Functional investigation of bone implant viability using radiotracers in a new model of osteonecrosis

OBJECTIVES: Conventional imaging methods are excellent for the morphological characterization of the consequences of osteonecrosis; however, only specialized techniques have been considered useful for obtaining functional information. To explore the affinity of radiotracers for severely devascularized bone, a new mouse model of isolated femur implanted in a subcutaneous abdominal pocket was devised. To maintain animal mobility and longevity, the femur was harvested from syngeneic donors. Two technetium-99m-labeled tracers targeting angiogenesis and bone matrix were selected. METHODS: Medronic acid and a homodimer peptide conjugated with RGDfK were radiolabeled with technetium-99m, and biodistribution was evaluated in Swiss mice. The grafted and control femurs were evaluated after 15, 30 and 60 days, including computed tomography (CT) and histological analysis. RESULTS: Radiolabeling achieved high (>95%) radiochemical purity. The biodistribution confirmed good blood clearance 1 hour after administration. For 99mTc-hydrazinonicotinic acid (HYNIC)-E-[c(RGDfK)2, remarkable renal excretion was observed compared to 99mTc-methylene diphosphonate (MDP), but the latter, as expected, revealed higher bone uptake. The results obtained in the control femur were equal at all time points. In the implanted femur, 99mTc-HYNIC-E-[c(RGDfK)2 uptake was highest after 15 days, consistent with early angiogenesis. Regarding 99mTc-MDP in the implant, similar uptake was documented at all time points, consistent with sustained bone viability; however, the uptake was lower than that detected in the control femur, as confirmed by histology. CONCLUSIONS: 1) Graft viability was successfully diagnosed using radiotracers in severely ischemic bone at all time points. 2) Analogously, indirect information about angiogenesis could be gathered using 999mTc-HYNIC-E-[c(RGDfK)2. 3) These techniques appear promising and warrant further studies to determine their potential clinical applications.

Decreased memory T-cell response and function in human immunodeficiency virus-infected patients with tegumentary leishmaniasis

The effects of human immunodeficiency virus (HIV) on the immune response in patients with cutaneous leishmaniasis have not yet been fully delineated. This study quantified and evaluated the function of memory T-cell subsets in response to soluble Leishmania antigens (SLA) from patients coinfected with HIV and Leishmania with tegumentary leishmaniasis (TL). Eight TL/HIV coinfected subjects and 10 HIV seronegative subjects with TL were evaluated. The proliferative response of CD4+and CD8+T-cells and naïve, central memory (CM) and effector memory (EM) CD4+T-cells in response to SLA were quantified using flow cytometry. The median cell division indices for CD4+and CD8+T-cells of coinfected patients in response to SLA were significantly lower than those in patients with Leishmania monoinfection (p < 0.05). The proportions of CM and EM CD4+T-cells in response to SLA were similar between the coinfected patients and patients with Leishmania monoinfection. However, the median CM and EM CD4+T-cell counts from coinfected patients were significantly lower (p < 0.05). The reduction in the lymphoproliferative response to Leishmania antigens coincides with the decrease in the absolute numbers of both EM and CM CD4+T-cells in response to Leishmania antigens in patients coinfected with HIV/Leishmania.

Clinical and ultramicroscopic myocardial randomized study of beating versus arrested heart for mitral surgery / Estudo randomizado clínico e ultramicroscópico na cirurgia valvar mitral com o coração com atividade elétrica versus sem atividade elétrica

INTRODUCTION: Beating heart surgery on normothermic bypass simulates physiologic cardiac status. OBJECTIVES: This study compared clinical and transmission electron microscopic aspects of myocardial protection during mitral valve replacement using warm retrograde perfusion in empty beating versus arrested heart with cold blood anterograde cardioplegia. METHODS: Randomized study to evaluate myocardial cellular ischemia-reperfusion of both techniques to replace the mitral valve. Thirty-four patients were randomly assigned into group A (beating heart) and group B (arrested heart). The following parameters were assessed: echocardiography, blood chemistry, hemoglobin, lactate. During the surgical procedure a total of 102 myocardial biopsies were performed for ultrastructural analysis from anterior left ventricular wall: before cardiopulmonary bypass, before aortic desclamping and 10 minutes after reperfusion. RESULTS: Elevation of lactate at 3 hours during the procedure was higher in group A, but similar at the end of surgery (P=0.06). Cardioversion was necessary in 5/17 (A) vs. 13/17 (B) P=0.07. Median intraoperative systemic temperature was significantly lower in the group B compared to A (32oC vs. 36oC), P<0.001. There was no significant difference of the ultramicroscopic aspects of the heart biopsies before, during and after surgery in both groups. Cellular and mitochondrial transient abnormalities such as mitochondrial swelling, glycogen loss and cytosol swelling were detected independently of the moment of the biopsies. CONCLUSION: Myocardial protection and ultrastructural abnormalities were similar for both types of mitral valve replacement beating or arrested heart techniques.

