4-Deoxyphorbol inhibits HIV-1 infection in synergism with antiretroviral drugs and reactivates viral reservoirs through PKC/MEK activation synergizing with vorinostat.

Latent HIV reservoirs are the main obstacle to eradicate HIV infection. One strategy proposes to eliminate these viral reservoirs by pharmacologically reactivating the latently infected T cells. We show here that a 4-deoxyphorbol ester derivative isolated from Euphorbia amygdaloides ssp. semiperfoliata, 4ß-dPE A, reactivates HIV-1 from latency and could potentially contribute to decrease the viral reservoir. 4ß-dPE A shows two effects in the HIV replication cycle, infection inhibition and HIV transactivation, similarly to other phorboids PKC agonists such PMA and prostratin and to other diterpene esters such SJ23B. Our data suggest 4ß-dPE A is non-tumorigenic, unlike the related compound PMA. As the compounds are highly similar, the lack of tumorigenicity by 4ß-dPE A could be due to the lack of a long side lipophilic chain that is present in PMA. 4ß-dPE activates HIV transcription at nanomolar concentrations, lower than the concentration needed by other latency reversing agents (LRAs) such as prostratin and similar to bryostatin. PKCθ/MEK activation is required for the transcriptional activity, and thus, anti-latency activity of 4ß-dPE A. However, CD4, CXCR4 and CCR5 receptors down-regulation effect seems to be independent of PCK/MEK, suggesting the existence of at least two different targets for 4ß-dPE A. Furthermore, NF-κb transcription factor is involved in 4ß-dPE HIV reactivation, as previously shown for other PKCs agonists. We also studied the effects of 4ß-dPE A in combination with other LRAs. When 4ß-dPE A was combined with another PKC agonists such as prostratin an antagonic effect was achieved, while, when combined with an HDAC inhibitor such as vorinostat, a strong synergistic effect was obtained. Interestingly, the latency reversing effect of the combination was synergistically diminishing the EC50 value but also increasing the efficacy showed by the drugs alone. In addition, combinations of 4ß-dPE A with antiretroviral drugs as CCR5 antagonist, NRTIs, NNRTIs and PIs, showed a consistent synergistic effect, suggesting that the combination would not interefer with antiretroviral therapy (ART). Finally, 4ß-dPE A induced latent HIV reactivation in CD4 + T cells of infected patients under ART at similar levels than the tumorigenic phorbol derivative PMA, showing a clear reactivation effect. In summary, we describe here the mechanism of action of a new potent deoxyphorbol derivative as a latency reversing agent candidate to decrease the size of HIV reservoirs.

Virus Size Analysis by Gas-Phase Mobility Measurements: Resolution Limits.

Electrospraying (ES) dissolved viral particles, followed by charge reduction and size analysis with a differential mobility analyzer (DMA), offers a flexible size-analysis tool for small particles in solution. The technique relies on pioneering work by Kaufman and colleagues, commercialized by TSI, and often referred to as GEMMA. However, viral studies with TSI's GEMMA have suffered from limited resolving power, possibly because of imperfections in either the instrument (DMA or charge reduction) or the sample solution preparation. Here, we explore the limits of the resolution achievable by GEMMA, taking advantage of (i) cleaner charge reduction methods and (ii) DMAs of higher resolving power. Analysis of the literature provides indications that mobility peak widths (fwhm) of 2% or less may be achieved by combining careful sample preparation with improved instrumentation. Working with purified PP7 bacteriophage particles small enough to be classifiable by existing high-resolution DMAs, we confirm that fairly narrow viral mobility peaks may be obtained (relative full width at half-maximum fwhm <5%). Comparison of spectra of a given apian virus sample obtained with TSI's GEMMA and our improved instrumentation confirms that one critical limitation is the DMA. This is further verified by narrow peaks from murine parvovirus, norovirus, and encephalomyelitis virus samples, obtained in our improved GEMMA with little sample preparation, directly from infected cell cultures. Classification of purified large (60 nm) coliphage PR772 particles leads to broad peaks, due to both viral degradation and limited intrinsic resolution of the DMAs used to cover the range of such large particles. We conclude that improved DMAs suitable for high-resolution analysis of particles larger than 30 nm need to be developed to determine the intrinsic mobility width of viral particles.

Physical activity in anorexia nervosa: How relevant is it to therapy response?

