Searching for a prognostic index in lupus nephritis.

BACKGROUND: Currently we do not have an ideal biomarker in lupus nephritis (LN) that should help us to identify those patients with SLE at risk of developing LN or to determine those patients at risk of renal progression. We aimed to evaluate the development of a prognostic index for LN, through the evaluation of clinical, analytical and histological factors used in a cohort of lupus. We have proposed to determine which factors, 6 months after the diagnosis of LN, could help us to define which patients will have a worse evolution of the disease and may be, more aggressive treatment and closer follow-up. METHODS: A retrospective study to identify prognostic factors was carried out. We have included patients over 18 years of age with a clinical diagnosis of systemic lupus erythematosus (SLE) and kidney involvement confirmed by biopsy, who are followed up in our centre during the last 20 years. A multi-step statistical approach will be used in order to obtain a limited set of parameters, optimally selected and weighted, that show a satisfactory ability to discriminate between patients with different levels of prognosis. RESULTS: We analysed 92 patients with LN, although only 73 have been able to be classified according to whether or not they have presented poor renal evolution. The age of onset (44 vs. 32; p = 0.024), the value of serum creatinine (1.41 vs. 1.04; p = 0.041), greater frequency of thrombocytopenia (30 vs. 7%; p = 0.038), higher score in the renal chronicity index (2.47 vs. 1.04; p = 0.015), proliferative histological type (100%) and higher frequency of interstitial fibrosis (67 vs. 32%; p = 0.017) and tubular atrophy (67 vs. 32%; p = 0.018) was observed between two groups. The multivariate analysis allowed us to select the best predictive model for poor outcome at 6 months based on different adjustment and discrimination parameters. CONCLUSION: We have developed a prognostic index of poor renal evolution in patients with LN that combines demographic, clinical, analytical and histopathological factors, easy to use in routine clinical practice and that could be an effective tool in the early detection and management.

Distribution patterns, carbon sources and niche partitioning in cave shrimps (Atyidae: Typhlatya).

Cave shrimps of the Typhlatya genus are common and widespread in fresh, brackish and marine groundwater throughout the Yucatan Peninsula (Mexico). These species are ideal models to test niche partitioning within sympatric species in oligotrophic systems. Nevertheless, their food sources remain unidentified, and despite their frequency and functional importance, distribution and abundance patterns of these species within caves have not been fully recognized. Here, we describe the abundance of three Typhlatya species in different temporal and spatial scales, investigate changes in water conditions, and potential sources of carbon as an indication of food origin. Species composition and abundance varied markedly in space and time revealing patterns that differed from one system to another and in relation to environmental parameters. Isotope analysis showed that each species reflects a particular δ13C and Δ14C fingerprint, suggesting they feed in different proportions from the available carbon sources. Overall, our findings suggest a niche partitioning of habitat and feeding sources amongst the three Typhlatya species investigated, where environmental characteristics and physiological differences could play an important role governing their distribution patterns.

Regulation of limb patterning by extracellular microfibrils.

To elucidate the contribution of the extracellular microfibril-elastic fiber network to vertebrate organogenesis, we generated fibrillin 2 (Fbn2)-null mice by gene targeting and identified a limb-patterning defect in the form of bilateral syndactyly. Digit fusion involves both soft and hard tissues, and is associated with reduced apoptosis at affected sites. Two lines of evidence suggest that syndactily is primarily due to defective mesenchyme differentiation, rather than reduced apoptosis of interdigital tissue. First, fusion occurs before appearance of interdigital cell death; second, interdigital tissues having incomplete separation fail to respond to apoptotic clues from implanted BMP-4 beads. Syndactyly is associated with a disorganized matrix, but with normal BMP gene expression. On the other hand, mice double heterozygous for null Fbn2 and Bmp7 alleles display the combined digit phenotype of both nullizygotes. Together, these results imply functional interaction between Fbn2-rich microfibrils and BMP-7 signaling. As such, they uncover an unexpected relationship between the insoluble matrix and soluble factors during limb patterning. We also demonstrate that the Fbn2- null mutation is allelic to the recessive shaker-with-syndactyly (sy) locus on chromosome 18.