INTRODUÇÃO: A cirurgia valvar mitral pode ser realizada com o coração com atividade elétrica, vazio e normotérmico com pinçamento aórtico, perfusão sanguínea no seio coronário, simulando um estado fisiológico. OBJETIVOS: Comparar as manifestações clínicas e ultramicroscópicas do miocárdio, na cirurgia valvar mitral, com o coração com atividade elétrica versus sem atividade elétrica. MÉTODOS: Estudo randomizado constituído de 34 pacientes: grupo A (batendo) e grupo B (parado). Os parâmetros foram: hematológico, bioquímico, ecocardiográfico, lactato. Foram realizadas 102 biopsias da parede anterior do ventrículo esquerdo preparadas para análise ultraestrutural: antes da circulação extracorpórea, antes do despinçamento aórtico e 10 minutos após a interrupção da circulação extracorpórea. RESULTADOS: Verificou-se elevação do lactato 3 horas após o início do procedimento, que foi maior no grupo A (P=0,06), todavia semelhantes no final da cirurgia. A cardioversão foi necessária em (A) 5/17 vs. (B) 13/17, P=0,07. A temperatura intraoperatória média foi significativamente menor no grupo B em relação ao grupo A (32oC vs. 36oC), P<0,001. A análise ultramicroscópica das amostras das biopsias do coração antes da circulação extracorpórea, ao término do pinçamento aórtico e após a saída da circulação extracorpórea, revelou anormalidades transitórias semelhantes no citoplasma, núcleos e mitocôndrias em ambos os grupos, independentemente do momento das biopsias. CONCLUSÃO: A proteção miocárdica na cirurgia valvar mitral apresentou aspectos semelhantes na preservação da integridade ultraestrutural dos cardiomiócitos quando realizada com o coração com ou sem atividade elétrica.

Paragonimiasis: first case reported in Brazil

The authors present a case from a 59 years old white female Brazilian patient, based in Salvador-Bahia, Brazil's northeastern side area, who experienced irritative cough and progressive dyspnea, and, after 18 months, was admitted to a hospital with respiratory insufficiency. The physical exam showed diffuse rales in both hemithoraces. Initial leukogram showed 14,400 cells/mL with 14 percent of eosinophils and chest X-ray showed peribronchovascular infiltrate, predominating in the lower half of the lung fields, and small opaque nodules. The high-resolution computed tomography scan of the chest (HRCT) presented compatible pattern with airways disease, especially from the small airways, with air trapping, tree sprouting images, central lobular nodules and bronchiectasis, making the results compatible with bronchiolitis and bronchiectasis. The transbroncho biopsy unveiled granulomatous lesion with necrosis, where was noticed a structure compatible to a parasitic case, and the research of the parasite eggs in the sputum was positive to paragonimus. After the praziquantel use, the patient presented a thick ferruginous expectoration and the result for BAAR examination was positive. The PCR exam and the sputum culture confirmed M. tuberculosis, and then the treatment for M. tuberculosis was initiated. The authors warn that this infection may have been a consequence of economics globalization process, where the importation of parasitized crustaceans might be the cause. However, there is the need of an accurate examination for the possibility of paragonimus specimens in this area of Brazil.

