Quintuplets and a mother's determination to provide human milk: it takes a village to raise a baby--how about five?

This is the first published case of quintuplets who breastfeed and receive expressed mother's own milk and supplemental pasteurized donor human milk. In this case, all 5 babies receive exclusively human milk at 7 months. This result is achieved because of the mother's strong advocacy for human milk feedings and a remarkable support system of 200 individuals drawn from family, friends, and congregation.

Cyclooxygenase-2 inhibition sensitizes human colon carcinoma cells to TRAIL-induced apoptosis through clustering of DR5 and concentrating death-inducing signaling complex components into ceramide-enriched caveolae.

Cyclooxygenase-2 (COX-2) is up-regulated in human colon carcinomas, and its inhibition is associated with a reduction in tumorigenesis and a promotion of apoptosis. However, the mechanisms responsible for the antitumor effects of COX-2 inhibitors and how COX-2 modulates apoptotic signaling have not been clearly defined. We have shown that COX-2 inhibition sensitizes human colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inducing clustering of the TRAIL receptor DR5 at the cell surface and the redistribution of the death-inducing signaling complex components (DR5, FADD, and procaspase-8) into cholesterol-rich and ceramide-rich domains known as caveolae. This process requires the accumulation of arachidonic acid and sequential activation of acid sphingomyelinase for the generation of ceramide within the plasma membrane outer leaflet. The current study highlights a novel mechanism to circumvent colorectal carcinoma cell resistance to TRAIL-mediated apoptosis using COX-2 inhibitors to manipulate the lipid metabolism within the plasma membrane.

National Trends in Pediatricians' Practices and Attitudes About Breastfeeding: 1995 to 2014.

BACKGROUND AND OBJECTIVES: The American Academy of Pediatrics (AAP) has affirmed breastfeeding as the preferred method of infant feeding; however, there has been little systematic examination of how pediatricians' recommendations, affiliated hospitals' policies, counseling practices, and attitudes toward breastfeeding have shifted over the past 2 decades. These trends were examined from 1995 to 2014. METHODS: Data are from the Periodic Survey (PS) of Fellows, a nationally representative survey of AAP members. PS #30 (1995; response rate = 72%; N = 832), PS #57 (2004; response rate = 55%; N = 675), and PS #89 (2014; response rate = 51%; N = 620) collected demographics, patient and practice characteristics, and detailed responses on pediatricians' recommendations, affiliated hospitals' policies, counseling practices, and attitudes toward breastfeeding. By using bivariate statistics and logistic regression models, the analysis investigated changes over time with predicted values (PVs). RESULTS: From 1995 to 2014, more pediatricians reported their affiliated hospitals applied for "baby-friendly" designation (PV = 12% in 1995, PV = 56% in 2014; P < .05), and more reported that they recommend exclusive breastfeeding (65% to 76% [P < .05]). However, fewer respondents indicated that mothers can be successful breastfeeding (PV = 70% in 1995, PV = 57% in 2014; P < .05) and that the benefits outweigh the difficulties (PV = 70% in 1995, PV = 50% in 2014; P < .05). Younger pediatricians were less confident than older pediatricians in managing breastfeeding problems (P < .01). CONCLUSIONS: Pediatricians' recommendations and practices became more closely aligned with AAP policy from 1995 to 2014; however, their attitudes about the likelihood of breastfeeding success have worsened. These 2 divergent trends indicate that even as breastfeeding rates continue to rise, continued efforts to enhance pediatricians' training and attitudes about breastfeeding are necessary.

Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C.

