Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling.

Radiation exposure accelerates the onset of age-related diseases such as diabetes, cardiovascular disease, and neoplasia and, thus, lends insight into in vivo mechanisms common to these disorders. Fibrosis and extracellular matrix (ECM) remodeling, which occur with aging and overnutrition and following irradiation, are risk factors for development of type 2 diabetes mellitus. We previously demonstrated an increased incidence of skeletal muscle insulin resistance and type 2 diabetes mellitus in monkeys that had been exposed to whole body irradiation 5-9 yr prior. We hypothesized that irradiation-induced fibrosis alters muscle architecture, predisposing irradiated animals to insulin resistance and overt diabetes. Rhesus macaques (Macaca mulatta, n = 7-8/group) grouped as nonirradiated age-matched controls (Non-Rad-CTL), irradiated nondiabetic monkeys (Rad-CTL), and irradiated monkeys that subsequently developed diabetes (Rad-DM) were compared. Prior radiation exposure resulted in persistent skeletal muscle ECM changes, including a relative overabundance of collagen IV and a trend toward increased transforming growth factor-ß1. Preservation of microvascular markers differentiated the irradiated diabetic and nondiabetic groups. Microvascular density and plasma nitrate and heat shock protein 90 levels were lower in Rad-DM than Rad-CTL. These results are consistent with a protective effect of abundant microvasculature in maintaining glycemic control within radiation-induced fibrotic muscle.

BMI: does it predict the need for component separation?

PURPOSE: Patient optimization and selecting the proper technique to repair large incisional hernias is a multifaceted challenge. Body mass index (BMI) is a modifiable variable that may infer higher intra-abdominal pressures and, thus, predict the need for component separation (CS) at the time of surgery, but no data exist to support this. This paper assesses if the ratio of anterior-posterior (AP): transverse (TRSV) abdominal diameter, from pre-operative CT imaging, indicates a larger proportion of intra-abdominal fat and correlates with a hernia defect requiring a component separation for successful tension-free closure. METHODS: Ninety patients were identified who underwent either an open hernia repair with mesh by primary closure (N = 53) or who required a component separation at the time of surgery (N = 37). Pre-operative CT images were used to measure hernia defect width, AP abdominal diameter, and TRSV abdominal diameter. Quantitative data, nominal data, and logistic regression was used to determine predictors associated with surgical group categorization. RESULTS: The average hernia defect widths for primary closure and CS were 7.7 ± 3.6 cm (mean ± SD) and 9.8 ± 4.5, respectively (p = 0.015). The average BMI for primary closure was 33.9 ± 7.2 and 33.8 ± 4.9 for those requiring CS (p = 0.924). The AP:TRSV diameter ratios for primary closure and CS were 0.41 ± 0.08 and 0.49 ± 0.10, respectively (p < 0.001). In a multivariate analysis including both defect width and AP:TRSV diameter ratio, only AP:TRSV diameter ratio predicted the need for a CS (p = 0.001) while BMI did not (p = 0.92). CONCLUSION: Intraabdominal fat distribution measured by AP:TRSV abdominal diameter ratio correlates with successful tension-free fascial closure during incisional hernia repair, while BMI does not.

Reduced Intestinal Motility, Mucosal Barrier Function, and Inflammation in Aged Monkeys.

OBJECTIVE: We aimed to examine the general health and intestinal physiology of young and old non-human primates with comparable life histories and dietary environments. DESIGN: Vervet monkeys (Chlorcebus aethiops sabaeus) in stable and comparable social and nutritional environments were selected for evaluation. Health phenotype, circulating cytokines and biomarkers of microbial translocation (MT) were measured (n=26-44). Subsets of monkeys additionally had their intestinal motility, intestinal permeability, and fecal microbiomes characterized. These outcomes document age-related intestinal changes present in the absence of nutritional stressors, which are all known to affect gastrointestinal motility, microbiome, and MT. RESULTS: We found that old monkeys have greater systemic inflammation and poor intestinal barrier function as compared to young monkeys. Old monkeys have dramatically reduced intestinal motility, and all changes in motility and MT are present without large differences in fecal microbiomes. CONCLUSION: We conclude that deteriorating intestinal function is a feature of normal aging and could represent the source of inflammatory burden yet to be explained by disease or diet in normal aging human primate populations. Intestinal changes were seen independent of dietary influences and aging within a consistent environment appears to avoid major microbiome shifts. Our data suggests interventions to promote intestinal motility and mucosal barrier function have the potential to support better health with aging.