Lack of effect of motivation on the adherence of HIV-positive/AIDS patients to antiretroviral treatment

As a result of the potent drug combinations of reverse transcriptase inhibitors and protease inhibitors currently available, it is now possible to achieve extreme reductions in the numbers of viral particles in the peripheral blood of HIV-positive patients undergoing treatment, to the point that they are undetectable. Moreover, the immunological recovery resulting from continued and prolonged use of these drugs significantly reduces both mortality and the incidence of opportunistic infections. However, the strict therapeutic regimens required, the number of pills, adverse events and the stigma of a disease that requires the patient to introduce pill-taking into his/her lifestyle brings into question one aspect of mental health, which is motivation to do that which is being proposed. We investigated the influence of each of the components of the adherence trilogy: information, motivation and behavioral abilities, as risk factors in a population of HIV-positive/AIDS patients undergoing antiretroviral treatment in the city of Salvador, Bahia, Brazil. MATERIAL AND METHODS: An intervention study was carried out by introducing motivational assistance into the routine recommendations for the treatment of patients who were initiating antiretroviral (ARV) therapy. Seventy-six treatment-naive patients, who had been selected to initiate ARV therapy, were included. These patients were divided into two groups. Group A, in which the regular routine of the institution was followed, received information on the disease and its treatment;patients in group B had the same routine, but they were also followed-up fortnightly and given motivational intervention. Evaluations of viral load and CD4 count before and following treatment were used to measure adherence. RESULTS: There was no significant difference between the two groups. CONCLUSIONS: As the rates of non-adhesion were at the lower limits of the ranges reported in the literature, it would appear that providing motivation and information can be of help to the patient.

The importance of the doctor-patient relationship in adherence to HIV/AIDS treatment: a case report

In this case report, which includes a statement related by the patient himself, the authors also discuss the importance of a good doctor-patient relationship in treating HIV patients and in assuring the patient's adherence to his treatment. Related issues, such as the importance of treating psychiatric comorbidities, of preserving the patient's hope and motivation, and of giving him an adequate amount of information regarding the disease and its treatment, are also discussed.

Efficacy and safety of Efavirenz in HIV patients on Rifampin for tuberculosis

Forty-nine AIDS patients, most of who were antiretroviral therapy (ARV) naïve, with active tuberculosis, were treated with Rifampin 600mg, Isoniazid 400mg and Pirazinamide 2g daily. They also received ARV, consisting of Efavirenz (600mg/day) plus 2 NRTIs. All patients were prospectively followed for at least 24 months. Baselines were: male/female ratio 2:1, mean age 34.7 ± 9.4 yrs; weight 51 ± 9.0 kg, viral load 5.6 ± 0.6 logs, CD4 cell count 101 ± 128 cells/ mm . Follow up mean values of data logs of VL and CD4+ cell /mm counts were: VL 1.7 and CD4+ 265; VL 1.3 and CD4+ 251; VL 1.4 and CD4+ 326 at 6, 12 and 24 months, respectively. Weight gain changes were: 5 ± 9.9 ± 12 and 21 ± 16 kg respectively at 6, 12 and 24 months. A non-concomitant ARV regimen was introduced at least three weeks after TB treatment initiation. Severe adverse reactions included rash (two), toxic hepatitis (six), Immune Reconstitution Syndrome (seven), and four deaths. We conclude that Efavirenz at a daily dose of 600 mg is sufficient and safe to treat HIV/TB patients using a Rifampin containing regimen.

An adherence trilogy is essential for long-term HAART success

Adherence is the milestone of a successful therapy. Over the last decade several authors have addressed the importance of adherence for optimal results of antiretroviral (ARV) therapy. Many health care systems are investing substantial resources to make available contemporary antiretroviral therapy. Despite the large investment in medications, insufficient investments have been made into an integrated adherence component to maximize the impact of these medications. Adherence, unlike drug therapy, cannot be defined as a single method with a defined prescription or formula. Instead, it is the result of a complex interaction between the patient, a prescribed medication and the health system. Many reports are available analyzing each of these components. We have found that critical elements of adherence include the patient's knowledge about the disease and how medications will help achieve a longer and healthier life, together with the motivation to adapt to a new style of life. A trilogy composed of information, motivation and behavioral skills is essential to achieve the maximum desired level of adherence. We have computerized this trilogy in a software program for self-administration in which each of the three components is provided to the patient as many times as necessary to transmit an understanding of the problem and to help make a rational decision to adhere to the ARV treatment program. In this review we analyze several efforts and techniques to improve adherence to any recommended medication that may interfere with the patient's lifestyle and outline how the adherence trilogy can be best used to optimize the ability of ARV therapy to durably suppress plasma HIV RNA to undetectable levels.