Signaling pathways involved in survival responses may attenuate the apoptotic response to the cytotoxic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human colon carcinomas. In six lines examined, three were sensitive (GC(3)/c1, VRC(5)/c1, HCT116), HT29 demonstrated intermediate sensitivity, and RKO and HCT8 were resistant to TRAIL-induced apoptosis. Calphostin c [an inhibitor of classic and novel isoforms of protein kinase C (PKC)] sensitized five of six cell lines to TRAIL, whereas Go6976, (inhibitor of classic PKC isoforms), did not influence TRAIL sensitivity. Rottlerin, an inhibitor of novel isoforms of PKC, specifically PKC delta, sensitized five of six cell lines to TRAIL-induced apoptosis, suggesting that PKC delta may be involved in the mechanism of TRAIL resistance. Transfection of HCT116 with a proapoptotic cleaved fragment of PKC delta or an antiapoptotic full-length PKC delta did not influence the sensitivity of HCT116 to TRAIL. Furthermore, the incubation of HCT116 or RKO with phorbol myristate acetate for 16 h, which down-regulated the expression of novel PKC isoforms, also did not influence sensitivity to TRAIL either in the absence or presence of rottlerin. However, after 15-min incubation with rottlerin, mitochondrial membrane potential (Delta psi m) was dramatically reduced in RKO cells, and, in cells subsequently treated with TRAIL, rapid apoptosis was evident within 8 h. Calphostin c, but not Go6976, also caused a decrease in Delta psi m. In RKO, rottlerin induced the release of cytochrome c, HtrA2/Omi, Smac/DIABLO, and AIF from the mitochondria, potentiated in combination with TRAIL, with concomitant caspase activation and down-regulation of XIAP. In HT29, the release of proapoptotic factors was demonstrated only when rottlerin and TRAIL were combined, and Bcl-2 overexpression inhibited this release and the induction of apoptosis. TRAIL-induced apoptosis was not influenced by rottlerin or Bcl-2 overexpression in type I (GC(3)/c1) cells. Data suggest that rottlerin affects mitochondrial function independent of PKC delta, thereby sensitizing cells to TRAIL, and that mitochondria constitute an important target in overcoming inherent resistance to TRAIL in colon carcinomas.

P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase inhibitors in colorectal carcinoma cells.

We have demonstrated previously that interferon (IFN)-gamma sensitizes human colon carcinoma cell lines to the cytotoxic effects of 5-fluorouracil combined with leucovorin and to the thymidylate synthase inhibitor, ZD9331, dependent on thymineless stress-induced DNA damage, independent of p53. Here we demonstrate that the cyclin-dependent kinase (CDK) inhibitor p21(Cip1) regulates thymineless stress-induced cytotoxicity in these cells. HCT116 wild-type (wt) and p53-/- cells underwent apoptosis and loss in clonogenic survival when exposed to ZD9331, whereas p21Cip1-/- cells were resistant. In contrast, IFN-gamma induced marked cytotoxicity in p21Cip1-/- cells only. ZD9331 induced p21Cip1 up-regulation in all of the cell lines examined, as did thymidine deprivation in thymidylate synthase-deficient (thymidylate synthase-) cells. Furthermore, selective induction of p21Cip1 in RKO was sufficient to induce apoptosis. P21Cip1, cdk1, cdk2, and cyclin E mRNA expression increased coincident with S-phase accumulation in HT29 cells treated with ZD9331 or 5fluorouracil/leucovorin, as demonstrated by cDNA microarray analyses. Cell cycle analyses revealed that HCT116 wt and p21Cip1 -/- cells accumulated in S phase within 24 h of ZD9331 exposure; however, wt cells exited S-phase more rapidly, where apoptosis occurred before mitosis, either in late S or G2. Finally, the CDK inhibitor roscovitine potentiated the cytotoxic activity of ZD9331 in both wt and p21Cip1-/- cells, strongly suggesting a role for p21Cip1-dependent CDK inhibition in cytotoxicity induced by thymidylate synthase inhibition. In summary, p21Cip1 positively regulates the cytotoxic action of thymidylate synthase inhibitors, negatively regulates the cytotoxic action of IFN-gamma, and enhances S-phase exit after thymineless stress, possibly via interaction with CDK-cyclin complexes.

The Effect of Interactive Web-Based Monitoring on Breastfeeding Exclusivity, Intensity, and Duration in Healthy, Term Infants After Hospital Discharge.

