The use of the acute Pd/Pa drop after intracoronary nitroglycerin infusion to rule out significant FFR: CANICA (Can intracoronary nitroglycerin predict fractional flow reserve without adenosine?) multicenter study.

OBJECTIVE: Functional assessment of coronary artery stenosis is performed by measuring the fractional flow reserve (FFR) under hyperemic conditions (Adenosine). However, the use of adenosine portends limitations. OBJECTIVE: We sought to investigate the relationship and correlation between FFR and the Pd/Pa value obtained just after the intracoronary infusion (acute drop) of nitroglycerin (Pd/Pa-NTG) and if this parameter enhances diagnostic accuracy for FFR prediction compared to the resting baseline Pd/Pa. METHODS: We conducted a multicenter study including prospectively patients presenting intermediate coronary artery stenosis (30-70%) evaluated with pressure wire. Resting baseline Pd/Pa, Pd/Pa-NTG and FFR were measured. RESULTS: 283 patients (335 lesions) were included. Resting baseline Pd/Pa value was 0.72 to 1.0 (0.93 ± 0.04), Pd/Pa-NTG was 0.60 to 1.0 (0.87 ± 0.07) and FFR 0.55 to 1.0 (0.83 ± 0.08). The ROC curves for resting baseline Pd/Pa and for Pd/Pa-NTG, using a FFR ≤ 0.80 showed an AUC of 0.88 (95% CI: 0.84-0.92, P < 0.001) and 0.94 (95% CI: 0.92-0.96, P < 0.001) respectively. The optimal cutoff values of resting baseline Pd/Pa and Pd/Pa-NTG for an FFR > 0.80, were >0.96 and >0.88, respectively. These values were present in a 29.8% (n = 100) and a 47.1% (n = 158), of the total lesions. Scatter plots showed a better correlation and agreement points with Pd/Pa-NTG than resting baseline Pd/Pa. The cutoff value of Pd/Pa-NTG > 0.88 showed an excellent NPV (96.2% for FFR > 0.8 and 100% for FFR > 0.75) and sensitivity (95% for FFR > 0.8 and 100% for FFR > 0.75) which were consistently high across all the subgroups analysis. CONCLUSION: The cutoff value of acute Pd/Pa-NTG > 0.88 has a high NPV meaning adenosine-FFR can be avoided in almost half of lesions.

[Diffuse erythema with lung and inguinal masses as the initial manifestation of a large cell neuroendocrine tumor of the lung]. / Eritema generalizado, masa pulmonar e inguinal como forma de presentación de un carcinoma neuroendocrino pulmonar de células grandes.

Large cell neuroendocrine carcinoma of the lung is defined as poorly differentiated and high-grade neuroendocrine tumor that is morphologically and biologically between atypical carcinoid and small cell lung carcinoma. The prognosis of this type of tumor is poor, specially in advanced disease. We report on a case with atypical presentation, with high blood levels of histamine as a previously unreported association, and IV stage, in which the diagnosis was made after biopsy of an inguinal mass.

Eritema generalizado, masa pulmonar e inguinal como forma de presentación de un carcinoma neuroendocrino pulmonar de células grandes / Diffuse erythema with lung and inguinal masses as the initial manifestation of a large cell neuroendocrine tumor of the lung

El carcinoma pulmonar neuroendocrino de células grandes se define como un tumor neuroendocrino pobremente diferenciado y de alto grado que se encuentra, morfológica y biológicamente, entre el carcinoide atípico y el carcinoma de células pequeñas. El pronóstico de este tipo de tumor es malo, sobre todo en estadios avanzados. Describimos un caso con una presentación atípica, con marcada elevación de los niveles de histamina en sangre, asociación no descrita anteriormente, y estadio IV, cuyo diagnóstico se realizó mediante biopsia de una masa inguinal (AU)

[Angiographic correlates of the high-risk criteria for conventional exercise testing and the Duke treadmill score]. / Correlación angiográfica de los criterios de alto riesgo para ergometría convencional y el índice de Duke.

