CD19 signal transduction in normal human B cells: linkage to downstream pathways requires phosphatidylinositol 3-kinase, protein kinase C and Ca2+

CD19 is required for normal antibody responses in mice. We have shown that CD19 enhances the activation of extracellular signal-regulated kinase (ERK) 2 by membrane (m) IgM but otherwise little is known of CD19 signaling in primary human cells. We now ask which pathways link CD19 with ERK2 in human tonsillar B cells. In analyses of signaling intermediates, the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin partially suppressed the release of Ca2+ induced by coligation of CD19 and mIgM but the selective PKC inhibitor bisindolylmaleimide I (BIM-I) did not. The Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, BIM-I and wortmannin each had only a small effect on ERK2 activation induced by surface IgM alone but blocked the enhancement of that activation by CD1 9/mIgM coligation. To analyze the mitogen-activated protein kinase (MAPK) cascade, we measured activation of Raf, MAPK- or ERK kinase (MEK) 1 and ERK2. CD19 consistently enhanced activation of ERK2 and MEK1. However, synergistic activation of Raf was variably observed. In subpopulation analyses, synergistic activation of Raf1 was consistently observed in the IgDlow but not in the IgDhigh cells. Thus, in normal human B cells, PI3K is upstream of the Ca2+ response while PI3K, Ca2+ release and protein kinase C are all required for ERK2 activation, and CD19 enhances the MAPK cascade at multiple levels, depending on the state of differentiation.     

Ontogeny of eyeblink conditioning in the rat: Auditory frequency and discrimination learning effects

The present study sought to determine whether acoustic properties of the auditory conditioned stimulus (CS) or the use of a discrimination learning procedure would alter the emergence of eyeblink conditioning between postnatal Days 17 and 24 (Days 17–24) in the rat. In Experiment 1, we employed a 3 × 2 × 2 factorial design, involving pitch of the auditory CS (2.8, 5.0, and 9.0 kHz), training condition (paired vs. unpaired), and age (Days 17 or 24). Associative learning was evident at all tone frequencies on Day 24, but increased across frequencies on Day 17, although large age differences in conditioning remained at all tone frequencies. In Experiment 2, rat pups were trained to discriminate 2.8 versus 9.0-kHz tones on Day 17 or Day 24. Eyeblink conditioning increased with tone frequency on Day 24 but discriminative conditioning failed to appear on Day 17. These findings are discussed in relation to the role of auditory system maturation in the ontogeny of eyeblink conditioning. © 1995 Johnv Wiley & Sons, Inc.     

The neurological and skeletal outcome in patients with closed cervical spinal cord injury

Sixty-one patients with closed cervical spinal cord injury were cared for within a defined protocol and followed for at least 1 year. Neurological recovery and healing of spinal structures were evaluated at intervals. Forty-three patients were managed without surgical intervention at the site of spine trauma, and the incidence of spontaneous fusion ("autofusion") was noted. Surgical fusion was performed on 17 patients, mainly to restore spinal stability and alignment. One patient underwent laminectomy without fusion. In both the surgical fusion and the autofusion groups, there were significant numbers of patients who improved neurologically, including some designated as having a complete spinal cord lesion at the initial neurological examination. As expected, better spinal alignment was achieved in the surgical group, although alignment in the nonsurgically treated group was generally acceptable. The majority of patients developed radiographically apparent callus formation anterior to the injured vertebral bodies, regardless of the mechanism of injury or the method of treatment. After 3 months all patients who underwent surgical fusion achieved spinal stability, as did the majority of patients in the autofusion group. Only individuals with flexion-distraction injuries who did not undergo surgical fusion appeared to be at risk for progressive spinal column deformity. Neither retropulsion of bone fragments nor angulation at the fracture site appeared to correlate with a poor neurological outcome, since improvement in neurological function occurred similarly in patients with and without these deformities.     

