The effects of rituximab on the lipid profile of patients with active systemic lupus erythematosus: results from a nationwide cohort in Spain (LESIMAB).

INTRODUCTION: Patients with systemic lupus erythematosus (SLE) have increased cardiovascular risk related to lipid changes induced by inflammatory activity, proteinuria and treatments. Our objective was to analyse lipid changes in a cohort of patients with SLE resistant to standard treatments who were treated with rituximab. METHODS: The study population comprised a retrospective multicentre, national cohort of patients with SLE resistant to standard treatments who were treated with rituximab. The basic lipid profile, concomitant treatment and disease activity were analysed at the start of the treatment, 24 weeks later, and at the end of the follow-up period. The effects of the main lupus variables and therapy on the lipid changes were analysed. RESULTS: Seventy-nine patients with active lupus treated with rituximab were assessed during 149.3 patient-years. Prior to the treatment, 69% had dyslipidaemia. The most frequent abnormalities were a low-density lipoprotein (LDL) level of ≥100 mg/dl (34%) and a high-density lipoprotein (HDL) level of <50 mg/dl (27%). Baseline total cholesterol (TC) and LDL levels correlated with the degree of proteinuria, while the concentration of triglycerides (TGs) correlated with the SLE Disease Activity Index (SLEDAI). TGs were reduced at short- and long-term follow-up after rituximab treatment. A multiple linear regression analysis identified that the reduction of the lupus inflammatory activity, particularly changes in proteinuria, was the only independent variable that was positively associated with the reduction in TGs after 24 weeks (p=0.001) and with TC (p=0.005) and TGs (p<0.001) at the end of the follow-up period. CONCLUSION: Our results suggest that rituximab may improve the long-term lipid profile of patients with SLE refractory to standard treatment, mainly by reducing inflammatory activity.

Multicenter longitudinal study of B-lymphocyte depletion in refractory systemic lupus erythematosus: the LESIMAB study.

OBJECTIVE: This study aimed to investigate the effectiveness and safety of single and repeated courses of rituximab in patients with refractory lupus. METHODS: LESIMAB is a multicenter, retrospective, longitudinal study of lupus patients who have not responded to standard therapy and have been treated with rituximab. Response rates at six months and at follow-up were defined as efficacy outcomes. Complete response was defined as a SELENA-SLEDAI score ≤ two and a SELENA-SLEDAI Flare Index of zero. Partial response was defined as a reduction in the SELENA-SLEDAI score of ≥four points with no new or worsening of symptoms. Adverse events were collected. RESULTS: Seventy-three (62.9%) of 116 patients achieved a response at six months (complete in 22 and partial in 51). Ninety-seven (77.6%) of 128 patients achieved a response after a mean follow-up of 20.0 ± 15.2 months (complete in 50 and partial in 47). High baseline SLEDAI score, previous treatment with ≥100 mg/day prednisone, and no history of severe hematologic flare were associated with response after the first treatment course. The median time to response was 6.5 months (95% CI, 5.0-8.0). Thirty-seven patients (38.1%) relapsed after the first infusion. The flare was severe in seven cases and mild to moderate in 29 cases. Serious infection rate was 12.6/100 patient-years. A schedule of four weekly doses was associated with more serious infections. Six patients died: two of infection and four of lupus complications. CONCLUSION: Rituximab can be an effective treatment option for patients who have refractory lupus with severe or life-threatening disease with an acceptable tolerance profile.

In-depth characterization of a new patient-derived xenograft model for metaplastic breast carcinoma to identify viable biologic targets and patterns of matrix evolution within rare tumor types.