OBJECTIVE: To compare the sensitivity, the specificity, the positive and negative predictive value and the predictive accuracy of the Duke Treadmill Score, the Spanish Society of Cardiology (SEC) and American College of Cardiology/American Heart Association (ACC/AHA) high-risk criteria for exercise testing in the detection of left main disease, three vessel disease and two vessel disease involving the proximal left anterior descending artery. PATIENTS AND METHOD: A cohort of 199 patients (age 75 years) consecutively admitted to hospital for unstable angina was studied. All patients underwent an exercise stress test and coronariography. RESULTS: The SEC high-risk Criteria showed a sensitivity of 69.2% and a specificity of 49.0%. The ACC/AHA high-risk Criteria demonstrated a sensitivity of 98.1% and a specificity of 23.8% and the Duke Treadmill Score presented a sensitivity of 30.8% and a specificity of 90.5%. In patients with moderate risk in the Duke Treadmill Score we found a sensitivity of 62.9% and a specificity of 39.8% for the SEC high-risk criteria, while the ACC/AHA high-risk Criteria presented a sensitivity of 100.0% and a specificity of 5.8%. CONCLUSIONS: The ACC/AHA high-risk Criteria showed a higher sensitivity while the Duke Treadmill Score presented a higher specificity for the detection of left main disease, three vessel disease and two vessel disease involving the proximal left anterior descending artery. The ACC/AHA and SEC high-risk Criteria were found to be very useful in the group of patients with moderate risk in the Duke Treadmill Score.

Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion.

To study effects of Bcl-x(L) in the pancreatic beta-cell, two transgenic lines were produced using different forms of the rat insulin promoter. Bcl-x(L) expression in beta-cells was increased 2- to 3-fold in founder (Fd) 1 and over 10-fold in Fd 2 compared with littermate controls. After exposure to thapsigargin (10 microM for 48 h), losses of cell viability in islets of Fd 1 and Fd 2 Bcl-x(L) transgenic mice were significantly lower than in islets of wild-type mice. Unexpectedly, severe glucose intolerance was observed in Fd 2 but not Fd 1 Bcl-x(L) mice. Pancreatic insulin content and islet morphology were not different from control in either transgenic line. However, Fd 2 Bcl-x(L) islets had impaired insulin secretory and intracellular free Ca(2+) ([Ca(2+)](i)) responses to glucose and KCl. Furthermore, insulin and [Ca(2+)](i) responses to pyruvate methyl ester (PME) were similarly reduced as glucose in Fd 2 Bcl-x(L) islets. Consistent with a mitochondrial defect, glucose oxidation, but not glycolysis, was significantly lower in Fd 2 Bcl-x(L) islets than in wild-type islets. Glucose-, PME-, and alpha-ketoisocaproate-induced hyperpolarization of mitochondrial membrane potential, NAD(P)H, and ATP production were also significantly reduced in Fd 2 Bcl-x(L) islets. Thus, although Bcl-x(L) promotes beta-cell survival, high levels of expression of Bcl-x(L) result in reduced glucose-induced insulin secretion and hyperglycemia due to a defect in mitochondrial nutrient metabolism and signaling for insulin secretion.

Manipulation of outer root sheath cell survival perturbs the hair-growth cycle.

Transgenic mice that overexpress the anti-apoptotic gene bcl-xL under the control of the keratin 14 promoter have significantly shorter hair than non-transgenic littermates. The deficit in hair length correlated with a decrease in the duration of anagen, the growth phase of the hair cycle. A prolongation in telogen, the resting phase of the hair cycle, was also observed in adult animals. In the developing hair bulb, bcl-xL transgene expression was observed exclusively in the outer root sheath (ORS) cells. Bcl-xL expression enhanced the survival of ORS cells treated with apoptotic stimuli. The results suggest that preventing the apoptotic death of ORS cells during anagen leads to a more rapid termination of progenitor cell commitment/proliferation, while the increased survival of ORS cells during telogen delays the initiation of a new hair cycle. ORS cells produce fibroblast growth factor-5 (FGF-5), which acts in a paracrine fashion to terminate precursor cell division during anagen. The short hair phenotype of bcl-xL transgenic mice was substantially reversed in FGF-5-deficient mice. Thus, the production of growth inhibitory factors by ORS cells may provide a mechanism through which the hair-growth cycle is regulated by cell survival.

