COPD alone. When these same patients were sitting the STI failed to change, in striking contrast to the normal subjects and to the patients with COPD alone. The similar responses of normal subjects and of patients with COPD in the two stress conditions as well as the different postural and postexercise responses of patients with both COPD and CHD suggest a normal left ventricular function in patients with COPD.

Active pulmonary tuberculosis in patients with AIDS: spectrum of radiographic findings (including a normal appearance).

PURPOSE: To assess the efficacy of chest radiography in the detection of active pulmonary tuberculosis in patients with acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: Initial interpretations of chest radiographs of 133 adult patients with AIDS and positive sputum or bronchoalveolar lavage cultures for Mycobacterium tuberculosis were reviewed. Radiographic findings were correlated with CD4 T-cell counts, sputum stains for acid-fast bacilli (AFB), and antituberculous drug sensitivity. RESULTS: Forty-eight (36%) patients had a primary M tuberculosis pattern, 38 (28%) had a postprimary M tuberculosis pattern, 19 (14%) had normal radiographs, 17 (13%) had atypical infiltrates, seven (5%) had minimal radiographic changes, and four (3%) had a miliary pattern. Normal chest radiographs were seen for 10 (21%) of 48 patients with less than 200 T cells per microliter and one (5%) of 20 patients with more than 200 T cells per microliter. Drug sensitivity and sputum staining for AFB did not correlate with radiographic findings. Overall, 19% of cases had multidrug resistance to antituberculous medications. CONCLUSION: Chest radiographs did not suggest active tuberculosis in 43 (32%) of 133 AIDS patients with active pulmonary tuberculosis.

HLA-DRB1 alleles in Greek rheumatoid arthritis patients and their association with clinical characteristics.

The association of certain HLA-DRB1 alleles in Green rheumatoid arthritis (RA) patients with several features of the disease, the gender of the patient and the age at onset was investigated. This case control study includes 86 Greek RA patients and 130 healthy controls unrelated to the patients. HLA typing was performed by polymerase chain reaction (PCR) and hybridization with sequence-specific oligonucleotide (SSO) probes. HLA-DR4 was significantly increased in RA patients. The alleles *0101, *0401, *0405 and *1001 were associated with a higher risk of RA. The *0408 allele was absent from our patients. Sixty-five per cent of RA patients carried the 'sharp epitope' (SE) compared with 31.5% of controls. The risk for RA in individuals carrying a single allele positive for SE was 2.85 times higher, and for those carrying two alleles positive for SE 8.57 times higher, than in SE-negative individuals. The risk was higher in those carrying the *0401 allele, followed by *0405 and *0101, while the genotype *0401/*0404 was absent. Alleles positive for SE comprise a predisposing factor for RA at an early age, particularly in men, and are associated with positive rheumatoid factor, nodules and erosions.

HLA class II polymorphism and IDDM susceptibility in the Greek population.

The frequencies of HLA-DQA1, DQB1 and DRB1 alleles were compared between 50 Insulin-Dependent Diabetes Melitus (IDDM) patients and 49 healthy controls in the Greek population. Statistically significant difference in the frequencies of HLA-DQA1*0501-DQB1*0201 (P = 10(-4)), DQA1*0301-DQB1*0201 (P = 0.01) and DQA1*0301-DQB1*0302 (P = 0.001) were observed. The DRB1*0405-DQA1*0301-DQB1*0201 was the only DR, DQ combination significantly associated with the disease. The unexpected increase of DRB1*0405 observed in the Greek IDDM may suggest as reported in Chinese and Japanese IDDM a contribution of DR beta and DQ alpha in susceptibility. Moreover, in contrast to the Asians, in the Greek, the DR beta, DQ alpha are found with the usual DQ beta 57-ve.

Noninherited maternal antigens do not increase the susceptibility for familial rheumatoid arthritis. European Consortium on Rheumatoid Arthritis Families (ECRAF).

OBJECTIVE: It has been proposed that noninherited maternal HLA-DR antigens (NIMA) might play a role in the susceptibility for rheumatoid arthritis (RA). This hypothesis has not been thoroughly tested in patients with familial RA, in whom genetic factors, either inherited or not, might have stronger influence than in patients with sporadic RA. We investigated the NIMA hypothesis in a large cohort of European patients with familial RA. METHODS: The distribution of NIMA, noninherited paternal antigens (NIPA), and inherited HLA-DR antigens was assessed in patients with familial RA from all family sets collected from 1996 onwards by the ECRAF. HLA-DRB1 oligotyping from patients and all available nonaffected siblings and parents was carried out. Familial RA was defined by the presence of at least 2 affected first-degree relatives in the same family. The frequencies of HLA-DR NIMA and NIPA were compared using odds ratios after stratification for HLA-DR*04, *0401, and/or *0404 and shared epitope (SE) status. NIMA/NIPA that coincided with inherited parental HLA-DR antigens were considered redundant and were excluded from analysis. RESULTS: NIMA and NIPA could be analyzed in 165 RA patients with familial RA and 84 nonaffected siblings. Patients were predominantly female, rheumatoid factor positive, and had erosive disease (81, 75, and 84%, respectively). Possession of HLA-DR*04 and *0401/*0404 alleles tended be more frequent in patients than in nonaffected siblings but this did not reach statistical significance. SE possession was similar in patients and healthy siblings, although the former had a double dose SE more often (37.6 vs 17.8%; p = 0.002). Transmission of SE encoding alleles from parents to offspring was skewed only in patients [OR (95% CI) 3.56 (2.55-4.95) vs 1.16 (0.75-1.79) in nonaffected siblings]. Using the NIPA as control, the frequencies of HLA-DRB1*04, *0401/*0404, and SE positive NIMA were not increased in patients lacking these susceptibility alleles. The frequencies of NIMA encoding susceptibility alleles in DR*04 and *0401/*0404 negative patients were lower than in nonaffected siblings. CONCLUSION: Our results corroborate the association between RA and inherited SE alleles and do not support a role for noninherited HLA-DR maternal antigens in the susceptibility for familial RA.