OBJECTIVE: Elevated physical activity has been observed in some patients with anorexia nervosa (AN) despite their emaciated condition. However, its effects on treatment outcome remain unclear. This study aimed to examine objectively measured physical activity in this clinical population and how it might be related to a partial hospitalization therapy response, after considering potential confounders. METHOD: The sample comprised 88 AN patients consecutively enrolled in a day hospital treatment program, and 116 healthy-weight controls. All participants were female and a baseline assessment took place using an accelerometer (Actiwatch AW7) to measure physical activity, the Eating Disorders Inventory-2 and the Depression subscale of the Symptom Checklist-Revised. Outcome was evaluated upon the termination of the treatment program by expert clinicians. RESULTS: Although AN patients and controls did not differ in the average time spent in moderate-to-vigorous physical activity (MVPA) (P=.21), nor daytime physical activity (P=.34), fewer AN patients presented a high physical activity profile compared to the controls (37% vs. 61%, respectively; P=.014). Both lower levels of MVPA and greater eating disorder severity had a direct effect on a poor treatment outcome. Depression symptoms in the patients were associated with lower MVPA, as well as with an older age, a shorter duration of the disorder and greater eating disorder psychopathology. CONCLUSIONS: There is a notable variation in the physical activity profile of AN patients, characterized by either low or very high patterns. Physical activity is a highly relevant issue in AN that must be taken into account during the treatment process.

Effect of recombinant growth hormone on leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-α and ghrelin levels in growth hormone-deficient children.

BACKGROUND: Treatment with GH promotes linear growth and decreases body fat in patients with isolated GH deficiency (GHD). However, few studies have analyzed how GH replacement modifies ghrelin levels and the adipokine profile and the relationship of these modifications with the metabolic changes. AIMS: To analyze the eventual differences between serum levels of leptin, leptin soluble receptor (sOBR), resistin, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), total (TG) and acylated ghrelin (AG) and lipid and glycemic profiles in children with GHD, as well as to determine the effect of GH replacement on these parameters during the first year of therapy. SUBJECTS AND METHODS: Thirty pre-pubertal (Tanner stage I) GHD children and 30 matched controls were enrolled. Children with GHD were studied before and after 6 and 12 months of GH treatment. Weight, height, BMI, fasting glucose, insulin, lipid profile and serum levels of adipokines and ghrelin were studied at every visit. Adi - pokines, insulin and ghrelin levels were determined by using commercial radio- and enzymoimmunoassays. RESULTS: At baseline children with GHD had significantly higher sOBR (p<0.01) and adiponectin (p<0.01) levels than controls. Treatment with GH resulted in a decline in leptin (p<0.05) and TG (p<0.001) levels, an increase of homeostasis model assessment index and restored IGF-I levels (p<0.001). CONCLUSIONS: These data indicate that GH replacement has a negative effect on leptin levels and may also produce a slight unfavorable effect on carbohydrate metabolism. In addition, the changes observed in the adipokine profile appear to be independent of body mass index.

[D-Lactic acidosis secondary to short bowel syndrome]. / Ácidosis D-láctica secundaria a síndrome de intestino corto.

The short bowel syndrome appears for the reduction of intestinal absorptive surface due to functional or anatomical loss of part of the small bowel. We present the case of a 35-year-old woman with severe short bowel syndrome secondary to acute intestinal ischemia in adults, who presented at 5 years of evolution episodes of dizziness with gait instability and loss of strength in hands. The diagnosis was D-lactic acidosis. D-lactic acidosis is a rare complication, but important for their symptoms, of this syndrome. It is due to a change in intestinal flora secondary to an overgrowth of lactic acid bacteria that produce D-lactate. D-lactic acidosis should be looked for in cases of metabolic acidosis in which the identity of acidosis is not apparent, neurological manifestations without focality and the patient has short bowel syndrome or patients who have had jejunoileal bypass surgery. Appropriate treatment usually results in resolution of neurologic symptoms and prevents or reduces further recurrences.

Effects on the glutathione pool of the insulin-induced hypoglycaemia test.

The growth hormone (GH) stimulation test shows that hypoglycaemia can cause the generation of free radicals, or reactive oxygen species (ROS), together with the migration of amino acids, glutathione and various ions to the interior of fat or muscle cells. The aim of the present study is to evaluate the splitting of plasma glutathione into its two fractions, oxidized (GSSG) and reduced (GSH), after the induction of hypoglycaemia with insulin in the course of the GH stimulation test. We studied 41 short children (47% boys and 53% girls) at the Paediatric Department of the San Cecilio Hospital (Granada, Spain) to evaluate their size and growth. A GH stimulation test using insulin-induced hypoglycaemia was carried out, and GSSG and GSH values in plasma were determined. The glutathione level is associated with the level of glucose reached at 30 min after initiating the test. This provoked an initial reduction in the GSH/GSSG ratio, which fell to a minimum at 30 min after starting the test, although the values rose again at 60 min. The results obtained show that the insulin-induced GH stimulation test produces a decrease in plasma levels of the glutathione pool, that persists at least for 2 hours following the beginning of the test.