Pre-Columbian medicine and the kidney.

Medicine in Mesoamerican cultures began in the year 1500 BC and ended with the conquest and destruction of Mexico-Tenochtitlan in 1521 by Spain. Mesoamerica started with the Olmec civilization followed by the Teoitihuacanes, Toltecs, and Mayas and perished with the Nahoa Empire. The medicine used by the Aztecs (ticiotl) is undoubtedly the sum of all Mesoamerican medicine. The medical history of the ticiotl was recovered in the years that followed the conquest from the works of Bernardino de Sahagún and Francisco Hernández and the Cruz-Badiano codex. All these works describe the use of plants and herbs in the treatment of diseases, including, edema, urinary retention, kidney stones, and podagra. The Aztec doctors (titicih) were also well acquainted with innumerable diseases and were excellent healers of wounds and fractures. The works of modern historians confirm the theory of the ticiotl medicine and its application by the titicih and define the differences between the hippocratic-galenic medicine and the ticiotl medicine. The latter used a complex and philosophically elaborated medical theory based on the polarity cold/warm, different from the four-humor theory. They demonstrate that every culture is capable to understand and 'invent' the meaning of disease and its cure, even when it is different from our modern medical views.

Bcl-xL and Bcl-2 expression in squamous cell carcinoma of the head and neck.

BACKGROUND: Inhibition of apoptosis, or programmed cell death, may be critical both in the development of cancer and in determining response to therapy. The authors examined the expression of two related apoptotic inhibitors, Bcl-2 and Bcl-xL, in pretreatment biopsies from a series of 42 patients with squamous cell carcinoma of the head and neck. The observed pattern of apoptotic inhibitor expression was compared with that of the p53 gene product, another factor implicated in carcinogenesis and therapeutic responsiveness. METHODS: Formalin fixed, paraffin embedded tumor biopsies from 42 patients with locally advanced squamous cell carcinoma of the head and neck were analyzed by immunohistochemistry using antibodies specific for Bcl-xL, Bcl-2, and p53. Measures of clinical outcome, including disease specific survival and overall survival, were compared among the groups. RESULTS: The majority of the tumors demonstrated enhanced expression of either Bcl-2 or Bcl-xL compared with surrounding normal epithelium. Fifty-two percent of the tumors had up-regulated Bcl-xL, and 17% had up-regulated Bcl-2. There was no overlap between these groups. Expression of Bcl-2, but not Bcl-xL, was correlated with improved disease specific survival. Immunohistochemically detectable p53 expression (48% of tumors) was not found to correlate with expression of either Bcl-xL or Bcl-2 and, in this series, was not a predictor of clinical outcome. CONCLUSIONS: These results suggest that disruption of apoptotic control pathways is an important event in the evolution of squamous cell carcinoma of the head and neck. A common mechanism for this disruption involves overexpression of Bcl-xL, Patients whose tumors demonstrate Bcl-2 positivity, even with locoregionally advanced disease, appear to have a high likelihood of cure with aggressive combined modality therapy and may be treated successfully with less toxic therapy.

A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas.

The role of apoptosis in the pathogenesis of skin cancer was analyzed in mice bearing a Bcl-xL transgene expressed under the control of the keratin 14 promoter. No spontaneous tumors developed in the skin of these transgenic mice. Bcl-xL transgenics also failed to develop skin lesions following treatment with the chemical mutagen 9,10-dimethyl-1,2-benzanthracene, or the tumor promoter O-tetradecanoylphorbol-13-acetate. However, Bcl-xL transgenics developed a two-fold greater number of benign papillomas than control littermates following treatment with the combination of 9,10-dimethyl-1,2-benzanthracene and O-tetradecanoylphorbol-13-acetate. More significantly, Bcl-xL transgenic mice developed invasive squamous cell carcinoma earlier and more frequently than wild-type controls in response to the chemical agents. These data suggest that Bcl-xL cannot functionally substitute for a mutagenic initiator or mitogenic promoter in tumorigenesis. In contrast, Bcl-xL overexpression can dramatically increase the malignant conversion rate of benign tumors, suggesting that inhibition of apoptosis can contribute to tumor progression.