Nuclear matrix targeting of the protein kinase CK2 signal as a common downstream response to androgen or growth factor stimulation of prostate cancer cells.

Protein kinase CK2, a messenger-independent serine/threonine kinase, has been implicated in cell growth. Androgenic stimulus in rat prostate modulates its association with nuclear matrix (NM) and chromatin. Because the growth of human prostate carcinoma cells is influenced by androgens and/or growth factors, we determined the nature of CK2 signaling in the NM in response to androgen and growth factor stimuli. Androgen-sensitive LNCaP and androgen-insensitive PC-3 cells were cultured in media to regulate their growth in the presence of 5alpha-dihydrotestosterone (5alpha-DHT) or growth factors (epidermal growth factor, keratinocyte growth factor, and transforming growth factor alpha). The activity of CK2 was measured in the cytosolic and NM fractions isolated from these cells after treatment with growth stimuli. The changes in CK2 in various fractions were also confirmed by immunoblotting with a specific antibody. LNCaP cells responded to both 5alpha-DHT and growth factors for growth. The presence of these agents in the culture medium evoked a translocation of CK2 to the NM from the cytosol. The PC-3 cells did not respond to 5alpha-DHT for growth but did respond to growth factors. Under these conditions, there was also a translocation of CK2 to the NM concomitant with a decrease in the cytosolic fraction. These results suggest that CK2 translocation to the NM occurs in response to various growth stimuli in cells in culture. Thus, CK2 is a common downstream signal transducer in response to diverse growth stimuli that may relate to the pathobiology of prostate cancer cells.

Phosvitin phosphate content. Implications for protein kinase assay.

The maximal rates of the protein kinase (ATP: protein phosphotransferase, EC 2.7.1.37) reaction studied with chicken egg yolk phosvitin as substrate are dependent on the level of dephosphorylation of phosvitin. 30 per cent dephospho-phosvitin gives the optimal initial rates. With varying levels of dephosphorylation, the apparent Km for the substrate also changes in a biphasic manner. If this factor is taken into account, and a suitable adjustment is made for the concentration of dephospho-phosvitin in the reaction it is possible to achieve maximal rates for the kinase reaction with phosvitin preparations of varying levels of dephosphorylation. Such a consideration is important for comparing the results of protein kinase studies using phosvitin as the substrate.

Protein kinase CK2 as regulator of cell survival: implications for cancer therapy.

Recent studies have generated sufficient information to warrant a consideration of protein kinase CK2 as a potential target for cancer therapy. CK2 is a ubiquitous and highly conserved protein serine/threonine kinase that has long been considered to play a role in cell growth and proliferation. It is essential for cell survival, and considerable evidence suggests that it can also exert potent suppression of apoptosis in cells. This is important since the cancer phenotype is characterized by deregulation of not only proliferation but also of apoptosis. In normal cells, the level of CK2 appears to be tightly regulated, and cells resist a change in their intrinsic level of CK2. However, in all the cancers that have been examined an elevation of CK2 has been observed. Further, it appears that modest deregulation in the CK2 expression imparts a potent oncogenic potential to the cells. Disruption of CK2 by treatment of cells with antisense CK2 results in induction of apoptosis in a time and dose-dependent manner. Thus, we propose that down-regulation of CK2 by employing specific strategies to deliver antisense CK2 in vivo could have a potential role in cancer therapy.

The reduction of dose in paediatric panoramic radiography: the impact of collimator height and programme selection.