OBJECTIVE: To determine whether a Web-based interactive breastfeeding monitoring system increased breastfeeding duration, exclusivity, and intensity as primary outcomes and decreased symptoms of postpartum depression as a secondary outcome. DESIGN: Two-arm, randomized controlled trial. SETTING: Three hospitals in the Midwestern United States. PARTICIPANTS: One hundred forty one (141) mother-newborn dyads were recruited before discharge. METHODS: Postpartum women were randomly assigned to the control or intervention groups. Women in the control group (n = 57) followed the standard hospital protocol, whereas women in the intervention group (n = 49) were given access to an online interactive breastfeeding monitoring system and were prompted to record breastfeeding and infant output data for 30 days. A follow-up online survey was sent to both groups at 1, 2, and 3 months to assess breastfeeding outcomes and postpartum depression. RESULTS: For mothers and infants, there were no significant differences in demographics between groups. No significant differences in breastfeeding outcomes were found between groups at discharge (p = .707). A significant difference in breastfeeding outcomes was found between groups at 1, 2, and 3 months (p = .027, p < .001, and p = .002, respectively). Members of the intervention group had greater exclusive breastfeeding rates at 1, 2, and 3 months. By the end of the third month, 84% of the intervention group was breastfeeding compared with 66% of the control group. Postpartum depression symptom scores decreased for both groups at 1, 2, and 3 months (control group: 4.9 ± 3.9, 4.3 ± 4.9, and 3.2 ± 3.9, respectively; intervention group: 4.7 ± 4.5, 3.0 ± 3.4, and 2.8 ± 3.6, respectively). However, there was no significant difference between groups at 1, 2, and 3 months (p = .389, .170, and .920, respectively) for depression. CONCLUSION: The Web-based interactive breastfeeding monitoring system may be a promising intervention to improve breastfeeding duration, exclusivity, and intensity.

Interferon-gamma-induced sensitization of colon carcinomas to ZD9331 targets caspases, downstream of Fas, independent of mitochondrial signaling and the inhibitor of apoptosis survivin.

We have demonstrated previously a Fas-dependent component in thymineless death of human colon carcinoma cells. Importantly, the cytotoxic effects of thymidine deprivation induced by 5-fluorouracil (FUra) combined with leucovorin (LV) was enhanced by IFN-gamma, and the synergism was shown to be dependent on Fas, FUra-induced DNA damage, and independent of p53. Subsequently we examined the potential for synergistic interactions between IFN-gamma and the specific thymidylate synthase inhibitor, ZD9331. IFN-gamma sensitized colon carcinomas to ZD9331-induced apoptosis and loss in clonogenic survival, also dependent on ZD9331-induced DNA damage, independent of p53. Synergism occurred in HCT116, demonstrating previously RNA-mediated FUra/LV cytotoxicity that could not be potentiated by IFN-gamma. Manipulation of the Fas death receptor pathway from the level of the receptor (Nok1/Nok2, Fas overexpression, and DN-FADD) to the mitochondria (Bcl-xL and Bcl-2) did not modulate ZD9331 +/- IFN-gamma-induced cytotoxicity in HT29, with the exception that Nok1/Nok2-blocking antibodies partially protected HT29 from the cytotoxic activity of ZD9331 alone. However, IFN-gamma alone (but not ZD9331) up-regulated the expression of caspases -3, -4, -7, and -8, and in combination with ZD9331 demonstrated enhanced caspase activation and cleavage of poly(ADP-ribose) polymerase that was not prevented by overexpression of Bcl-2. Additionally, IFN-gamma increased the activity of the proteasome in HT29, leading to selective down-regulation of the antiapoptotic protein survivin, whereas simultaneously increasing Fas expression. However, reduction in the survivin:Fas ratio by transfection of survivin small interfering RNA and/or overexpression of Fas did not affect sensitivity of HT29 to ZD9331 +/- IFN-gamma. Data demonstrate that IFN-gamma combined with ZD9331 is synergistic in additional cell lines that demonstrate RNA-mediated FUra/LV cytotoxicity, and that a major target of interaction is at the level of caspases, downstream of Fas, and independent of involvement of either the mitochondria or survivin.

