Breastfeeding the premature newborn: a protocol without bottles

Premature babies can, and should, breastfeed. Although establishing a milk supply and the transition to breastfeeds can be difficult, both are possible. Because early bottle-feeds can impede later attempts to breastfeed, the newborn intensive care unit at Methodist Hospital in Indianapolis developed a protocol for successfully breastfeeding premature infants that excludes bottle-feeding. The babies are introduced to the breast as soon as possible, and supplementation is provided by gavage feeding. The amount of supplement is adjusted based on maternal and nursing observations of the breastfeeding experience. The hospital stays are not prolonged by this approach and most of the babies whose mothers intended to breasfeed are discharged exclusively breastfeeding.     

PTD-mediated Loading of Tumor-Seeking Lymphocytes with Prodrug-Activating Enzymes

Using the approach of peptide transduction domain (PTD)-mediated loading of interleukin-2(IL-2)-activated natural killer (A-NK) cells, tumor-seeking lymphocytes, with prodrug-activating enzymes, we primarily aim to generate a cytotoxic drug selectively within tumors and minimize damage to normal tissues. A-NK cells are able to accumulate selectively at tumor sites. While these cells by themselves possess significant antitumor effect in vivo, we suggest that they can also serve as Trojan horses, by bringing anticancer agents, such as prodrug-activating enzymes, selectively to tumors. We have successfully demonstrated in a mouse model that A-NK cells can be rapidly loaded with prodrug-activating enzymes, such as alkaline phosphatase (AP) and beta-galactosidase (beta-gal), in vitro using enzyme-conjugated peptide PTD5. Upon adoptive transfer into lung-tumor-bearing animals, the loaded A-NK cells are able to bring their cargo of the prodrug-activating enzymes selectively to pulmonary metastases. The targeting of the AP to the tumor tissues is highly specific, since more than a fivefold higher concentration of AP was found in the tumor tissues compared to the surrounding normal lung tissue at 24 h after injection. The approach of transporting prodrug-activating enzymes selectively into tumors clearly shows potential for future targeted chemotherapy. Ongoing studies in our laboratory are evaluating the antitumor efficacy of cellular-dependent enzyme prodrug therapy.     

Modulation of mammalian O6-alkylguanine-DNA alkyltransferase in vivo by O6-benzylguanine and its effect on the sensitivity of a human glioma tumor to 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea

Experiments were carried out in mice and hamsters to determine whether the activity of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase, in tissues and tumors was reduced by treatment with O6-benzylguanine in vivo. Following intraperitoneal injection of O6-benzylguanine, there was a rapid and complete loss of alkyltransferase activity in both livers and kidneys of mice and hamsters. The activity in mouse tissues was slowly restored, reaching pretreatment activities at 16 hr and 72 hr after injection of O6-benzylguanine at 10 mg/kg or 126 mg/kg, respectively. The activity in hamster liver was restored at a significantly lower rate, reaching less than 20% pretreatment activity 72 hr after treatment with 100 mg/kg of O6-benzylguanine. The efficient reduction of alkyltransferase activity by O6-benzylguanine was in sharp contrast to the inability of O6-methylguanine to bring about similar reductions. Activities dropped to about 55% of pretreatment activities in several mouse organs 4 hr after treatment with 126 mg/kg of O6-methylguanine compared to a more than 90% reduction in activity in animals after treatment with O6-benzylguanine. The sensitivity of SF767 cells to meCCNU after treatment with O6-benzylguanine was increased substantially. Furthermore, treatment of nude mice carrying SF767 tumor with 60 mg/kg of O6-benzylguanine prior to either 7.5 or 15 mg/kg of meCCNU led to significant inhibition of tumor growth. These studies indicate that O6-benzylguanine is a suitable compound for use in experiments to examine the role of the alkyltransferase protein in vivo in counteracting the effects of alkylating agents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of association between COMT gene and deficit/nondeficit schizophrenia

Background  

The dopamine dysregulation hypothesis of schizophrenia posits that positive, negative and cognitive symptoms correlate with cortical/subcortical imbalances in dopaminergic transmission. A functional polymorphism (Val¹⁵⁸Met) in the catechol-O-methyltransferase (COMT) gene is implicated in the pathophysiology of schizophrenia by its effect on prefrontal dopamine transmission, and its unique impact on prefrontal cognitive and behavioral phenotypes. Cognitive impairments and negative symptoms in schizophrenia have been hypothesized to be associated with hypodopaminergic states. Schizophrenia patients with the deficit syndrome are characterized by primary enduring negative symptoms, impairment on neurocognitive tasks sensitive to frontal and parietal cortical functioning, and poorer functional outcome compared to non-deficit patients.     