[A series of 618 cases of monoclonal gammopathies of undetermined significance: predictive factors of disappearance of monoclonal component or evolution to malignant gammopathies]. / Serie de 618 casos de gammapatías monoclonales de significado indeterminado (GMSI): factores predictivos de desaparición del componente monoclonal o de evolución a gammapatías malignas.

INTRODUCTION: How to identify monoclonal gammopathies of undeterminated significance (MGUS) at risk for progression has been studied for the last years. AIMS: To study the incidence of MGUS in a region with 300,000 inhabitants and factors which associate with a) monoclonal gammopathy disappearance (transient MGUS) b) evolution to malignant gammopathy. METHODS: Study of 618 MGUS. RESULTS: Incidence: 30/40 new cases a year with increase to 70 cases a years in the latest years of study. Age and gender: 71,4 y (32-100), male/female ratio 1.4. Associated pathology: infection 328, heart diseases 249, rheumatic diseases 211, liver diseases 108, cancer 80, neuropathy 43. Monoclonal proteins: IgG 407, IgM 78, IgD 2, biclonal 16, triclonal 1; no heavy chain 21, light chain Kappa 389. Variables (mean): monoclonal component: 14 g/l, ESR 32,5, bone marrow: 5,9% plasma cells beta2-microglobulin: 2,59 mg/l, albumin: 3,1g/l, bone survey: normal 39,5%. Evolution: transient MGUS 20 cases. Time to disappearance 2,6 months (1,4-4,6). Evolution to malignant gammopathy 24 cases, time to progression 3 years (IC 1,82-4,3). RESULTS: Several factors were associatedç with malignant transformation: heavy chain IgA (p < 0,002), ESR (p < 0,001), age < 70 (p < 0,05), bone marrow percentage of plasma cells (p < 0,002) y ostheoporosis (p < 0,005). A MGUS follow up model is suggested.

[Effectiveness of medical counseling for alcoholic patients and patients with excessive alcohol consumption seen in primary care]. / Efectividad del consejo médico a pacientes alcohólicos y bebedores excesivos atendidos en consultas de atención primaria.

AIM: To determine the effectiveness of medical counseling for alcohol abuse, when it is provided in primary care centers. DESIGN: Quasi-experimental, open, multicenter before-after study.Setting. 14 primary care physician's practices (7 rural, 7 urban) in the province of Córdoba (Spain). PARTICIPANTS: 306 patients of both sexes, recruited with a case-finding strategy, who consumed >=35 (men) or >=21 (women) IU per week, or who had alcohol dependence syndrome (ADS) (MALTS score O>=11). Interventions. All patients were offered brief counseling to reduce drinking, and all were followed to evaluate their status 3 months, 1 year and 2 years later. MAIN MEASURES: The response variable was self-reported alcohol consumption together with normal GGT values or confirmation of alcohol consumption by a relative. The results were subjected to intention-to-treat analysis. RESULTS: Of the 306 patients included in the study, 95.1% were men and 78.4% had ADS. After 2 years 38.89% (95% CI, 32.2%-44.3%) had attained their treatment goal: 23.85% were in complete abstinence, and 15.0% consumed moderate amounts of alcohol below the limit considered to indicate risk. Starting excessive consumption at less than 16 years of age (odds ratio [OR], 3.0885), living in a slum (OR, 3.2103), smoking (OR, 1.7187), and a positive CAGE test (OR, 1.9949) were associated with failure of the intervention (P<.05). CONCLUSIONS: Counseling provided by the family doctor was highly effective under the usual conditions of general practice, both for patients with excessive alcohol consumption and for patients with con ADS.

[Alcohol consumption among students in a basic health area in Córdoba]. / Consumo de alcohol entre los escolares de una zona básica de salud de Córdoba.