Inability of dendritic cells to prevent the blood transfusion effect in a mouse cardiac allograft model

The beneficial effect of blood transfusions before clinical renal transplantation is well established, but this can result in sensitization of some potential first graft recipients. Dendritic cells (DC), present in human blood, are potent stimulators of immune responses in vitro and in vivo, and in different systems they can overcome immune unresponsiveness. We therefore investigated whether DC could prevent the transfusion effect in a murine cardiac allograft model. C57BL/10 (C57) hearts were normally rejected by untreated DBA/2 recipients with a median survival time (MST) of 17 days. Long-term survival (MST greater than 100 days) was induced when the recipients were transfused with C57 blood 14 days before transplantation (d-14). Similar survival times were obtained when up to 1.5 x 10(5) splenic DC were added to the transfused blood. This number of DC or as few as 10(3), in "unsorted" preparations that were 70-85% pure, similarly enhanced when transfused alone at d-14. This enhancement was probably due to the contaminating cells rather than the DC since 10(3) lymphocytes prolonged survival, but an equivalent dose of "sorted" DC (ca. 93% pure, most contaminating cells being removed by sorting on an Ortho Cytofluorograf) did not. Transfusion of unsorted preparations containing 1.5 x 10(5) DC at d-3 led to accelerated graft rejection (MST 4 days). This sensitization was most likely due to the DC because equivalent numbers of lymphocytes were ineffective. Nevertheless, if a blood transfusion was given at d-14 followed by a normally sensitizing dose of DC at d-3, graft survival was still prolonged. Thus in no case were DC able to prevent the blood transfusion effect in this strain combination. Furthermore, DC of donor origin given to DBA/2 recipients with long-surviving C57 hearts, produced by prior blood transfusion, did not trigger rejection of the hearts.     

Preeclampsia and reproductive performance in a community of vegans

Studies at "the Farm," a community of spiritually gathered young people in Summertown, Tenn, have shown that it is possible to sustain a normal pregnancy on a vegan diet. The source of dietary protein (ie, animal or vegetable) does not seem to affect birth weight, as long as vegans are health conscious, receive continuous prenatal care, supplement their diets with prenatal vitamins, calcium, and iron, and apply protein-complementing nutritional principles. Preeclampsia may be caused by a relative prostacyclin deficiency in the face of excessive production of thromboxane A2. A vegan diet (one low in arachidonic acid) might provide protection against this condition, especially if the conversion of linoleic acid to arachidonic acid is inhibited by decreased activity of the enzyme delta-6-desaturase. We examined the maternity care records of 775 vegan mothers for symptoms of preeclampsia, and only one case met the clinical criteria. Since preeclampsia in our culture is frequently associated with unrestrained consumption of "fast foods" (foods having high levels of saturated fat) and rapid weight gain, it is possible that a vegan diet could alleviate most, if not all, of the signs and symptoms of preeclampsia.     

TNO-6 has no effect in gastrointestinal cancer:N-acetyl-glucosaminidase shows renal damage

Twenty-five patients, 16 with gastric cancer and nine with colonic cancer, received TNO-6 30 mg m^?2 every four weeks. No objective tumour response was recorded. Nausea and vomiting occurred in 21 patients and was severe in 17. Severe marrow suppression developed in five patients. Renal function was unaffected in all but one patients who developed renal failure, probably as a result of septicaemia. However, the renal tubular enzymeN-acetyl-\-d-glucosaminidase was measured in six patients and showed a rise in all. In this study TNO-6 had no anti-tumour activity in gastrointestinal malignancy, but produced significant renal tubular damage.     