OBJECTIVES: The aim of this work was to estimate the doses to radiosensitive organs in the head of a young child undergoing panoramic radiography and to establish the effectiveness of a short collimator in reducing dose. METHODS: Thermoluminescent dosemeters were used in a paediatric head phantom to simulate an examination on a 5-year-old child. The panoramic system used was an Instrumentarium OP200 D (Instrumentarium Dental, Tuusula, Finland). The collimator height options were 110 and 140 mm. Organ doses were measured using exposure programmes intended for use with adult and child size heads. The performance of the automatic exposure control (AEC) system was also assessed. RESULTS: The short collimator reduced the dose to the brain and the eyes by 57% and 41%, respectively. The dose to the submandibular and sublingual glands increased by 32% and 20%, respectively, when using a programme with a narrower focal trough intended for a small jaw. The effective dose measured with the short collimator and paediatric programme was 7.7 µSv. The dose to the lens of the eye was 17 µGy. When used, the AEC system produced some asymmetry in the dose distribution across the head. CONCLUSIONS: Panoramic systems when used to frequently image children should have programmes specifically designed for imaging small heads. There should be a shorter collimator available and programmes that deliver a reduced exposure time and allow reduction of tube current. Programme selection should also provide flexibility for focal trough size, shape and position to match the smaller head size.

Monoclonal antibody-based therapy of lymphoid neoplasms: what's on the horizon?

Although exciting advances in monoclonal antibody therapy have already occurred, a review of agents in earlier stages of development reveals that many new agents may be approaching the clinic in the years to come. A look at the horizon of monoclonal antibody therapy reveals the following: novel strategies for augmenting the efficacy of monoclonal antibodies with which many clinicians are already familiar; novel antibodies with activity against lymphoma cells; novel technologies for generating and humanizing monoclonal antibodies; novel types of antibody-based therapeutics; and novel uses for these agents as modulators of the host immune system or other aspects of host-tumor interaction. Research in each of these areas will be reviewed.

Taurine concentrations in serum of critically injured patients and age- and sex-matched healthy control subjects.

Sulfur-containing amino acid concentrations were measured in serum of nine previously healthy adult trauma patients after 7 d of taurine-free parenteral nutrition and were compared with fasting serum concentrations in age- and sex-matched healthy subjects. Serum taurine concentrations in the patient group were depressed by 60% relative to control values (P less than 0.05) whereas serum methionine concentrations were significantly higher in the patient group. Serum cysteine concentrations were not significantly different between the two groups. This early decline in serum taurine concentrations in unsupplemented trauma patients suggests that taurine may be essential in the post-injury state.

Taurine supplementation at three different dosages and its effect on trauma patients.

We studied the effect of different amounts of intravenous taurine supplementation on restoring serum taurine concentrations in trauma patients. The nature of the hypotaurinemia in trauma patients was also studied by following renal-clearance dynamics. Five trauma patients in each of four groups were randomly assigned to receive, in their parenteral nutrition solutions, one of three dosages of taurine (5, 10.8, or 50 mg/kg ideal body wt as group 1, 2, or 3, respectively) or no taurine. Serum taurine concentrations rose significantly over 7 d, relative to control values, in both groups 2 and 3, but even with the highest dosage (group 3) only recovered about one-half of the deficit to the normal value. Despite low serum taurine concentrations in group 3, in contrast with handling of other amino acids, tubular reabsorption of taurine remained abnormally low after 7 d, resulting in a large taurine excretion. Hypotaurinemia in trauma patients persists longer than other hypoaminoacidemias because of depressed renal tubular reabsorption. Even 7 d of a high-dose taurine supplementation does not fully correct the hypotaurinemia of trauma.

Increased plasma carnitine in trauma patients given lipid-supplemented total parenteral nutrition.

The purpose of this study was to determine the effects of altering the fuel substrate mix of total parenteral nutrition (TPN) on plasma and urinary carnitine in trauma patients. TPN solutions were either 100% carbohydrate (CHO) based or lipid based (70% CHO, 30% lipid). There were statistically significant (p less than 0.05) increases in plasma levels of free carnitine, short-chain acyl carnitine, and total carnitine in trauma patients receiving lipid-based TPN. No significant differences in urinary carnitine excretion were noted between groups. We conclude that the use of lipids in the TPN of trauma patients leads to an alteration in plasma carnitine metabolism.

Studies of prostatic cytosol protein kinases of the aging ACI rat.