Metaplastic breast carcinoma (MBC) is a rare breast cancer subtype with rapid growth, high rates of metastasis, recurrence and drug resistance, and diverse molecular and histological heterogeneity. Patient-derived xenografts (PDXs) provide a translational tool and physiologically relevant system to evaluate tumor biology of rare subtypes. Here, we provide an in-depth comprehensive characterization of a new PDX model for MBC, TU-BcX-4IC. TU-BcX-4IC is a clinically aggressive tumor exhibiting rapid growth in vivo, spontaneous metastases, and elevated levels of cell-free DNA and circulating tumor cell DNA. Relative chemosensitivity of primary cells derived from TU-BcX-4IC was performed using the National Cancer Institute (NCI) oncology drug set, crystal violet staining, and cytotoxic live/dead immunofluorescence stains in adherent and organoid culture conditions. We employed novel spheroid/organoid incubation methods (Pu·MA system) to demonstrate that TU-BcX-4IC is resistant to paclitaxel. An innovative physiologically relevant system using human adipose tissue was used to evaluate presence of cancer stem cell-like populations ex vivo. Tissue decellularization, cryogenic-scanning electron microscopy imaging and rheometry revealed consistent matrix architecture and stiffness were consistent despite serial transplantation. Matrix-associated gene pathways were essentially unchanged with serial passages, as determined by qPCR and RNA sequencing, suggesting utility of decellularized PDXs for in vitro screens. We determined type V collagen to be present throughout all serial passage of TU-BcX-4IC tumor, suggesting it is required for tumor maintenance and is a potential viable target for MBC. In this study we introduce an innovative and translational model system to study cell-matrix interactions in rare cancer types using higher passage PDX tissue.

Effects of pulsed electromagnetic field vibration on tooth movement induced by magnetic and mechanical forces: a preliminary study.

BACKGROUND: This study was designed to determine whether or not high-frequency and low-magnitude vibration affects orthodontic tooth movement caused by magnetic or/and mechanical forces. METHODS: Forty-four 7-week-old Wistar rats were randomly divided into four groups, with each group further divided into experimental and control subgroups. Neodymium-Iron-Boron (Nd-Fe-B) magnets and Sentalloy closed coil springs were placed between maxillary or mandibular first molars and incisors to activate tooth movement. The animals of experimental subgroups were exposed to the vibration induced by pulsed electromagnetic fields (PEMF) whilst the control subgroups were under normal atmosphere. The experiment lasted for 14 days and all of the animals were sacrificed for examination. The changes in the space between the molar and incisor were measured to indicate the amount of tooth movement. RESULTS: The coil springs, either with sham or active magnets, move molar much more than magnets alone, regardless of absence or presence of PEMF (p < 0.001). Under PEMF, the coil spring moved significantly more amount of tooth movement than that of coil-magnet combination (p < 0.01), as did the magnets compared to sham magnets (p < 0.019). Under a non-PEMF scenario, there was no significant difference in tooth movement between coil spring and coil-magnets combination, nor was there difference between magnets and sham magnets. CONCLUSIONS: It is suggested that the PEMF-induced vibration may enhance the effect of mechanical and magnetic forces on tooth movement.

Primary chemically induced tumors induce profound immunosuppression concomitant with apoptosis and alterations in signal transduction in T cells and NK cells.

Whereas transplantable tumors can be readily cured with immunotherapeutic approaches, similar therapies in cancer patients have been less effective. This difference may be explained by an immunosuppression resulting from the presence of a slowly growing primary tumor in the patient, whereas the immune system in a mouse with a rapidly proliferating transplantable tumor would be less affected. As a more appropriate model to the immune dysfunction in patients, slowly progressing primary tumors were induced by the carcinogen methylcholanthrene (MC) in mice. Their ability to induce immunosuppression in T cells and natural killer (NK) cells was compared to that of rapidly growing transplanted MC-induced tumors. The results demonstrate that mice bearing primary MC tumors had significantly diminished T-cell and NK-cell functions, impaired capacity to produce Th1 cytokines, and markedly reduced levels of the signal-transducing zeta chain in T cells and NK cells, similar to that described in cancer patients. Moreover, a substantial number of CD8+ T cells in mice with large primary MC tumors were undergoing apoptosis, correlating with alterations in CD4/CD8 ratios. In contrast, T cells and NK cells from mice bearing rapidly growing transplanted tumors were only marginally affected. These findings could explain the apparent discrepancy between the consistent findings of a diminished immune response and alterations in signal transduction in cancer patients as compared to the less reproducible observations in murine transplantable tumors. In addition, they could explain the differences in the high efficacy of immunotherapy in mice with transplantable tumors and the low therapeutic results in cancer patients.