[The antiproteinuric effect of the blockage of the renin-angiotensin-aldosterone system (RAAS) in obese patients. Which treatment option is the most effective? ]. / Efecto antiproteinúrico del bloqueo del sistema renina-angiotensina-aldosterona (SRAA) en los pacientes obesos. ¿Cuál es la opción terapéutica más eficaz?

BACKGROUND: Obesity increases the risk of proteinuria and chronic renal insufficiency and hastens the progression of renal diseases. Increased activity of renin-angiotensin-aldosterone system and elevated levels of aldosterone are common in obese patients. No studies have compared the efficacy of the currently available antiproteinuric strategies (ACE inhibitors -ACEI-, angiotensin receptor blockers -ARB-, aldosterone antagonists) in obese patients with proteinuric renal diseases. METHODS: Single centre, prospective, randomized study. Twelve obese patients (body mass index > 30 Kg/m2) with proteinuria > 0.5 g/24 h were selected from our outpatient renal clinic. Patients were consecutively treated during 6 weeks with an ACEI (lisinopril 20 mg/day), combined therapy ACEI+ARB (lisinopril 10 mg/day + candesartan 16 mg/day) and eplerenone (25 mg/day) in random order. A drug washout period of 6 weeks was established between the different treatment periods. The primary outcome point was the change in 24-h proteinuria at the end of each treatment period and the number of patients showing a proteinuria reduction greater than 25% of baseline. RESULTS: The reduction in proteinuria induced by lisinopril (11.3+/-34.8%) was not statistically significant with respect to baseline, whereas that of lisinopril plus candesartan (26.9+/-30.6%) and eplerenone (28.4+/-31.6%) showed a statistically significant difference both with respect to baseline values and to lisinopril group. The number of patients who showed a greater than 25% proteinuria reduction was significantly higher with eplerenone (67%) and lisinopril+candesartan (67%) than with lisinopril (25%). CONCLUSIONS: Monotherapy with an aldosterone antagonist and combination therapy with ACEI+ARB were more effective than ACEI monotherapy to reduce proteinuria in obese patients with proteinuric renal diseases.

Human platelet-specific antigens frequencies in the Argentinean population.

The frequencies of several human platelet antigens (HPAs) vary between different populations and are a major determinant for the prevalence of HPA alloimmunization and its clinical associated entities. The aim of this study was to characterize the allele frequencies of seven HPA systems in two different ethnic groups from the Argentinean city of Rosario, the major population and a minority Amerindian group recently arrived from the north of the country, the Tobas. A total of 192 healthy unrelated individuals from blood donors and hospital staff from the Hospital Italiano Garibaldi and 27 unrelated Toba Amerindians were genotyped for HPA-1, -2, -3, -4, -5, -6 and -15 systems by polymerase chain reaction with sequence specific primers (PCR-SSP). The present data showed that the distribution of the HPA alleles among Argentineans from Rosario is quite similar to that reported among Europeans. The frequencies seen in Tobas, although limited by the small number of aboriginal samples studied, are similar to those reported for other Amerindians populations. Statistically significant differences were found for the genotype distribution of HPA-1, -3, -5 and -15 between both groups, indicating important differences in the potential risk of HPA alloimmunization associated to transfusion and pregnancy. The study of these polymorphisms represents the first step in the elucidation of pathological conditions that are underdiagnosed in our population. It allowed us to establish a panel of characterized blood donors necessary for the serological work out and as a source for compatible platelets transfusion.

The molecular genetics of Marfan syndrome and related disorders.

Marfan syndrome (MFS), a relatively common autosomal dominant hereditary disorder of connective tissue with prominent manifestations in the skeletal, ocular, and cardiovascular systems, is caused by mutations in the gene for fibrillin-1 (FBN1). The leading cause of premature death in untreated individuals with MFS is acute aortic dissection, which often follows a period of progressive dilatation of the ascending aorta. Recent research on the molecular physiology of fibrillin and the pathophysiology of MFS and related disorders has changed our understanding of this disorder by demonstrating changes in growth factor signalling and in matrix-cell interactions. The purpose of this review is to provide a comprehensive overview of recent advances in the molecular biology of fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 and other genes found in MFS and related disorders will be discussed, and novel concepts concerning the complex and multiple mechanisms of the pathogenesis of MFS will be explained.