Bcl-x expression influences keratinocyte cell survival but not terminal differentiation.

The epidermis is characterized by the continual turnover of its basic cellular unit, the keratinocyte. To determine whether genes known to regulate apoptosis could affect keratinocyte biology, transgenic mice overexpressing bcl-xL or bcl-xS under the control of the human keratin 14 promoter were generated. The maturation process and cellularity of the stratified epidermis were not compromised in the transgenic mice. Transgene function was demonstrated by enhanced cell survival of bcl-xL transgenic versus wild-type primary keratinocyte cultures treated with etoposide. To test the response of these mice to genotoxic damage, wild-type and transgenic mice were irradiated with UV light. The bcl-xL transgenic mice showed a dramatically increased resistance to irradiation, whereas the bcl-xS transgenic mice showed an increased sensitivity to irradiation. In contrast, neither transgene influenced the rate of would repair. Interestingly, endogenous Bcl-x was rapidly induced in keratinocytes adjacent to the would. Taken together, these findings demonstrate that although the terminal differentiation program is not altered by Bcl-x, acute stress responses within the skin can be influenced by regulators of apoptosis such as Bcl-x.

bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice.

We have assessed during B cell development, the regulation and function of bcl-x, a member of the bcl-2 family of apoptosis regulatory genes. Here we show that Bcl-xL, a product of bcl-x, is expressed in pre-B cells but downregulated at the immature and mature stages of B cell development. Bcl-xL but not Bcl-2 is rapidly induced in peripheral B cells upon surface immunoglobulin M (IgM) cross-linking, CD40 signaling, or LPS stimulation. Transgenic mice that overexpressed Bcl-xL within the B cell lineage exhibited marked accumulation of peripheral B cells in lymphoid organs and enhanced survival of developing and mature B cells. B cell survival was further increased by simultaneous expression of bcl-xL and bcl-2 transgenes. These studies demonstrate that Bcl-2 and Bcl-xL are regulated differentially during B cell development and activation of mature B cells. Induction of Bcl-xL after signaling through surface IgM and CD40 appears to provide mature B cells with an additional protective mechanism against apoptotic signals associated with antigen-induced activation and proliferation.

Adynamic bone lesion in renal transplant recipients with normal renal function.

Adynamic bone lesion has been defined as low bone turnover, normal or low osteoid volume and decreased bone formation rate (BFR). A prospective cross-sectional study was performed in 16 asymptomatic post-transplant kidney patients with normal renal function, to evaluate low bone mineral density. The mean age of the nine women and seven men was 33.9 +/- 7.3 years, the mean serum creatinine was 1.1 +/- 0.2 mg/dl and the mean creatinine clearance 71.5 +/- 13.8 ml/min/1.73 m2. Six patients received triple immunosuppressive therapy for a period of 10.3 +/- 3.7 months and nine received double therapy. Eighty-four months after renal grafting, we carried out bone densitometry, biochemical markers and bone biopsy. Bone densitometry showed 78 +/- 8.7% and 80.4 +/- 8% for hip and lumbar spine, with a mean Z score of 1.79 +/- 0.72 and 1.88 +/- 0.78 (SD), significantly less than normal in the Hispanic young population for those two regions. Serum PTH (0.83 +/- 0.23 microgram/ml normal range 0.32-0.65), urine cAMP (4.1 +/- 1.3, normal range 0.5-4.7 nmol/mg Cr) and total and nephrogenic fraction (3.1 +/- 1.1, normal range 0.29-2.9 nmol/100 ml GFR) were significantly greater than normal (P < 0.01). The bone biopsy in 12/16 patients showed decreased percentage osteoid area (1.59 +/- 0.86% vs 3.19 +/- 0.82%), percentage mineralized area (13 +/- 4.7% vs 21.03 +/- 3.36%) and bone formation rate (505 +/- 237 vs 1275 +/- 168 microns2/mm2/day), with a P value < 0.05 compared with 10 normal bone biopsies. The remaining four patients exhibited low bone turnover image with normal bone formation rate (1442 +/- 206 microns2/mm2/ day). Iron deposits were demonstrated at the mineralization front in 10/16 patients. No aluminium or amyloid deposits were observed. The histomorphometric results showed the presence of adynamic bone lesion in 12 renal transplant recipients with normal renal function and osteopenia, which explains the low bone density. The long-term use of glucocorticoids and the presence of iron deposits may contribute to this bone lesion. The biochemical markers of bone remodelling showed abnormalities compatible with moderate increase in parathyroid function. The adynamic lesion in the presence of hyperparathyroid function may suggest down-regulation of PTH bone receptors, alterations of the bone microenvironment or both.