Loss of T-cell receptor zeta chain and p56lck in T-cells infiltrating human renal cell carcinoma.

Cancer patients and mice bearing tumors develop a progressive immunosuppression manifested by a decreased delayed-type hypersensitivity, decreased T-cell lytic activity, diminished production of lymphokines, and a reduced T-cell proliferative response. The mechanisms underlying these changes are incompletely understood. We recently reported the presence of marked alterations in signal transduction in T-cells from mice bearing long-term (28-day) tumours. We hypothesized that a soluble product produced by the tumor or resulting from the immune response to tumor might be responsible for inducing the changes in T-cells. Tumor-infiltrating lymphocytes from patients with renal cell carcinoma tested here showed, in 10 of 11 cases, a marked decrease in the expression of the T-cell receptor zeta chain and in p56lck tyrosine kinase. The presence of major alterations in the tumor-infiltrating lymphocytes with only minor changes in the peripheral blood leukocyte T-cells supports the notion that the defects are induced by exposure to tumor. These results suggest that tumor-infiltrating lymphocytes may be compromised in their antitumor efficacy in patients with renal cell cancer.

Partial degradation of T-cell signal transduction molecules by contaminating granulocytes during protein extraction of splenic T cells from tumor-bearing mice.

Flavone-8-acetic acid plus recombinant human interleukin 2 is a successful antitumor therapy in mice bearing the Renca murine renal cell carcinoma. This report demonstrates that T cells, particularly CD8+ T cells, are critical for the generation of this response. Initial experiments examining T-cell signal transduction proteins demonstrated that T cells from Renca-bearing mice had undetectable levels of p56lck and zeta-chain of the T-cell receptor and that flavone-8-acetic acid and recombinant human interleukin 2 therapy could be used as a model for reversal of these alterations. However, further experimentation showed that the majority of the reduction in zeta-chain and part of the reduction in p56lck was due to degradation of these molecules during protein extraction caused by mature granulocytes contaminating the enriched T-cell population. This was not the case for nuclear c-Rel or NF kappa B p65, which remained at undetectable/reduced levels in the absence of granulocytes, confirming our previous data that transcription factor alterations exist in tumor-bearing mice. Thus, most of the reduction in zeta-chain in T cells from Renca-bearing mice is due to granulocyte contamination and emphasizes the need to use pure T-cell populations and/or sufficient amounts and types of protease inhibitors when quantitating proteins in T cells from tumor-bearing mice.

Laparoscopic repair of complex ventral hernia facilitated by pre-operative chemical component relaxation using Botulinum Toxin A.

PURPOSE: The operative management of complex ventral hernia poses a formidable challenge, despite recent advances in surgical techniques. Recurrence rates after complex ventral hernia repair remain high, and increase with each failed attempt. This study examines the effect of pre-operative abdominal wall chemical component relaxation using Botulinum Toxin A (BTA) to induce temporary flaccid paralysis in order to facilitate laparoscopic repair of large complex ventral hernia. METHODS: This is a prospective evaluation of 27 patients from January 2013 to August 2015 who underwent ultrasound guided BTA injections to the lateral abdominal wall muscles prior to elective complex ventral hernia repair. Non-contrast serial CT imaging was obtained pre- and post-BTA injection to measure change in fascial defect size and abdominal wall muscle thickness and length. Fascial defects were closed and hernias repaired using laparoscopic or laparoscopic-assisted intra-peritoneal onlay mesh (IPOM) techniques. RESULTS: 27 patients received pre-operative BTA injections which were well tolerated with no complications. Comparison of pre-BTA and post-BTA CT imaging demonstrated a significant increase in mean length of the lateral abdominal wall from 15.7 cm pre-BTA to 19.9 cm post-BTA (p < 0.0001), with mean unstretched length gain of 4.2 cm/side (range 0-11.7 cm/side). All hernias were surgically reduced and repaired with mesh, with no early recurrences. CONCLUSION: Pre-operative administration of BTA is a safe and effective technique in the pre-operative preparation of patients undergoing elective complex ventral hernia repair. This technique lengthens and relaxes the laterally retracted abdominal muscles and enables laparoscopic closure of large complex ventral hernia.