FAK phosphorylation plays a central role in thrombin-induced RPE cell migration.

The migration of retinal pigment epithelial (RPE) cells is an important step in various pathologic conditions including subretinal neovascularization (SRN), proliferative vitreoretinopathy (PVR) and, importantly, as a consequence of retinal surgery. Therefore, the elucidation of the mechanisms underlying RPE trans-differentiation and migration is essential for devising effective treatments aimed to the prevention of these disorders. A common event in these pathologies is the alteration of the blood-retina barrier (BRB), which allows the interaction of RPE cells with thrombin, a pro-inflammatory protease contained in serum. Our previous work has demonstrated that thrombin induces RPE cell cytoskeletal remodeling and migration, hallmark processes in the development of PVR; however, the molecular mechanisms involved are still unclear. Cell migration requires the disassembly of focal adhesions induced by Focal Adhesion Kinase (FAK) phosphorylation, together with the formation of actin stress fibers. The aim of the present work was to identify thrombin-activated signaling pathways leading to FAK phosphorylation and to determine FAK participation in thrombin-induced RPE cell migration. Results demonstrate that the activation of PAR1 by thrombin induces FAK autophosphorylation at Y397 and the subsequent phosphorylation of Y576/577 within the activation loop. FAK phosphorylation was shown to be under the control of c/nPKC and PI3K/PKC-ζ, as well as by Rho/ROCK, since the inhibition of these pathways prevented thrombin-induced FAK phosphorylation and the consequent disassembly of focal adhesions, in parallel to FAK-dependent actin stress fiber formation and RPE cell migration. These findings demonstrate, for the first time, that thrombin stimulation of RPE cell transformation and migration are regulated by FAK tyrosine phosphorylation. Thus, targeting FAK phosphorylation may provide a strategical basis for PVR treatment.

[Tansitional vesical cell carcinoma metastatizing to the sphenoid sinus]. / Metástasis esfenoidal de un carcinoma de células trancisionales de la vejiga.

Secundary tumors of the paranasal sinus are very uncommon with only one hundred cases reported in the literature up to 2001. The commonest site of the primary tumor is the kidney. The maxillary sinus is most often involved. The Sphenoid sinus is the rarest site. We report a rare case of metastasis to the sphenoid sinces from a transitional cell bladder tumor in a 69-year-old man who died after treatment with chemotherapy and we also review the liteature.

Risk factor analysis for the major hazards following heart transplantation--rejection, infection, and coronary occlusive disease.

This study demonstrates the importance of analyzing survival by cause of death in order to achieve a better understanding of the prognostic indicators involved. It further emphasizes the need for analysis of risk factors in both univariate and multivariate models, and the danger of making judgements based on premature analysis of data on follow-up after heart transplantation. Survival following transplantation is characterized by the major hazards of early death due to infection and rejection and late graft loss due to coronary occlusive disease (COD). This study summarizes the first-graft survival experience for 323 transplant patients at Papworth Hospital, and assesses a number of potential risk factors for (1) early mortality, (2) late mortality from COD, and (3) development of COD. The potential risk factors considered for all hazards are donor and recipient age, sex, blood group, and matching of these factors; donor cause of death and recipient immunosuppression; inotropic support; waiting time; preoperative diagnosis and previous cardiac surgery; ischemic time; and extubation time. In addition, for development of, and graft loss from, COD, perioperative rejection and cytomegalovirus infection; hypertension at discharge; and cholesterol, triglycerides, and lipids at two years were assessed as risk factors. Advances in immunosuppression were observed to have increased overall survival rates and decreased mortality from infection, rejection, and COD, as well as decreasing morbidity from COD. Fatal rejection was found to be more likely in female recipients, recipients over 40 years, recipients of grafts from donors over 30 years old, patients who were transplanted for valvular heart disease, and patients who waited less than three months for their transplant. Male recipients of female donor organs were more likely to lose their grafts as a result of COD. Patients older than 50 and hearts from donors older than 40 conferred a high risk of development of and loss from COD. Patients transplanted for ischemic heart disease were more likely to develop COD. High cholesterol, low HDL, high LDL, and high triglycerides at two years after transplant showed some evidence of high risk for the subsequent development of COD, although these relationships are not statistically significant at this stage. Contrary to other recent studies, cytomegalovirus infection was not found to be a risk factor for the development of COD.