Changes in prostatic cytosolic cyclic AMP (cAMP)-dependent and independent protein kinases associated with aging in ACI rats were determined. A decrease in prostatic weight and tissue protein content (but not DNA) with age was noted. The cytosolic cAMP-dependent protein kinase was present predominantly as the type II isozyme. Total content of this enzyme per prostate declined by 37% in 12-month-old rats but remained relatively stable thereafter. However, the activity ratio (+cAMP/-cAMP) increased with aging, indicating an elevation in the amount of the holoenzyme or a decrease in the amount of the free catalytic subunit. Concomitantly the specific activity (activity/unit protein in the cytosol) of this enzyme was found to be increased; this is most likely due to the loss of bulk proteins in the cytosol, and may indicate a slower loss of this enzyme protein in relation to other cytosolic proteins. By comparison, the cAMP-independent protein kinase demonstrated a marked and progressive decline in amount as well as in specific activity with aging, e.g. 80-90% decline at 12 months of age. The above changes in these enzymes did not appear to be due to low circulating androgen in the animals, since they were not reversed on administration of 3.0 mg of testosterone propionate per rat daily for four consecutive days. It is therefore suggested that the above-described changes in prostatic cytosolic protein kinases are primarily associated with cellular senescence in this organ.

Behavioral management of psychogenic cough: alternative to the "bedsheet" and other aversive techniques.

The treatment of persistent psychogenic cough, a potentially debilitating condition among pediatric patients, can pose diagnostic and treatment dilemmas. Its treatment by the use of a procedure called reinforced suggestion technique was described previously. The use of an alternative procedure relying upon parental and self-monitoring of coughing and either social or material rewards for decreasing rates of coughing is presented.

An explosive outbreak of Mycoplasma pneumoniae infection in a summer camp.

An outbreak of Mycoplasma pneumoniae infection occurred in the summer of 1978 in a boys' camp in northern Wisconsin and affected 139 of 196 persons (71%); 115 (59%) had laboratory evidence of infection. In 77% of the cases, onset of disease occurred within three weeks after arrival at camp, in contrast to the usually indolent spread of the disease. Attack rates decreased with increasing age. The sensitivity of serology for detecting M pneumoniae disease may have been as low as 79%. There was shorter duration of cough in those treated with erythromycin within four days after onset of symptoms.

Enterobacter aerogenes primary bacteremia in pediatric patients.

Enterobacter aerogenes bacteremia associated with the infusion of contaminated admixed intravenous (IV) fluid occurred in seven patients in a pediatric hospital over a five-day period. Clinical illness was characterized by spiking fever in all patients. The temporal clustering of cases allowed for rapid recognition of the problem. The primary control measure was the prompt replacement of the IV fluids, although IV antibiotics were also administered. Hospital pharmacy practices for admixing IV solutions should follow published recommendations to minimize this source of potential contamination of fluids.

Association of a mosaic chromosomal 22q11 deletion with hypoplastic left heart syndrome.

The atypical presentation of CATCH 22 raises several important concerns. First, in this patient, as in others, the heart defects were found in association with subtle facial abnormalities but with few of the other criteria normally seen in CATCH 22. This association alone may be sufficient to raise suspicion that an interstitial 22q11 deletion may be present. Second, the incidence of chromosome 22 deletions in parents of children with a 22q11 deletion (25%) suggests that siblings or subsequent fetuses may also be at risk. Parents with subtle or unusual manifestations of CATCH 22 may be unaware of their potential carrier status. Finally, the recognition of chromosomal mosaicism in this patient may have been fortuitous, as cytogenetic studies of leukocytes from other individuals with a mosaic karyotype may sometimes fail to reveal a 22q11 deletion that is present in cardiac tissues. Molecular cytogenetic analysis of cardiac specimens that are removed during routine surgical procedures may be warranted in appropriate clinical situations.

Effects of thyroid hormone deprivation on immunity in postmetamorphic frogs.