BACKGROUND: To determine alcohol consumption amongst schoolchildren, and to discover the factors which are associated with the said consumption. METHODS: A cross-sectional study, by means of a health questionnaire administered to 548 schoolchildren in the 6th and 8th years of Primary Education (EGB) in schools within the Basic Health Area of Cordoba, with a median age of 12.4 years old (limits at 10 and 15 years old). Data were gathered on the consumption of alcohol by schoolchildren and in their social environment, as well as other variables in the lives of schoolchildren. RESULTS: 43.7% (interval of confidence at 95% -IC95%: 39.4-47.9) have tried alcohol, 3.8% (IC95% 2.5-5.9) drink regularly, while 26.8% (IC95% 23.2-30.8) drink occasionally. By means of logical regression analysis we found a connection between the consumption of alcohol and increasing age (Odds Ratio -OR: 0.83; IC95% 0.07-0.98), being male (OR: 1.78; IC95% 1.16-2.73), the consumption of alcohol by older brothers or sisters (OR: 2.25; IC95% 1.35-3.75), the consumption of medicines to treat nervousness (OR: 5.33; IC95%: 1.26-22.5), poor educational performance (OR: 1.002; IC95% 1.0-1.005), the consumption of tobacco (OR: 4.55; IC95% 2.4-8.61) and the feeling of loneliness (OR: 1.41; IC95% 1.01-1.97). CONCLUSIONS: Although the number of schoolchildren who try alcohol is low in comparison with other areas, the percentage of current drinkers is very similar. It would seem that older brothers and sisters have an important influence on starting consumption. The profile of a school age child who drinks corresponds to a male, a smoker, and having feelings of loneliness.

Life-style factors associated with changes in serum lipids in a follow-up study of cardiovascular risk factors.

We studied some life-style characteristics that may predict changes in total serum cholesterol and cholesterol bound to high density lipoproteins (HDL-cholesterol) in a sample of 980 healthy Spanish employees of both sexes who were followed for three years. All workers participated in a multifactorial program aimed at preventing cardiovascular disease. Linear regression models were fitted with changes in total and HDL-cholesterol as the dependent variables, after eliminating variability due to the influence of basal values. The association between lifestyle factors and lipid changes was controlled for dietary modifications. In the multivariate analysis, decreases in body mass index, and in alcohol consumption were associated with significant reductions in total serum cholesterol. Maintaining sports at post-test or starting to practice them in the interim was also significantly and independently associated with favourable changes in serum cholesterol. Leisure-time exercise (p = 0.002) and giving up smoking (p = 0.06) were each associated with increased HDL-cholesterol.

[Treatment results with external radiotherapy in prostate cancer]. / Resultados del tratamiento con radioterapia externa en el cáncer de próstata.

OBJECTIVE: External irradiation is an accepted curative treatment modality for patients with localized prostatic tumor. The 15-year results in patients treated by radical irradiation alone are presented. The determinant prognostic factors for local tumor control and disease free survival are analyzed. METHODS: 135 patients with a histologically confirmed localized carcinoma of the prostate were treated at our department from May 1972 to January 1998. Fifty patients received Co-60 therapy; the linear accelerator and high energy photons were utilized in the remaining 80 patients. By tumor stage, 53 patients were B1, 49 B2 and 33 C. The mean follow-up was 61 months (range 1-180). Most patients were exposed to localized fields of irradiation; dose ranged from 50-74 Gy, fractionated at a dose of 180-200 cGy/day. RESULTS: Overall local tumor control was 77% at 5 years and 73% at 15 years, with a disease free survival of 63% and 45% at 5 and 15 years, respectively. Local tumor control at 13 years was 71% for stage B1, 82% for B2 and 70% for C. The disease free survival at 13 years for stages B1, B2 and C were 46%, 49% and 36%, respectively. The BD and MD tumors had a 15-year disease free survival of 48% vs 32% for the PD tumors (p = 0.005). Patients with PSA < or = 20 ng/ml before treatment showed a disease free survival of 87% vs 48% for those with PSA > 20 ng/ml ((p = 0.011). Multivariate analysis showed dose to be a determinant prognostic factor for local tumor control (0.0432); dose and histological grade were determinants for disease free survival (p = 0.029 and 0.033). CONCLUSIONS: This retrospective study found dose to be a determinant prognostic factor for local tumor control and both dose and histological grade were determinants for disease free survival. Radiotherapy is a therapeutic option for these patients. The results can be enhanced if the dose delivered to the prostate can be increased while maintaining the complication rate within the same ranges.

Waldeyer's ring lymphomas: an epidemiological study of 55 cases.

Waldeyer's ring is a relatively common location for non-Hodgkin's lymphoma. Here, we report an epidemiological study of Waldeyer's ring lymphomas based on data for 55 cases treated over a 19-year period at three centers in northern Spain. In most respects our results confirm those of previous studies. The average delay between first consultation and diagnosis was 3.8 months, and was longer for nasopharyngeal lymphomas than for tonsillar lymphomas.