Quantification of deposition of neutrophilic granulocytes on vascular grafts in dogs with 111In-labeled granulocytes.

A new radioisotopic technique has been developed for quantification of deposition of neutrophilic granulocytes on vascular grafts. Nine healthy mongrel dogs underwent bilateral femoral artery resection and reconstruction with grafts of femoral vein and Gore-Tex. Pure granulocytes that had been separated from whole blood by centrifugal elutriation were labeled with 111In-tropolone in plasma. The granulocyte harvesting efficiency was 25 +/- 12%, and the labeling efficiency was 87 +/- 7%. Three hours after injection of labeled granulocytes and 2 hours after reperfusion, the grafts were harvested and cut into several segments for study of areas of anastomoses and midsections. On the basis of the radioactivity in the blood and in anastomotic and graft sections, the area of graft sections, and the neutrophilic granulocyte and differential leukocyte counts, the number of neutrophilic granulocytes adherent to a unit area and the total number of neutrophilic granulocytes on graft sections were calculated. These quantifications of the deposition of neutrophilic granulocytes indicated that the midsections of Gore-Tex grafts retained more neutrophilic granulocytes than did the midsections of vein grafts. Although the anastomotic areas retained more neutrophilic granulocytes than did the midsections of vein grafts, the opposite finding prevailed for the Gore-Tex grafts. A major fraction of neutrophilic granulocytes on Gore-Tex grafts was incorporated into thrombus. Semiquantitative information obtained by scintigraphy of the deposition of neutrophilic granulocytes on vascular grafts also confirmed this observation.

Quantification of regional platelet and calcium deposition on pericardial tissue valve prostheses in calves and effect of hydroxyethylene diphosphonate.

Mitral valves were replaced with 25 mm bovine pericardial tissue valve prostheses (Ionescu-Shiley) in 45 calves (23 controls and 22 treated daily with hydroxyethylene diphosphonate). Before being killed 1, 14, 30, and 90 days later, the calves received In-labeled autologous platelets intravenously. Regional variations in platelet deposition were measured by a new technique. Thrombus was noted early on the flexion zone of the valve; with time it increased on the free edge and central zone. Platelet deposition was initially high on the flexion zone, attachment zone, sewing ring, and perivalvular tissue but decreased with time. Hydroxyethylene diphosphonate treatment tended to decrease platelet deposition in all zones. Calcium content was high in thrombus and increased in all zones with time, in both groups, but the deposition was less in the group treated with hydroxyethylene diphosphonate. Collagenous tissue and adherent thrombus appear to provide nucleation sites for calcification.

Orthotopic transplantation after implantation of a Jarvik 7 total artificial heart.

A total artificial heart was used to support the circulation in 33 heart transplantation candidates who were expected to die before procurement of a donor heart. Twelve of these patients (mean age 35 +/- 10 years) underwent cardiac transplantation. Another patient is still being supported with the total artificial heart 90 days after implantation. The other 20 patients died during mechanical support because their condition could not be stabilized for transplantation, despite blood flow restoration. Fifty-six percent of the patients younger than 40 years underwent successful transplantation and six of nine patients are long-term survivors. By comparison, in the older group, 17.6% of patients underwent transplantation and one of three survived long term. Forty-four percent of patients in the acute decompensation group had successful transplantation and four of seven patients are long-term survivors. In the chronic decompensation group these figures were 29.4% and three of five patients. All patients who were heavily immunosuppressed (n = 4) died of sepsis. Transplantation was considered and performed only when the patient's condition was correct and stable. In six patients an infection developed in the immediate posttransplant period. Three of the infections were resolved with antibiotic therapy. One originated in the mediastinum and is still unresolved, although the patient's condition is improving. Another patient died of an anoxic coma caused by ventilatory problems. There were two late deaths at 14 and 19 months, one resulting from a combination of toxoplasmosis and rejection and the other from a Kaposi sarcoma caused by azathioprine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement activation during cardiopulmonary bypass. Comparison of bubble and membrane oxygenators.

