Prolactin-screening tumors and hypogonadism in 22 men.

We studied 22 men with prolactin-secreting pituitary tumors and hypogonadism. Twenty complained of impotence, nine had visual impairment, and three experienced galactorrhea. None of the 17 patients undergoing operation or radiotherapy, or both, were subsequently normoprolactinemic. In all 13 patients treated with bromocryptine major clinical improvement was associated with a decrease in serum prolactin levels and in nine with an increase in serum testosterone. Two patients receiving testosterone replacement therapy showed improved potency only after bromocryptine was administered. The results indicate that hyperprolactinemia frequently induces hypogonadism in men, that bromocryptine ameliorates symptoms of disease previously unchanged by operation or radiotherapy, and that the impotence observed may not be solely the result of hypogonadism.     

Mechanisms of neutrophil damage to human alveolar extracellular matrix: the role of serine and metalloproteases.

Many syndromes of lung injury are associated with accumulation of neutrophils within the pulmonary parenchyma. These neutrophils have the capacity to produce lung injury by products including proteases and reactive oxygen species (ROS). We examined the ability of activated neutrophils to solubilize human alveolar extracellular matrix (ECM), and by use of scavengers and inhibitors, evaluated the role of ROS and proteases in this process. Supernatants of phorbol myristate acetate-activated neutrophils routinely solubilized 10.2% +/- 0.8% (n = 30) of collagen in human alveolar ECM, as measured by hydroxyproline release. Scavengers of ROS had no significant effect on ECM solubilization. Inhibitors of metalloproteases partially inhibited ECM solubilization (38.5% +/- 4.6% inhibition by ethylenediaminetetraacetic acid [n = 6], and 37.0% +/- 14.7% by 1,10-phenanthroline [n = 6]; p less than 0.05). Inhibitors of the neutrophil serine proteases, elastase and cathepsin G, markedly inhibited ECM solubilization (100.9% +/- 3.7% by alpha 1-protease inhibitor [alpha 1-PI] [n = 6] and 81.9% +/- 0.1% by soybean trypsin inhibitor [n = 6]; p less than 0.01). Since alpha 1-PI completely inhibited solubilization, metalloprotease activity appeared to be related to serine protease activity. This finding was confirmed by the observation that addition of a metalloenzyme activator, p-aminophenylmercuric acetate, in the presence of alpha 1-PI, restored solubilization to the same level as that inhibited by metal chelators. We conclude that human neutrophil metalloproteases and serine proteases directly solubilize human alveolar ECM. Furthermore, neutrophil serine proteases activate latent metalloproteases. However, ROS were not demonstrated to play a major role in ECM solubilization in our system.     

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.     

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.     

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...