Use of rhu-GM-CSF in pulmonary tuberculosis patients: results of a randomized clinical trial

It has been postulated that deficient or incomplete clinical and/or microbiological response to tuberculosis treatment is associated with cell-mediated immunological dysfunction involving monocytes and macrophages. A phase 2 safety trial was conducted by treating patients with either recombinant human granulocyte-macrophage colony-stimulating factor (rhu-GM-CSF) or a placebo, both in combination with anti-tuberculosis chemotherapy. Thirty-one patients with documented pulmonary tuberculosis were treated with rifampin/isoniazid for six months, plus pyrazinamide for the first two months. At the beginning of treatment, rhu-GM-CSF (125æg/M²) was randomly assigned to 16 patients and injected subcutaneously twice weekly for four weeks; the other 15 patients received a placebo. The patients were accompanied in the hospital for two weeks, then monthly on an out patient basis, for 12 months. Clinical outcomes were similar in both groups, with no difference in acid-fast bacilli (AFB) clearance in sputum at the end of the fourth week of treatment. Nevertheless, a trend to faster conversion to negative was observed in the rhu-GM-CSF group until the eighth week of treatment (p=0.07), after which all patients converted to AFB negative. Adverse events in the rhu-GM-CSF group were local skin inflammation and an increase in the leukocyte count after each injection, returning to normal 72 hours after rhu-GM-CSF injection. Three patients developed SGOP and SGPT > 2.5 times the normal values. All patients included in the GM-CSF group were culture negative at six months, except one who had primary TB resistance. None of the patients had to discontinue the treatment in either group. We conclude that rhu-GM-CSF adjuvant immunotherapy could be safely explored in a phase 3 trial with patients who have active tuberculosis

Post-kala-azar dermal leishmaniasis associated with AIDS

Post-kala-azar dermal leishmaniasis (PKDL) is rarely reported in South America. In spite of the fact that there are many reports about the association of visceral leishmaniasis and AIDS, PKDL is very uncommon in HIV-positive patients, and so far only four cases have been documented in the literature. We present another case with unusual clinicopathological aspects. The patient, a 28-year-old male, from Salvador, Bahia (an endemic area) presented with clinical manifestations of visceral leishmaniasis three years after the diagnosis of AIDS. During treatment for visceral leishmaniasis he developed disseminated miliary papules. Microscopically, the skin biopsy showed a "saw-tooth" pattern with a lichenoid mononuclear infiltrate simulating lichen planus. The histopathological diagnosis was achieved through the finding of amastigotes. The authors discuss the clinicopathological aspects of this case based on a review of the specific literature

Post-kala-azar dermal leishmaniasis associated with AIDS

Post-kala-azar dermal leishmaniasis (PKDL) is rarely reported in South America. In spite of the fact that there are many reports about the association of visceral leishmaniasis and AIDS, PKDL is very uncommon in HIV-positive patients, and so far only four cases have been documented in the literature. We present another case with unusual clinicopathological aspects. The patient, a 28-year-old male, from Salvador, Bahia (an endemic area) presented with clinical manifestations of visceral leishmaniasis three years after the diagnosis of AIDS. During treatment for visceral leishmaniasis he developed disseminated miliary papules. Microscopically, the skin biopsy showed a "saw-tooth" pattern with a lichenoid mononuclear infiltrate simulating lichen planus. The histopathological diagnosis was achieved through the finding of amastigotes. The authors discuss the clinicopathological aspects of this case based on a review of the specific literature.

A multicenter comparative study of cefepime versus broad-spectrum antibacterial therapy in moderate and severe bacterial infections