A prospective randomized trial involving 91 patients undergoing cardiopulmonary bypass compared the effects of bubble oxygenators (with and without methylprednisolone sodium succinate) and membrane oxygenators on complement activation and transpulmonary sequestration of leukocytes. Patients were divided as follows: Group I, 30 patients, bubble oxygenator; Group II, 31 patients, bubble oxygenator and methylprednisolone sodium succinate (30 mg/kg); Group III, 30 patients, membrane oxygenator. In Group I, C3a increased from 323 +/- 171 ng/ml during cardiopulmonary bypass to 1,564 +/- 785 ng/ml at 25 minutes after bypass (p less than 0.0001). A significant decrease in C3a was found in Groups II and III compared to Group I (p less than 0.0001). C5a did not change significantly during cardiopulmonary bypass in any group. Reestablishment of pulmonary circulation at the end of bypass produced significant transpulmonary leukocyte sequestration in Group I; the median cell difference was 1,700/microliter. Transpulmonary sequestration was significantly (p less than 0.0001) less in Group II (median cell difference = 200/microliter) and in Group III (median cell difference = 400/microliter) than in Group I. We conclude that cardiopulmonary bypass with a bubble oxygenator alone initiates significantly (p less than 0.0001) more C3a activation and leukocyte sequestration than when methylprednisolone sodium succinate (30 mg/kg) is given 20 minutes before the start of cardiopulmonary bypass with a bubble oxygenator or when a silicone membrane oxygenator is used.

EEG resonant responses in schizophrenia: a photic driving study with improved harmonic resolution.

Twenty seven drug-free schizophrenic patients and 25 normal controls were studied in an EEG photic driving paradigm with an improved harmonic resolution. Consistent with previous results, the present data show that schizophrenics have lower EEG responses to photic stimulation in alpha frequency. The differences between normal and schizophrenic subjects were distributed across major brain areas except centro-temporal regions. It also demonstrated that 1-Hz narrow-pulsed stimulation was feasible in EEG photic driving studies. The enhanced harmonic resolution produced significantly more information in the frequency domain about EEG oscillatory responses to visual stimulus. Using this new technique, the authors showed for the first time that alpha photic driving was a well defined resonant system and that the group differences in harmonic responses were primarily confined in the high frequency portion of alpha band, suggesting a peak frequency shift of EEG resonance in schizophrenia.

The analgesic and hypothermic effects of nefopam, morphine, aspirin, diphenhydramine, and placebo.

One hundred and ninety-six hospitalized patients were randomly assigned to one of eight treatment groups consisting of oral or intramuscular analgesics and placebo. Patients were monitored for 6 hours for pain relief, vital signs, and side effects. No statistically significant differences in pain intensity or relief were seen for nefopam (Acupan), diphenhydramine (Benadryl), aspirin, or placebo despite a numerically higher score for nefopam. This is attributed to an unexpectantly high placebo response. Significant pain relief and reduction of pain intensity were seen with both parenteral nefopam and morphine. Side effect incidence, in general, paralleled analgesic efficacy and was higher in patients receiving parenteral drugs. An early hypothermic effect was noted with oral and parenteral nefopam, aspirin, and morphine. Lower temperatures persisted to a statistically significant degree only in nefopam-treated patients.

Percutaneously adjustable pulmonary artery band.

Conventional banding techniques result in up to 50% mortality as a result of improper and fixed constriction of the pulmonary artery in patients in unstable condition. We developed a percutaneously adjustable band with a fluid-filled reservoir that allows variable constriction without thoracotomy or other surgical procedures. Six pigs ranging in weight from 7 to 10 kg underwent pulmonary artery banding. Swan-Ganz catheterization, ultrasound studies, and Doppler studies were used to adjust and monitor the pressure gradient across the band. Thirty days after banding, the pigs were killed; their hearts were sectioned, weighed, and compared with hearts from a control group of six pigs weighing 11 to 13 kg. The ratio of mean total heart weight to total body weight (X 10(-3] was 6.3 +/- 0.7 in the banded group and 4.4 +/- 0.3 in the controls (p less than 0.001). The ratio of left ventricular weight to right ventricular weight was 0.76 +/- 0.1 in the banded group and 1.6 +/- 0.1 in the controls (p less than 0.001). The thickness of the right ventricular free wall was 4.9 +/- 0.5 mm in the banded group and 2.6 +/- 0.5 mm in the controls (p less than 0.001). Right ventricular free wall weight in the banded group was 25.9 +/- 5.8 gm compared with 11.1 +/- 1.3 gm in the controls (p less than 0.001). These results demonstrate the effectiveness of the band in inducing right ventricular hypertrophy. Since the band is easily placed and simply adjusted percutaneously, this device promises to be of importance clinically in improving the safety of pulmonary artery banding procedures.