Cancer in survivors of childhood soft tissue sarcoma and their relatives

One hundred fifty-nine 3-year survivors of childhood soft tissue sarcoma and their relatives were surveyed to determine the frequency of second malignant neoplasms (SMNs) in patients and cancer in their relatives. The cancer experience of the patients, their offspring, siblings, parents, parental siblings, and grandparents was compared to that expected of the general population based on age-, sex- and calendar year-specific rates from the Connecticut Tumor Registry. A significant excess of SMNs was observed in the patients (observed expected = 8:0.38). Among 758 first-degree relatives, a significant cancer excess was observed (34:20.68), attributable largely to cancer of soft tissue and bone (6:0.44) and breast (9:3.39) and to cancers occurring before age 35 years (12:4.14). Overall, a significantly lower than expected cancer incidence was confirmed in the 1,693 second-degree relatives (142:178). To identify patient characteristics associated with higher than expected familial cancer risk, kindreds were partitioned by patient age at diagnosis tumor type, tumor site SMN and other factors. A highly significant cancer excess was observed in the relatives of SMN patients (26:12.78). The tumor types occurring in excess in close relatives were also observed as SMNs in the patients. The findings confirm an association among childhood soft tissue sarcoma and cancers of the breast, bone, joint, or soft tissue as SMN in patients and in close relatives and suggest that the risk of a second tumor is associated with a familial predisposition to cancer.     

The impact of a tailored follow-up intervention on comprehensive geriatric assessment in older patients with cancer - a randomised controlled trial

PurposeComprehensive Geriatric Assessment (CGA) can identify health problems in older persons. In addition, CGA includes intervention towards the identified problems. With follow up, more problems may be identified and the interventions can be adjusted. We wanted to compare CGA with or without tailored follow-up in a randomised design.Patients and MethodsPatients 70+ years referred for oncology treatment with four primary tumour sites. Participants were randomised 1:1 to either control group with no follow-up or intervention group with a tailored follow-up by a multidisciplinary team. Primary outcome was adherence to cancer treatment. Secondary outcomes were daily life activities, physical performance and hospitalisation.ResultsIn total, 363 participants were randomised. After randomisation only 301 were planned to receive specific cancer treatment. Median age was 75 years. Among the 301 participants, 52% of control group vs. 61% of intervention group completed treatment. Risk Rate (RR): 1.16 (95% Confidence Interval (CI): 0.95–1.42), p = .14. The impact varied between the included tumour-sites, p < .01. We found no difference in 90 days physical performance or daily life activities between groups. During the study period, 55% of controls vs. 47% in the intervention group were admitted to hospital, RR: 0.86 (95%CI: 0.69–1.07), p = .19.ConclusionIn frail and vulnerable patients with cancer, a tailored follow-up on CGA showed no differences in ability to complete initially planned cancer treatment. The impact varied between the included tumour sites. We did not find any impact of tailored follow-up on daily life activities, physical performance or hospitalisation.     

Viable, lyophilized lactobacilli do not increase iron absorption from a lactic acid-fermented meal in healthy young women, and no iron absorption occurs in the distal intestine