The safety and efficacy of cefepime empiric monotherapy compared with standard broad-spectrum combination therapy for hospitalized adult patients with moderate to severe community-acquired bacterial infections were evaluated. In an open-label, multicenter study, 317 patients with an Acute Physiology and Chronic Health Evaluation (APACHE II) score ranging from >5 to =19 were enrolled with documented pneumonia (n=196), urinary tract infection (n=65), intra-abdominal infection (n=38), or sepsis (n=18). Patients were randomly assigned 1:1 to receive cefepime 1 to 2 g IV twice daily or three times a day or IV ampicillin, cephalothin, or ceftriaxone ± aminoglycoside therapy for 3 to 21 days. For both treatment groups, metronidazole, vancomycin, or macrolide therapy was added as deemed necessary. The primary efficacy variable was clinical response at the end of therapy. Two hundred ninety-six (93 percent) patients met evaluation criteria and were included in the efficacy analysis. Diagnoses included the following: 180 pneumonias (90 cefepime, 90 comparator), 62 urinary tract infections (29 cefepime, 33 comparator), 37 intra-abdominal infections (19 cefepime, 18 comparator), and 17 sepses (8 cefepime, 9 comparator). At the end of therapy, overall clinical success rates were 131/146 (90 percent) for patients treated with cefepime vs 125/150 (83 percent) for those treated with comparator (95 percent confidence interval [CI]: - 2.6 percent to 16.3 percent). The clinical success rate for patients with community-acquired pneumonia, the most frequent infection, was 86 percent for both treatment groups. Among the patients clinically evaluated, 162 pathogens were isolated and identified before therapy. The most commonly isolated pathogens were Escherichia coli (n=49), Streptococcus pneumoniae (n=29), Haemophilus influenzae (n=14), and Staphylococcus aureus (n=11). Bacteriologic eradication/presumed eradication was 97 percent for cefepime vs 94 percent for comparator-treated patients. Drug-related adverse events were reported in 16 percent of cefepime patients and 19 percent of comparator patients. In conclusion, cefepime had higher cure rates compared with broad-spectrum combination therapy as an initial empiric treatment for hospitalized patients with moderate to severe community-acquired infections, including urinary tract infections, intra-abdominal infections, and sepsis

High prevalence of giardiasis and stronglyloidiasis among HIV-infected patients in Bahia, Brazil

Diarrhea due to intestinal microbial infections is a frequent manifestation among HIV-infected patients. It has been postulated that HIV-infected patients may have special types of intestinal infections, and that immune activation from such parasites may affect the progression of HIV disease. To evaluate these associations, the frequency of infections was examined in HIV-infected patients in Bahia, Brazil. To determine the potential impact of the presence of intestinal parasitic infections on HIV disease progression, a retrospective study approach was used. The medical charts of 365 HIV-infected patients who had been treated at the AIDS Clinic of the Federal University of Bahia Hospital were reviewed, and the prevalence of parasites was compared with 5,243 HIV-negative patients who had attended the hospital during the same period of time. Among HIV-infected subjects, CD(4) count, RNA plasma viral load (VL), and number of eosinophils were compared according to their stool examination results. The overall prevalence of each parasite was similar for HIV-positive and HIV-negative patients. However, the prevalence of S. stercoralis (p<10(-7)) and G. lamblia (p=0.005) was greater for HIV-infected subjects. The mean CD(4) count and viral load of HIV patients in our clinic who had stool examinations was 350 cells +/- 340 and 4.4 +/- 1.4 log RNA viral load, respectively. In this patient group there was no clear association between the level of the absolute CD(4) count or the viral load and a specific parasitic infection. The presence of an intestinal parasitic infection was not associated with faster progression of the HIV disease among HIV-infected patients. We conclude that strongyloidiasis and giardiasis are more frequent in HIV-infected patients in Bahia, Brazil. If this association is due to immune dysregulation, as has been proposed elsewhere, it must occur in patients after only minor shifts in CD(4) count from normal levels, or as a result of immune dysfunction not represented by CD(4) count. These infections do not appear to alter the progression of HIV disease.

Sucessful use of a defined antigen/GM-CSF adjuvant vaccine to treat mucosal leishmaniasis refractory to antimony: a case report

Immunotherapy has been proposed as a method to treat mucosal leishmaniosis for many years, but the approach has been hampered by poor definition and variability of antigens used, and results have been inconclusive. We report here a case of antimonial-refractory mucosal leishmaniasis in a 45 year old male who was treated with three single injections (one per month) with a cocktail of lour Leishmania recombinant antigens selected after documented hyporesponsiveness of the patient to these antigens, plus 50µg of GM-CSF as vaccine adjuvant. Three months after treatment, all lesions had resolved completely and the patient remains without relapse after two years. Side effects of the treatment included only moderate erythema and induration at the injection site after the second and third injections. We conclude that carefully selected microbial antigens and cytokine adjuvant can be sucessful as immunotherapy for patients with antimonial-refractory mucosal leishmaniasis.