Phase I trial of anti-CD3-stimulated CD4+ T cells, infusional interleukin-2, and cyclophosphamide in patients with advanced cancer.

PURPOSE: We performed a phase I trial to determine whether in vivo expansion of activated CD4+ T cells was possible in cancer patients. 111Indium labeling was used to observe trafficking patterns of the infused stimulated CD4+ T cells. The influence of cyclophosphamide (CTX) dosing on immunologic outcome was also examined. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphoma received CTX at 300 or 1,000 mg/m2 intravenously (i.v.). Leukapheresis was performed to harvest peripheral-blood mononuclear cells (PBMCs) either just before the CTX dose, or when the patient was either entering or recovering from the leukocyte nadir induced by CTX. An enriched population of CD4+ T cells was obtained by negative selection. The CD4+ T cells were activated ex vivo with anti-CD3, cultured with interleukin-2 (IL-2) for 4 days, and adoptively transferred. After adoptive transfer, patients received IL-2 (9.0 x 10(6) IU/m2/d) by continuous infusion for 7 days. RESULTS: The absolute number of CD4+, CD4+/DR+, and CD4+/CD45RO+ T cells increased in a statistically significant fashion in all cohorts after the first course of therapy. The degree of CD4 expansion was much greater than CD8 expansion, which resulted in a CD4:CD8 ratio that increased in 26 of 31 patients. The greatest in vivo CD4 expansion occurred when cells were harvested as patients entered the CTX-induced nadir. One complete response (CR), two partial responses (PRs), and eight minor responses were observed. Trafficking of 111Indium-labeled CD4 cells to subcutaneous melanoma deposits was also documented. CONCLUSION: CD4+ T cells can be expanded in vivo in cancer patients, which results in increased CD4:CD8 ratios. The timing of pheresis in relation to CTX administration influences the degree of CD4 expansion. Tumor responses with this regimen were observed in a variety of tumors, including melanoma and non-Hodgkin's lymphoma; a high percentage of patients had at least some tumor regression from the regimen that produced the greatest CD4+ T-cell expansion.

L-Arginine regulates the expression of the T-cell receptor zeta chain (CD3zeta) in Jurkat cells.

L-Arginine is a versatile amino acid that plays a central role in the normal function of several organ systems including the immune system. Its availability is tightly controlled and varies significantly in different organs and tissues in the body. L-Arginine plays an important role in supporting T-cell proliferation. Its depletion in certain disease states results in a diminished T-cell response. The main purpose of this study was to determine the effect of the depletion of L-arginine on the expression of the T-cell receptor (TCR) proteins. When the helper T-cell line Jurkat was cultured in arginine-free medium, there was a preferential decrease in the expression of the TCR zeta chain (CD3zeta). The reduced expression of CD3zeta was observed within 24 h of culture in L-arginine-free medium and was completely reversed with the replenishment of L-arginine. Furthermore, the absence of L-arginine blocked the normal re-expression of the TCR that had been internalized after antigen stimulation. There also was a significant decrease in proliferation of Jurkat cells in the absence of L-arginine; however, L-arginine depletion did not prevent the up-regulation of the interleukin 2 receptor chains upon stimulation, nor did it significantly diminish the production of interleukin 2. The changes in the expression of CD3zeta chain were not induced by apoptosis. Thus, the availability of L-arginine in the microenvironment may play a significant role in regulating the expression of the TCR.

Alterations in T cell receptor and signal transduction molecules in melanoma patients.