Invasion of the mandible by squamous carcinomas of the oral cavity and oropharynx

The radiologic and histologic features of mandibular invasion, and its clinical implications, are considered in a retrospective series of 111 patients with squamous carcinomas of the oral cavity and oropharynx treated by composite resection. Eighty percent of the entire group had either recurrent or advanced (T3, T4) local disease, and 33 patients (30%) had histologic evidence of mandibular invasion by tumor. Preoperative radiologic assessment was unreliable in cases in which infiltrating tumor was confined to the periosteum and superficial cortex-44% false negatives. The extent of bone invasion was found to correlate with the size of the tumor, but not with its histologic grade. The mandibular periosteum was not seen as a morphologically discrete "barrier" and infiltration occurred at various points along the mandibular body, mainly related to the course of the inferior dental canal. The gross and microscopic patterns of bone invasion appeared to be similar in irradiated and nonirradiated resections. The incidence and pattern of recurrent disease following composite resection was the same in the groups with and without mandibular invasion: in each group half the patients were dead from disease and one third alive and free of disease at 2 years. Mandibular invasion alone did not appear to influence prognosis in this series.     

CT detection of retroperitoneal gas associated with gas in intervertebral disks

Three cases are presented with computed tomographic evidence of gas in retroperitoneal soft tissues in association with the so-called "vacuum phenomenon" (Knutsson sign) in lumbar disks. We review the explanations of Knutsson sign and offer an explanation of how extradiscal gas can occur in association with it.     

Early gastric cancer.

Although common in Japan, early gastric cancer (EGC = gastric adenocarcinoma confined to the mucosa and submucosa of the stomach, with or without regional lymph node metastases) is thought to be an infrequent occurrence in the United States. However, a review of all "curative" resections for carcinoma of the gastric body and antrum at the University of Virginia between 1974 and 1982 revealed EGC in five of 31 patients (16%). The purpose of the present study was to compare EGC to more advanced gastric cancer (ADV; n = 26) to determine whether any presenting historical, laboratory, x-ray, or endoscopic features distinguished the two groups before surgery and to ascertain whether postoperative survival in the United States mimicked the Japanese experience. All surviving patients were contacted, all charts were abstracted, all pathologic specimens were reexamined, and all radiographs were reviewed blindly by an experienced radiologist. Statistical evaluation was accomplished using Kaplan-Meier plots, chi square analysis, and unpaired "t" tests, as appropriate. At presentation, patients with EGC were younger (44 +/- 6 vs. 67 +/- 2 years, p less than 0.01) with higher admission albumin levels (4.1 +/- 0.2 vs. 3.7 +/- 0.1 mgm/dl, p less than 0.01). Although not significantly different, admission hemoglobin tended to be higher (41 +/- 2 vs. 35 +/- 2%), the incidence of weight loss tended to be less (40 vs. 65%), duration of symptoms tended to be longer (21 +/- 11 vs. 8 +/- 3 months), and tumor diameter tended to be smaller (1.7 +/- 0.6 vs. 5.8 +/- 0.7 cm) in EGC. No differences were apparent with respect to endoscopic or radiographic appearance, tumor location (greater than 70% antrum), presence of regional lymph node metastases (EGC = 2/5; ADV = 20/26), or type of resection (subtotal gastrectomy in 4/5 EGC, in 19/26 ADV). On median 5-year follow-up, however, survival with EGC has been 100%. In contrast, the Kaplan-Meier estimate of 5-year survival in ADV is 15% (42% with muscularis invasion, 0% with serosal invasion, 12% with extra-gastric spread; p less than 0.01 vs. EGC). One suture line recurrence in EGC was successfully treated by re-resection. No ADV patient with recurrence survives (p less than 0.01). Thus, EGC behaves similarly in the United States and Japan; for example, prognosis is excellent even in the presence of lymph node metastases. Inability to distinguish EGC from ADV before surgery justifies an aggressive surgical approach to all patients with resectable gastric neoplasms.     

Treatment of infants with ureteropelvic junction obstruction: findings from the PURSUIT network

International Urology and Nephrology - Studies based on administrative databases show that infant pyeloplasty is associated with minority race/ethnicity but lack clinical data that may influence...