Parental Leave Policies and Pediatric Trainees in the United States.

BACKGROUND: The American Academy of Pediatrics (AAP) states that each residency program should have a clearly delineated, written policy for parental leave. Parental leave has important implications for trainees' ability to achieve their breastfeeding goals. OBJECTIVE: This study aimed to measure the knowledge and awareness among members of the AAP Section on Medical Students, Residents, and Fellowship Trainees (SOMSRFT) regarding parental leave. METHODS: An online survey was emailed to SOMSRFT members in June 2013. Quantitative data are presented as percentage of respondents. Awareness of leave policies was analyzed based on having children and the sex of respondents. RESULTS: Nine hundred twenty-seven members responded to the survey. Among those with children, 40% needed to extend the duration of their training in order to have longer maternity leave, 44% of whom did so in order to breastfeed longer. Thirty percent of respondents did not know if their program had a written, accessible policy for parental leave. Trainees without children and men were more unaware of specific aspects of parental leave such as eligibility for the Family Medical Leave Act as compared to women and those with children. CONCLUSION: Despite the fact that United States national policies support parental leave during pediatrics training, and a majority of programs comply, trainees' awareness regarding these policies needs improvement.

"Frustrated," "depressed," and "devastated" pediatric trainees: US academic medical centers fail to provide adequate workplace breastfeeding support.

BACKGROUND: Exclusive breastfeeding (EBF) is recommended until about 6 months of age. Pediatricians are at the forefront of encouraging mothers to achieve this goal, yet pediatricians who parent during their training may face substantial barriers in achieving their own breastfeeding goals. OBJECTIVES: This study aimed to assess breastfeeding support available to US pediatricians in training and the effect of trainees' personal experiences on their attitude toward breastfeeding. METHODS: An online survey was emailed to American Academy of Pediatrics Section on Medical Students, Residents, and Fellowship Trainees members. RESULTS: There were 927 respondents, of which 421 had children and 346 breastfed their children. Almost 80% agreed that 6 months is the ideal duration for EBF. One in 4 did not have access to or were not aware of a private room to express milk or breastfeed. Forty percent needed to extend the duration of their training for a longer maternity leave, with breastfeeding a factor for longer leave among 44%. One in 4 did not meet their breastfeeding duration goal, and 1 in 3 did not meet their goal for EBF. Negative emotions were common among those not meeting goals. Ninety-two percent felt that their or their partner's experience with breastfeeding affected their clinical interaction with patients' mothers. CONCLUSION: A majority of respondents cited problems with breastfeeding support during training, and many failed to meet their intended goals. Not meeting personal breastfeeding goals was associated with negative emotions and influenced how they counsel about breastfeeding as a result of personal and often negative attitudes.

Does Circadian Disruption Play a Role in the Metabolic-Hormonal Link to Delayed Lactogenesis II?

Breastfeeding improves maternal and child health. The American Academy of Pediatrics recommends exclusive breastfeeding for 6 months, with continued breastfeeding for at least 1 year. However, in the US, only 18.8% of infants are exclusively breastfed until 6 months of age. For mothers who initiate breastfeeding, the early post-partum period sets the stage for sustained breastfeeding. Mothers who experience breastfeeding problems in the early post-partum period are more likely to discontinue breastfeeding within 2 weeks. A major risk factor for shorter breastfeeding duration is delayed lactogenesis II (DLII; i.e., onset of milk "coming in" more than 72 h post-partum). Recent studies report a metabolic-hormonal link to DLII. This is not surprising because around the time of birth the mother's entire metabolism changes to direct nutrients to mammary glands. Circadian and metabolic systems are closely linked, and our rodent studies suggest circadian clocks coordinate hormonal and metabolic changes to support lactation. Molecular and environmental disruption of the circadian system decreases a dam's ability to initiate lactation and negatively impacts milk production. Circadian and metabolic systems evolved to be functional and adaptive when lifestyles and environmental exposures were quite different from modern times. We now have artificial lights, longer work days, and increases in shift work. Disruption in the circadian system due to shift work, jet-lag, sleep disorders, and other modern life style choices are associated with metabolic disorders, obesity, and impaired reproduction. We hypothesize that DLII is related to disruption of the mother's circadian system. Here, we review literature that supports this hypothesis, and describe interventions that may help to increase breastfeeding success.