We have recently described molecular changes in T cells from tumor-bearing patients that are associated with depressed immune function. The present work investigates changes in T-cell signal transduction proteins including the T-cell receptor-zeta (TCR-zeta) chain and receptor-associated tyrosine kinases in patients with metastatic malignant melanoma. A marked decrease in the expression of the TCR-zeta chain was observed in the peripheral blood T cells of 19 (43%) of 44 patients. Decreases in several tyrosine kinases were found in 12 (57%) of 21 patients tested. T cells from patients with diminished TCR-zeta chain expression also showed statistically significant differences in cytokine production pattern, with lower interleukin 2 and IFN-zeta production compared with normal subjects and melanoma patients with normal TCR-zeta chain status. The overall survival of melanoma patients with low TCR-zeta chain expression was significantly shorter than that of patients with normal TCR-zeta chain expression (P = 0.0013). TCR-zeta-deficient patients showed a trend toward having faster growing tumors. There was no correlation between the pretreatment TCR-zeta chain status and albumin or performance status. These findings suggest that alterations in T-cell function occur commonly in melanoma patients and may be independent predictors of clinical outcome.

Didelphis marsupialis, an important reservoir of Trypanosoma (Schizotrypanum) cruzi and Leishmania (Leishmania) chagasi in Colombia.

The role of Didelphis marsupialis as a reservoir of zoonotic hemoflagellates was examined in two ecologically distinct settings in Colombia. While 72% (12 of 18) of the opossums collected in the tropical rain forest harbored Trypanosoma cruzi, other mammals in the area had lower infection rates: 1.3% (Proechymis semispinosus [spiny rat]; 13% Tylomys mirae [climbing rat]; and 6% Rattus rattus). Trypanosoma cruzi isolates from D. marsupialis were similar to zymodeme 1 (Z1), and two of four phenotypes were shared with Tylomys mirae, which is also predominantly arboreal. Terrestrial (P. semispinosus) and peridomestic (R. rattus) animals were infected with Z3 or other Z1 phenotypes, respectively. Schizodeme analysis showed polymorphisms among isolates from mammals, reflecting diverse modes of transmission, and a complex epidemiologic situation. Despite the lower infection rate of the opossum (14%) found in our study in the tropical dry forest as compared with the tropical wet forest, Chagas' disease has been reported only in the former area. This suggests that the lack of alternative blood sources for triatomines of the tropical dry forest, where mammals are less abundant than in the wet forest, may increase the risk of human infection. Among several species of mammals captured in the tropical dry forest, Leishmania chagasi was isolated from 22.7% (5 of 22) D. marsupialis. This finding confirms the important role of opossums in Colombian foci of visceral leishmaniasis, including those where the phlebotomine species involved in transmission is Lutzomyia evansi, an alternative vector to the more common Lutzomyia longipalpis.

Antimonial treatment of hamsters infected with Leishmania (Viannia) panamensis: assessment of parasitological cure with different therapeutic schedules.

The objective of the study was to establish the effective dose and route of administration of Glucantime for treating hamsters infected with Leishmania (Viannia) panamensis and to use this method to test new treatment regimens to attain clinical and parasitological cure. In the first experiments animals were inoculated subcutaneously in the hind foot with 5 x 10(6) promastigotes of L. panamensis (HOM/COL/84/1099) from a 6 d culture. One month after inoculation, Glucantime was administered intramuscularly (i.m.) at 20, 40 or 60 mg/kg/d for 20 d to groups of hamsters. Only 60 mg/kg/d resulted in both clinical improvement and parasite elimination from the skin and draining lymph node. In the second set of experiments, i.m., local and combined antimonial regimens were compared. The local regimen, of 4 intralesional (i.l.) injections of 4 mg of antimony at 5 d intervals, and the combined regimen (i.m. and i.l.), were more efficient at clearing parasites than the systemic (i.m.) schedule, especially when a low dosage of Glucantime (30 mg/kg/d x 20 d) was used. The results suggest that combining local treatment and low systemic dosages of antimonials results in clearance of L. panamensis.