Bclx regulates the survival of double-positive thymocytes.

The bclx gene has been shown to regulate programmed cell death in vitro. We now show that Bclx expression increases dramatically when T cells differentiate from CD4- CD8- (double negative) thymocytes to CD4+ CD8+ [double positive (DP)] thymocytes. In contrast single-positive (SP) thymocytes express negligible amounts of Bclx protein. This expression pattern contrasts with that of Bcl2, which is present in double-negative thymocytes, down-regulated in DP thymocytes, and reinduced upon maturation to SP thymocytes. Elimination of Bclx by gene targeting dramatically shortens the survival of DP thymocytes but not the survival of SP thymocytes or peripheral SP T cells. These data suggest that the induction of Bclx during thymic maturation plays a critical role in regulating the length of time DP thymocytes survive in the absence of selection.

A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene.

The squamous cell carcinoma antigen (SCCA) is a member of the ovalbumin family of serine proteinase inhibitors (serpins). A neutral form of the protein is found in normal and some malignant squamous cells, whereas an acidic form is detected exclusively in tumor cells and in the circulation of patients with squamous cell tumors. In this report, we describe the cloning of the SCCA gene from normal genomic DNA. Surprisingly, two genes were found. They were tandemly arrayed and flanked by two other closely related serpins, plasminogen activator inhibitor type 2 (PAI2) and maspin at 18q21.3. The genomic structure of the two genes, SCCA1 and SCCA2, was highly conserved. The predicted amino acid sequences were 92% identical and suggested that the neutral form of the protein was encoded by SCCA1 and the acidic form was encoded by SCCA2. Further characterization of the region should determine whether the differential expression of the SCCA genes plays a causal role in development of more aggressive squamous cell carcinomas.

[Renal and extra-renal mechanisms of sodium and water retention in cirrhosis with ascites]. / Mecanismos renales y extrarrenales en la retención de sodio y agua en la cirrosis con ascitis.

In this work we analyze the renal and systemic factors involved in the sodium retention in two conditions: in extracellular volume depletion and in edema forming states, particularly liver cirrhosis with ascitis. In this paper we accept that the volume loss of body fluids stimulates the "effective arterial blood volume" (VAE). This term results from a decrease in the arterial blood volume secondary to a fall in cardiac output or a peripheral arterial vasodilatation. The reduction in the VAE stimulates: the high pressure baroreceptors (carotid sinus and aortic arch); the intrarrenal mechanisms, such as the yuxtaglomerular apparatus and the renin angiotensin aldosterone system; the sympathetic adrenergic system; the non osmotic release of antidiuretic hormone; prostaglandins (PGE1, Tromboxane) and endothelin; and inhibits the atrial natriuretic peptide. We also describe the sodium transport mechanisms along the nephron during physiological conditions and after volume depletion, and in edema formation states, specially hepatic cirrhosis with ascitis. We speculate that the intrarenal mechanisms are more important and persistent than the systemic mechanisms. It is possible that the sodium retention of these states might be the result of direct stimuli of the tubular sodium transport mechanisms in the different segments of the nephron, mediated by the co and counter transports, ATPase activity or by the second messengers cyclic AMP and cyclic GMP. The clonation and structural characterization of the different sodium transports may help us to establish, more precisely, the intracellular tubular mechanisms responsible for the tendency of the body to retain sodium. The amount of information generated in the future may help us to demonstrate, with more precision, the mechanisms responsible for the sodium retention and excretion in normal and pathological conditions, particularly the edema forming states such as cardiac failure, nephrotic syndrome and hepatic cirrhosis with ascitis.