Previously, we showed that sodium perchlorate treatment of larval frogs (Xenopus laevis) interferes with the normal expansion of T and B lymphocytes and development of an adult-type T-cell population. It was unclear whether these effects resulted from preventing metamorphosis or from long-term thyroid hormone (TH) deprivation. To try to distinguish between these possibilities, we have now studied the effects of perchlorate treatment beginning immediately after metamorphosis. After 5 months, treated animals, but not untreated controls, had large thyroid goiters, were significantly smaller, and had significantly fewer erythrocytes, thymocytes, and splenocytes. Although the number of IgM- splenocytes and thymocytes was reduced, the estimated percent of major histocompatibility complex (MHC) class II+ cells within this subset was not significantly different from that of controls. Furthermore, splenocytes from perchlorate-treated frogs could respond normally by [3H]TdR incorporation to the T-cell mitogens, phytohemagglutinin-P (PHA) and concanavalin A (Con A). Thus, unlike perchlorate-treated larvae, perchlorate-treated juveniles appear to be able to develop T cells with an adult phenotype competent to respond to activation and proliferation signals.

Late thymectomy in Xenopus tadpoles reveals a population of T cells that persists through metamorphosis.

To investigate the persistence of larval T lymphocytes in the adult period, tadpoles of the South African clawed frog, Xenopus laevis, were allowed to develop to prometamorphic stages 57-58 and thymectomized (Tx). Thymectomy at this stage allows for maximal expansion of the larval T cell population but prevents emergence of the adult T cell population. Using a T cell-specific monoclonal antibody (mAb) which recognizes the XTLA-1 determinant, we examined the absolute numbers of thymic and splenic T cells expressing XTLA-1 in normal tadpoles, postmetamorphic Tx frogs, and intact age-matched adult frogs. A small, but measurable, number of larvally-derived XTLA-1+ cells persists through metamorphosis. By simultaneously staining with a mAb specific for class II major histocompatibility (MHC) antigens, we determined the phenotype of the persisting XTLA-1+ cells in the Tx frogs. Like XTLA-1+ splenocytes in intact adult controls which are predominantly class II+, most XTLA-1+ cells in Tx adults also express class II. In contrast, most XTLA-1+ cells in the tadpole are class II-. This suggests that a small population of class II+ larval T cells survives metamorphic transition to become a long-lived population in the adult. Alternatively, some class II- larval T cells may express class II in the adult period.

Cryoprecipitates in Kawasaki syndrome: association with coronary artery aneurysms.

Cryoprecipitates are postulated to play a role in the pathogenesis of several vasculitis illnesses and infectious diseases. To investigate the presence of cryoprecipitates in Kawasaki syndrome, we studied sera from 25 children with acute Kawasaki syndrome. None of the subjects was treated with intravenous gamma-globulin. Cryoprecipitates were detectable in sera of 11 of 25 (44%) children studied. The mean (+/- SE protein concentration of the cryoprecipitates was 88.0 (+/- 20.2) micrograms/ml serum. Cryoprecipitates consisted primarily of IgG and IgM; no complement components were detected but highly sensitive methods were not used. The presence of cryoprecipitates in the serum of children with acute Kawasaki syndrome was associated with the subsequent development of coronary artery aneurysms detected by echocardiogram (P less than 0.05). There was no association between detectable cryoprecipitates and either peak platelet count or erythrocyte sedimentation rate. In one patient, measurement of cryoprecipitates in serial samples showed a reduction in concentrations that paralleled subsidence of disease activity. We speculate that cryoprecipitates may be a marker for increased risk of coronary aneurysm formation and may play a role in the pathogenesis of the cardiac disease in Kawasaki syndrome.

Hemangioendothelioma of the cavernous sinus: case report.

OBJECTIVE AND IMPORTANCE: Hemangioendothelioma is an uncommon vascular neoplasm, and its intracranial occurrence is extremely rare. The occurrence of such a tumor within the cavernous sinus has not been reported previously. CLINICAL PRESENTATION: We report a 36-year-old woman who presented with right-sided retro-orbital pain and diplopia caused by a right sixth nerve paresis. Magnetic resonance imaging revealed a lesion within the right inferior cavernous sinus. INTERVENTION: The tumor was excised completely via an orbitozygomatic approach. CONCLUSION: Hemangioendothelioma is a rare, indolent vascular tumor, and its characteristics are reviewed. The need for complete excision is emphasized, and the advantages of the orbitozygomatic approach for the removal of tumors of the cavernous sinus is discussed.