Cyclosporine A shows immunosuppressor activity on T lymphocytes from the peripheral blood and synovial fluid of patients with autoimmune arthritis.

OBJECTIVE: This work studies the effects of Cyclosporine A (CsA) upon the activation and proliferation of mononuclear cells (MNC) from the peripheral blood (PB) of patients with chronic autoimmune arthritis and from healthy controls, and from the synovial fluid (SF) of patients. METHODS: In vitro studies of activation, proliferation, mRNA expression and lymphokine production were carried out. RESULTS: We found in the PB and SF MNCs from patients with autoimmune arthritis that CsA inhibits the proliferative response, activation antigen expression, IL-2 mRNA expression and IL-2 production induced by polyclonal mitogens in a dose dependent manner. CONCLUSION: CsA blocks lymphocyte activation in PB and SF MNCs from patients with autoimmune arthritis.

Local and remote sustained trigger point therapy for exacerbations of chronic low back pain. A randomized, double-blind, controlled, multicenter trial.

STUDY DESIGN: A randomized, double-blind, controlled, multicenter trial was conducted. OBJECTIVES: To assess the efficacy of neuroreflexotherapy in the management of low back pain. SUMMARY AND BACKGROUND DATA: Neuroreflexotherapy consists of temporary implantation of epidermal devices in trigger points in the back and referred tender points in the ear. METHODS: The rheumatology and rehabilitation departments of three teaching hospitals in Madrid recruited 78 patients with chronic low back pain. These patients were randomly assigned to the control group (37 patients) or to the treatment group (41 patients). Patients in the treatment group underwent one neuroreflexotherapeutic intervention. The control group received sham treatment consisting of placement of the same number of epidermal devices within a 5-cm radius of the target zones. Patients from both groups were allowed to continue drug treatment as previously prescribed. The use of medications during the trial was recorded. RESULTS: Patients underwent clinical evaluations on three occasions: within 5 minutes before intervention, within 5 minutes after intervention, and 45 days later. The preintervention assessment was carried out by the physician from each hospital department who included the patient in the study. Each of the two follow-up assessments were carried out independently by two of three physicians who had no connection with the research team. Patients in the treatment group showed immediate lessening of pain compared with the results in patients in the control group. The pain relief was clinically relevant and statistically significant, and it persisted up to the end of the trial. CONCLUSIONS: Neuroreflexotherapy intervention seems to be a simple and effective treatment for rapid amelioration of pain episodes in patients with chronic low back pain. At this time, the duration of pain relief beyond 45 days has not been evaluated.

Trypanosoma (Herpetosoma) leeuwenhoeki in Choloepus hoffmanni and Didelphis marsupialis of the Pacific Coast of Colombia.

Trypanosoma (Herpetosoma) leeuwenhoeki, originally described in Panamanian sloths, was isolated from Didelphis marsupialis (Marsupialia) and Choloepus hoffmanni (Edentata) inhabiting the Pacific coast of Colombia. Trypanosomes were characterized by their large blood forms (total length 51-53 microns), poor infectivity for mice, and lack of development in Rhodnius prolixus. Isoenzyme studies, with either strains or clones, revealed homogeneous profiles clearly distinct from Trypanosoma cruzi and Trypanosoma rangeli reference strains. The present report extends the geographical distribution of T. leeuwenhoeki to South America and broadens its known host range to another order of mammals.