Left ventricular preparation with an extrathoracically adjustable balloon occluder.

We developed a hydraulic occluder that could be adjusted percutaneously through a subcutaneous reservoir. Because of the potentially high pressures that may occur in preparing patients with transposition of the great vessels for an atrial switch procedure, the band on that hydrauler was modified to withstand arterial pressure and was subjected to studies involving banding of the aorta. Data indicate the suitability of this hydraulic occluder to withstand and maintain pressure in the systemic circulation.

Total artificial heart: survival and complications.

A total artificial heart was implanted in 28 patients as a bridge to transplantation. Mean time of mechanical support was 14.8 +/- 10 days. The 70-mL Jarvik-7 was used in 12 patients and the 100-mL Jarvik-7 in the remaining 16. No clinical thromboembolic complications occurred during implantation. There was no postoperative bleeding requiring operation. Both survival and the rate of complications were similar in the two Jarvik-7 groups. Eleven patients underwent successful transplantation, and 1 patient is still on mechanical support. Sepsis and multiple-organ failure were the most important causes of death. All patients receiving the total artificial heart for severe acute rejection after transplantation died of infection. Early implantation of the total artificial heart is advised in younger patients and in older patients with acute cardiac failure. The use of this device should be contraindicated in immunosuppressed patients because of the high risk of infection.

Current problems in cardiac transplantation.

Since our initial orthotopic heart transplant (OHT) in 1968, the first in Europe, 1130 patients with ages ranging from 1 month to 66 years have been referred to us. The cause of irreversible myocardial damage was idiopathic cardiomyopathy in 74%, ischemic heart disease in 19% and left ventricular failure after valvular replacement in 7%. A total of 540 transplantations, 463 orthotopic, 40 heterotopic and 37 heart-lungs were carried out. Features of the early post-operative course include temporary (first week) cardiac instability treated by isoproterenol. Later complications included rejection (95%) and side-effects of immunosuppressive therapy; infection (83%), osteoporosis, malignancy, graft atherosclerosis (2%). Cyclosporine (Cy) was responsible for diastolic hypertension, renal dysfunction, hirsutism, hyperplasia of the gingiva, hepatic dysfunction, and seizures. The survival rate of the Cy-treated patients was 68% at 7 years. All survivors have virtually normal social and professional lives, included the longest survivor 14 years after the operation. Recently in 34 patients in acute irreversible cardiac failure and who cannot have a transplant in time, we implant a total artificial heart (TAH) type JARVIK 7 during a period from 1-150 days. There has been no mechanical failure, hemolysis or thrombo-embolism and only one right ventricular device malposition; 20 patients died before transplantation, 13 were successfully transplanted, 1 is still on the artificial heart. Heart transplantation, and TAH used as a bridge to transplantation are now an accepted therapeutic means for irreversibly cardiac failure in selected patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Management following heart and lung transplantation: five years experience.

Since April 1984, 70 patients have received heart-lung transplants at our institution. Actuarial survival is 76% at 1 year and 68% at 2 years. All but 4 surviving patients have an unrestricted life style. Rejection was confirmed by lung transbronchial biopsy (TBB) on 277 occasions in 66 patients. Forty-two percent of episodes occurred within 1 month of surgery. Eight patients have developed evidence of chronic rejection with progressive irreversible fall in FEV1, of whom 4 have died or undergone single lung retransplantation. Seven patients had primary cytomegalovirus (CMV) of whom 4 patients died. Eight patients developed pneumocystis pneumonia of whom 1 died. Seven episodes of herpes simplex pneumonitis occurred of which one episode was fatal. Heart-lung transplantation is a valuable treatment for terminal cardiopulmonary disease and offers increasing hope of long-term survival.