Lactic acid-fermented foods have been shown to increase Fe absorption in human subjects, possibly by lowering pH, activation of phytases, production of organic acids, or by the viable lactic acid bacteria. In this study the effect of a heat-inactivated lactic acid-fermented oat gruel with and without added viable, lyophilized Lactobacillus plantarum 299v on non-haem Fe absorption was investigated. Furthermore, Fe absorption in the distal intestine was determined. In a randomized, double-blinded crossover trial eighteen healthy young women aged 22 (SD 3) years with low Fe status (serum ferritin < 30 microg/l) were served the two test gruels, extrinsically labelled with 59Fe and served with two enterocoated capsules (containing 55Fe(II) and 55Fe(III), respectively) designed to disintegrate in the ileum. The meals were consumed on two consecutive days, e.g. in the order AA followed by BB in a second period. Non-haem Fe absorption was determined from 59Fe whole-body retention and isotope activities in blood samples. The concentrations of Fe, lactate, phytate, and polyphenols, and the pH were similar in the heat-inactivated lactic acid-fermented oat gruels with and without added L. plantarum 299v, and no difference in Fe absorption was observed between the test gruels (1.4 and 1.3%, respectively). Furthermore, no absorption of Fe in the distal intestine was observed. In conclusion, addition of viable, lyophilized lactobacillus to a heat-inactivated lactic acid-fermented oat gruel does not affect Fe absorption, and no absorption seems to occur in the distal part of the intestine from low Fe bioavailability meals in these women.     

Activation of the CPP32 protease in apoptosis induced by 1-beta-D- arabinofuranosylcytosine and other DNA-damaging agents

The response of human myeloid leukemia cells to treatment with 1-beta- arabinofuranosylcytosine (ara-C) includes the induction of apoptosis. Ara-C induced apoptosis is associated with proteolytic cleavage of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. However, the signals involved in this response are unknown. The present studies show that ara-C treatment of U-937 cells is associated with induction of a protease activity that cleaves the tetrapeptides Ac-DEVD- pNA and Ac-DMOD-pNA found at the cleavage sites of PARP and PKC delta, respectively. The ara-C-induced protease activity was sensitive to overexpression of the anti-apoptotic protein Bcl-xL and the baculovirus protein p35. By contrast, overexpression of the cowpox virus protein CrmA blocked apoptosis induced by engagement of the Fas receptor but not that induced by ara-C. CrmA overexpression also had no detectable effect on ara-C-induced cleavage of PKC delta. The results further show that ara-C induces activation of the CPP32 protease by a CrmA- insensitive and p35-sensitive mechanism. Similar results were obtained with cisplatinum, etoposide, and camptothecin. These findings indicate that ara-C and other DNA-damaging agents activate a CrmA-insensitive apoptotic pathway involving CPP32 and that these signals differ from those associated with apoptosis induced by the Fas receptor.     

Basic fibroblast growth factor in patients with intermittent claudication: results of a phase I trial

OBJECTIVES: This phase I study was designed to evaluate the safety, tolerability and pharmacokinetics of intra-arterial basic fibroblast growth factor (bFGF) in patients with atherosclerotic peripheral arterial disease (PVD) and intermittent claudication. We also assessed the effects of basic fibroblast growth factor (bFGF) on calf blood flow as a measure of biologic activity. BACKGROUND: Preclinical studies have shown that bFGF, an angiogenic peptide, promotes collateral development in animal models of myocardial and hind limb ischemia. The safety and efficacy of bFGF in patients is unknown, and early clinical trials are underway in coronary and peripheral arterial disease. METHODS: A double-blind, placebo-controlled, dose-escalation trial was conducted in patients with claudication demonstrating ankle/brachial index <0.8. Patients were randomly assigned to placebo (n = 6), 10 microg/kg of bFGF (n = 4), 30 microg/kg of bFGF once (n = 5) and 30 microg/kg of bFGF on two consecutive days (n = 4). Study drug was infused into the femoral artery of the ischemic leg. Detailed safety information including retinal photography for neovascularization were obtained through one year. Calf blood flow was measured with strain gauge plethysmography in the two higher dose treatment groups and in four placebo patients at baseline, one month and three to seven months after treatment. RESULTS: Intra-arterial bFGF was safe and well-tolerated. The half-life was 46 +/- 21 min. Calf blood flow increased at one month by 66 +/- 26% (mean +/- SEM) and at six months by 153 +/- 51% in bFGF-treated patients (n = 9, p = 0.002). Flow did not change significantly in the placebo group. CONCLUSIONS: In this initial randomized, double-blind, placebo-controlled trial in patients with atherosclerotic PVD and claudication, bFGF was well-tolerated. The data suggest a salutary biologic effect, and initiation of phase 2 trials is warranted.