Percepciones de terapeutas ocupacionales sobre el lenguaje y la comunicación de los niños con déficit de integración sensorial / Language and communication in children with sensory deficit: the occupational therapists perception

Antecedentes. Los terapeutas ocupacionales y fonoaudiólogos trabajan, con frecuencia, en equipo interdisciplinario, para que los niños con déficit de integración sensorial puedan mejorar su desempeño personal, social y escolar. Estos equipos interprofesionales desarrollan con la práctica una valiosa comprensión de las características lingüísticas y comunicativas de los niños en tratamiento. Objetivo. Describir la percepción que tienen los terapeutas ocupacionales sobre las características lingüísticas y comunicativas de los niños con déficit de integración sensorial. Material y métodos. Se realizaron entrevistas semiestructuradas a cinco terapeutas ocupacionales de Bogotá, certificadas como integradoras sensoriales, con experiencia en el manejo de niños (entre los 4 y 6 años) con diagnóstico de déficit de integración sensorial. Resultados. Los resultados muestran que los niños con déficit de integración sensorial, dependiendo del tipo de sistema sensorial afectado, se describen como niños con un lenguaje desorganizado, dificultades de habla y de escritura. Esta situación sugiere la necesidad de trabajo interdisciplinario con el fonoaudiólogo. Conclusión. Según la opinión de las terapeutas ocupacionales entrevistadas, la intervención en terapia ocupacional basada en la integración sensorial es efectiva y produce cambios positivos en el lenguaje, y no siempre es necesaria la intervención fonoaudiológica a menos que el niño muestre problemas importantes con el habla y la escritura. Estos hallazgos sugieren la necesidad de trabajo interprofesional.

Restoration of expression of signal-transduction molecules in lymphocytes from patients with metastatic renal cell cancer after combination immunotherapy.

A decrease in lymphocyte signal-transduction molecules, described in cancer patients and patients with chronic infectious diseases, has been proposed as a possible mechanism leading to an impaired immune response in cancer patients. Here we report the effects of combination immunotherapy on the levels of T cell receptor zeta chain and p56lck tyrosine kinase in a retrospective study of cryopreserved lymphocytes from 26 metastatic renal cell carcinoma patients treated with high-dose interleukin-2 (IL-2), interferon alpha (IFNalpha) and ex vivo IL-2-activated lymphocytes. Of the 26 patients, 12 were responders (5 complete and 7 partial) and 14 were non-responders (6 stable and 8 with progressive disease). Prior to treatment, 21 of 26 patients (81%) and 13 of 21 patients (62%) respectively expressed zeta chain and p56lck at less than 50% of the levels observed in healthy controls. During therapy, this low zeta chain and p56lck expression increased to at least 50% of normal in 13 of the 21 patients (62%) and in 6 of the 13 patients (46%) respectively; in the remaining patients expression levels remained at 50% of normal or more, or declined. Although, in this limited study, pretreatment levels of and p56lck did not show significant correlation with antitumor response, 4 of 5 patients that achieved a complete response (80%) corrected both zeta chain and p56lck levels to at least 50% of normal, while restoration of both signal-transduction molecules to such levels was only observed in 3 of 7 partial responders (43%), 1 of 5 patients with stable disease (20%) and 2 of 7 patients with progressive disease (29%). Thus, these results suggest that analysis of changes in signal-transduction molecules may a be useful tool for immunological monitoring of patients throughout immunotherapy, and could provide important information for designing new clinical trials that restore impaired signal transduction while activating T cell responses.

Acute respiratory tract infections among a birth cohort of children from Cali, Colombia, who were studied through 17 months of age.

For this study, 340 children less than 18 months old from a low-income, urban neighborhood in Cali, Colombia, were observed from birth by means of weekly home visits to detect cases of acute respiratory tract infection. All suspected cases were confirmed by trained doctors in a special clinic. Information on symptoms, signs, and potential risk factors was documented prospectively. Etiologic agents were identified in cases of lower respiratory tract infection (LRI). The overall incidence of acute respiratory tract infection was 6.6 cases per child-year at risk. The incidence of upper respiratory tract infection was 4.9 cases per child-year at risk and that of LRI was 1.7 cases per child-year at risk. Crowding in the home was found to be significantly associated with an increased incidence of LRI. Respiratory syncytial virus was the viral agent most frequently isolated from cultures of nasopharyngeal aspirates of children with LRI. Staphylococcus aureus was the bacterial agent most frequently isolated from the blood of patients with LRI.