Development of T cell receptor-gamma delta cells. Phenotypic and functional correlations of T cell receptor-gamma delta thymocyte maturation.

The development of TCR-gamma delta cells during thymic ontogeny has been studied using fetal thymic organ cultures of normal and transgenic (Tg) mice. The expression of the cell-surface markers--heat stable Ag (HSA), MEL-14, CD5, CD25 (IL-2R), and CD44 (Pgp-1)--correlated with TCR-gamma delta maturation. As the fetal thymus developed, there was an increase in HSA-, CD5dull, and CD44+ cells for each TCR-gamma delta cell subset. Moreover, the expression of recombination activating genes-1 and -2 (RAG-1 and RAG-2) also correlated with TCR-gamma delta maturation as only HSA+ TCR-gamma delta cells transcribed these genes. Cyclosporin A inhibited the development of the TCR-gamma delta thymocytes if it was introduced early during thymic ontogeny by arresting the differentiation of TCR-gamma delta thymocytes at the HSA+ stage. Immature HSA+ TCR-gamma delta thymocytes isolated from both TCR-gamma delta Tg and normal mice did not respond to nominal Ag or anti-TCR mAb unless exogenous IL-2 was added to the cultures. In contrast, HSA- TCR-gamma delta cells from Tg and normal mice responded to TCR/ligand interactions in the absence of additional IL-2. Finally, the development of functionally mature TCR-gamma delta cells could be induced in vitro. Interaction of the HSA+ Tg+ TCR-gamma delta cells with anti-TCR-gamma delta mAb or Ag-bearing thymic stromal cells resulted in RAG-1 and RAG-2 down-regulation. These data strongly suggest that TCR-gamma delta HSA+, RAG+ thymocytes differentiate into a more mature stage under the pressure of positive selection and that TCR-gamma delta cell development is regulated in a manner similar to TCR-alpha beta cells. In addition, the ability of Cyclosporin A to inhibit TCR-gamma delta cell development combined with the findings that Ag-bearing stromal cells can induce Tg TCR-gamma delta cell development suggests that maturation and selection of TCR-gamma delta cells depends on receptor-mediated physiologic stimuli delivered during thymic development.

Death risk in CAPD patients. The predictive value of the initial clinical and laboratory variables.

The characteristics, survival rate and risk factors associated with death in patients with end-stage renal failure treated with chronic ambulatory peritoneal dialysis (CAPD) were studied. This is a retrospective study of a cohort of 206 patients, from which the follow-up was complete in 190 patients (92%). Only 16 patients (8%) were lost. The study group is composed of 118 males and 88 females, with a mean age of 39 +/- 15 years. The origin of the renal disease was: unknown in 90 patients (44%); diabetes mellitus in 50 (24%); systemic lupus erythematosus in 16 (8%); obstructive uropathy in 15 (7%); glomerulonephritis in 14 (7%), and miscellaneous in 21 (10%). The average follow-up was 12 +/- 11 months. At the end of study, 66 patients were dead (32%). CAPD was discontinued in 12 (6%). Thirty-eight patients (18%) received kidney transplantation. The survival rate for the whole group was 67 and 48% at 1 and 3 years, respectively. Multivariate survival analysis according to the Cox proportional-hazard model showed that the most powerful predictor associated with high risk of death was low serum albumin levels. According to the Cox model other independent variables significantly associated with increase in the probability of death while on CAPD were advancing age, low serum creatinine concentrations and elevated serum cholesterol levels. These results indicate that the risk factors associated with death in CAPD patients are similar to those observed for hemodialysis patients and suggest that using simple laboratory measurements at the enrollment in CAPD the relative risk of death for each patient can be estimated.