Lysophosphatidylcholine is a regulator of tyrosine kinase activity and intracellular Ca(2+) level in Jurkat T cell line.

Lysophospholipids, particularly lysophosphatidylcholine (lyso-PC), have been implicated in modulating T cell functions at the sites of inflammation and atherosclerosis. Although the chemotactic and immunomodulatory effects are well documented, the exact signaling pathway of lyso-PC action is poorly defined. In this work, we studied the earliest biochemical events in T cells triggered by lyso-PC. A marked and immediate tyrosine phosphorylation was induced in the leukemic T cell line, Jurkat. Phosphorylation of cellular substrates included src family kinase, p56(lck) and syk family kinase, ZAP70. The lyso-PC induced tyrosine phosphorylation was largely dependent on the presence of functional p56(lck). Tyrosine phosphorylation was followed by the elevation of intracellular Ca(2+) concentration. The magnitude of the mobilization of the intracellular Ca(2+) was similar in the absence of the p56(lck) activity in JCaM1.6 cells as in Jurkat cells, however, it was slightly but reproducibly delayed compared to that in the wild type cells. Inhibition of the Ser/Thr kinases and tyrosine kinases with staurosporine and genistein, respectively, decreased the rise in the intracellular Ca(2+) content. Moreover, pertussis toxin completely blocked the Ca(2+) signal supporting the role of the G-protein coupled LPC receptor in this event.

Nascent regional system for alerting infection preventionists about patients with multidrug-resistant gram-negative bacteria: implementation and initial results.

OBJECTIVE: To build and to begin evaluating a regional automated system to notify infection preventionists (IPs) when a patient with a history of gram-negative rod multidrug-resistant organism (GNRMDRO) is admitted to an emergency department (ED) or inpatient setting. DESIGN: Observational, retrospective study. SETTING: Twenty-seven hospitals, mostly in the Indianapolis metropolitan area, in a health information exchange (HIE). PATIENTS: During testing of the new system: 80,180 patients with microbiology cultures between October 1, 2013, and December 31, 2013; 573 had a GNRMDRO. METHODS/INTERVENTION: A Health Level Seven (HL7) data feed from the HIE was obtained, corrected, enhanced, and used for decision support (secure e-mail notification to the IPs). Retrospective analysis of patients with microbiology data (October 1, 2013, through December 31, 2013) and subsequent healthcare encounters (through February 6, 2014). RESULTS: The 573 patients (median age, 66 years; 68% women) had extended-spectrum ß-lactamase-producing Enterobacteriaceae (78%), carbapenem-resistant Enterobacteriaceae (7%), Pseudomonas aeruginosa (9%), Acinetobacter baumannii (3%), or other GNR (3%). Body sources were urine (68%), sputum/trachea/bronchoalveolar lavage (13%), wound/skin (6%), blood (6%), or other/unidentified (7%). Between October 1, 2013, and February 6, 2014, 252 (44%) of 573 had an ED or inpatient encounter after the GNRMDRO culture, 47 (19% of 252) at an institution different from where the culture was drawn. During the first 7 weeks of actual alerts (January 29, 2014, through March 19, 2014), alerts were generated regarding 67 patients (19 of 67 admitted elsewhere from where the culture was drawn). CONCLUSIONS: It proved challenging but ultimately feasible to create a regional microbiology-based alert system. Even in a few months, we observed substantial crossover between institutions. This system, if it contributes to timely isolation, may help reduce the spread of GNRMDROs.

Family-centered, evidence-based phototherapy delivery.