[Testicular germinal cell tumors. Authors' case load. Treatment review]. / Tumores testiculares germinales. Nuestra casuística. Revisión del tratamiento.

This article reports our case series of testicle germinal cell tumours, consisting of 14 cases, between 1974-1991. 42.85% (6 cases) were seminomas, 4 (66.6%) in Stage I. There was one case (16.6%) in Stage III and another one in Stage IV. 14.29% (2 cases) were embryonic carcinomas, one in Stage I and one in Stage II. Teratomas represented 14.29% (2 cases), in Stages I and IV respectively. There were 4 cases of mixed tumours (2 cases) in which teratomatous components (3 out of 4) were predominant. 50% were in Stage I and 50% in Stage III. Inguinal orchiectomy was performed in all cases, and three received radiotherapy (seminomas in Stages I (2 cases) and III), with survival ranging from 1 to 7 years. Two cases (seminoma and embryonic carcinoma) received chemotherapy under different regimes depending on the time of diagnosis. One patient has survived 11 years following rescue lymphadenectomy while the other one died 14 months later from pulmonary metastasis. Among the mixed tumours, 50% (2 cases in Stages II and III) died 5 and 11 months afterwards without further treatment due to overall affectation at diagnosis. An abstentionist approach in Stage I (seminomas and non-seminomas), which was "strictly" applied in 5 cases showing disease-free survival ranging from 1 to 5 years, is defended. Follow-up was not feasible in 2 cases (14.2%). Both the diagnostic means and a review of treatment by Stages, reflecting the evolution of chemotherapy and the results obtained, are analyzed. Also the most widely accepted approaches in the management of these tumours.

[The complete testicular feminization syndrome: apropos 2 new cases]. / Síndrome de feminización testicular completo: a propósito de dos nuevos casos.

Two additional cases of complete testicular feminization syndrome or Morris syndrome are described. The patients had consulted for primary amenorrhea. Patient work up revealed a female phenotype, hormone profile and 46,XY karyotype. They were submitted to abdominal surgical exploration and orchidectomy of the cryptorchid male gonads. The potential etiologic factors, pathogenesis, incidence and clinical features of this syndrome are discussed. Furthermore, the surgical treatment and outcome are described, highlighting the incidence of gonadal malignancy if these are not removed early.

[Calcified bladder lesions secondary to the instillation of mitomycin C]. / Lesiones vesicales calcificadas secundarias a instilación de mitomicina C.

We report on 10 cases of bladder wall calcification after mitomycin C instillation. The cystoscopic and microscopic features of these lesions are described. In our view, these lesions can be ascribed to the use of mitomycin C instillation therapy immediately after TUR. Because they are asymptomatic and occasionally present features of tumor recurrence, biopsy is advocated to determine the true nature of these lesions.

[Incidence of epidermoid cancer of the esophagus in Asturias (1975-85)]. / Incidencia del cáncer epidermoide de esófago en Asturias (1975-85).

We present the incidence the esophageal squamous cell carcinoma in Asturias, based on the review of the clinical histories of eleven years (1975-85). Of 356 total cases, 92.4% were male patients and the remaining 7.6% females; the relation M:F was 12.2:1. Mean age at the time of diagnosis was 59.4 +/- 9.6 for males and 70 +/- for females. Total annual incidence was 2.8 +/- 0.8 cases/10(5) + population/year. Maximal annual incidence was registered in 1981: 1.1 cases/10(5) population/year. Asturias has eight health districts; those with highest incidence were mining areas: Mieres, Cangas de Narcea and Riaño. Compared to that of some developing countries, the incidence of esophageal cancer in Asturias is low, similar to that in European countries (except France) and white population of the USA; there is an aggregation of cases in males living in mining areas.

[The reflex sympathetic dystrophy syndrome associated with breast cancer]. / Síndrome de distrofia simpática refleja asociado a cáncer de mama.

Reflex sympathetic dystrophy syndrome (RSDS) is a rare entity of unknown etiopathogenesis, associated to different precipitating factors such as malignant tumors of several localizations. A new clinical variety has been recently described which has been denominated palmar fasciitis and polyarthritis syndrome. We present here two patients with RSDS associated to breast cancer: one case presenting fasciitis and polyarthritis and another case also associated to polymyalgia rheumatica. We emphasize the importance of reducing the tumor mass in the treatment of this syndrome, as well as including it in the gammagraphic differential diagnosis of bone metastasis.