Jaundice develops in most newborn infants and is one of the most common reasons infants are rehospitalized after birth. American Academy of Pediatrics clinical practice guidelines strongly support the recommendation that clinicians promote and support breastfeeding. Recognizing that the disruptions associated with phototherapy interfere with breastfeeding, the challenge often faced by clinicians is how to provide effective phototherapy while supporting evidence-based practices, such as rooming-in, skin-to-skin contact, and breastfeeding. We report here on a case that reflects a common clinical scenario in newborn medicine in order to describe a technique for providing phototherapy while maintaining evidence-based practices. This approach will assist clinicians in providing best-practices and family-centered care.

Breastfeeding experiences among physicians.

BACKGROUND: During medical school and residency training, physicians are taught that breastfeeding is the preferred feeding for all infants, with rare exceptions. But evidence is accumulating that while physician mothers have a high rate of breastfeeding initiation, they face significant obstacles to sustained breastfeeding. METHODS: In our academic medical center, we conducted a brief survey of physicians who have young children, to explore their own experiences with breastfeeding. The survey explored the physician-as-parent's own experiences with breastfeeding -- prenatal intentions, postnatal difficulties, ability to meet goals, emotions if goals were not met, resources for support pre- and postnatally, and ideas about what would have helped her breastfeed longer. RESULTS: Two-thirds of the physicians who initiated breastfeeding had difficulties. Among those with difficulties, about three-fourths were able to resolve them. CONCLUSIONS: Even mothers who are medical professionals experience, and often cannot overcome, difficulties with breastfeeding. Women in medicine need enhanced breastfeeding support and services/resources. Advocacy is needed, in our work environments, for better breastfeeding support not only for our physician colleagues, but also for all lactating employees within our institutions.

American Academy of Pediatrics Section on Breastfeeding.

The Section on Breastfeeding is one of 50 sections of the American Academy of Pediatrics. In this Physicians' Focus, we describe the mission, vision, and activities of the Section on Breastfeeding and the benefits it provides to patients, health care professionals, and the general public. We also highlight opportunities to participate in the section.

The Academy of Breastfeeding Medicine.

The Academy of Breastfeeding Medicine is a worldwide organization of physicians dedicated to the promotion, protection, and support of breastfeeding and human lactation. In this Physician Focus, we describe the mission and activities of the Academy. We also highlight opportunities for physicians to participate.

Breastfeeding and the Bahá'í Faith.

The Bahá'í Sacred Writings reference breastfeeding literally and symbolically and provide guidance as to its practice. Breastfeeding is endorsed as the ideal form of infant nutrition. The importance of breastfeeding is underscored by the exemption of breastfeeding women from fasting, as well as by the identification of breastfeeding as being linked to the moral development of children. Several of the central principles of the Bahá'í Faith, such as the equality of women and men and the harmony of science and religion, may engender attitudes that support the practice of breastfeeding. The implications of the Bahá'í Writings with regard to breastfeeding are explored and summarized here.

Contemporary ethical issues in human milk-banking in the United States.

Donor human milk has been used in the United States for >90 years, but recent advances in human milk science and laboratory techniques have led to increasing use of this resource. Pediatricians began using donor human milk in the 1900s in response to anecdotal observation that premature infants had better health outcomes when receiving their own mothers' milk. Since then, a formalized human milk-banking system developed in the mid-1980s and distributed >1 million ounces of pasteurized donor human milk in 2008. Despite growth in the use of pasteurized donor human milk, there is little discussion in the medical literature regarding the ethical considerations of collection and use of this resource. Key ethical considerations include issues surrounding medical decision-making and informed consent, increasing the limited supply of human milk, how ethically to allocate this scarce resource, and concerns linked to the marketing of a human milk.

Maternal membranous glomerulonephritis and successful exclusive breastfeeding.

Despite the fact that exclusive breastfeeding is the gold standard for feeding babies through 6 months of age, there is a notable paucity of information regarding the effect of various chronic maternal illnesses on lactation. With increasingly effective obstetrical and subspecialty management of pregnancy in these women, a growing number of questions about breastfeeding in the context of chronic maternal illnesses will be asked. Here we describe a case of successful exclusive breastfeeding by a woman with long-standing membranous glomerulonephritis.