Differential disease phenotypes and progression in relapsing-remitting multiple sclerosis: comparative analyses of single Canadian and Saudi Arabian clinics.

OBJECTIVE: Relapsing-remitting multiple sclerosis (RR-MS) phenotypes differ widely although the variables contributing to this heterogeneity remain uncertain. To assess geographic and ethnic effects on RR-MS phenotypes, we investigated RR-MS patients in Canada and Saudi Arabia. METHODS: A retrospective analysis of patients followed in two MS Clinics was performed in Medina, Saudi Arabia and Edmonton, Canada. Demographic and clinical data were collected for each patient and analyzed using univariable and multivariable statistics. Univariable and multivariable linear regression were used to distinguish the significant clinical and demographic features and neurological systems associated with the change in expanded disability status scale (EDSS) between clinical assessments. RESULTS: Patients with treated RR-MS were recruited (n = 51, Saudi; n = 47, Canada) although the disease duration was longer in the Canadian cohort (5.6 ± 2.2 yr.) compared to the Saudi cohort (4.4 ± 1.4 yr.) (P < 0.05), annual relapse rate and EDSS change were higher in the Saudi cohort (P < 0.05). Infratentorial lesion-associated presentation differed (Canada, n = 23; Saudi, n = 13) among groups (P < 0.05). Spinal cord lesions on MRI were more frequently detected in Canadian (n = 23) compared to Saudi (n = 1) patients (P < 0.05). Patients within the Saudi cohort displayed a significantly greater change in Expanded Disability Status Scale (EDSS) between first and second assessments. CONCLUSIONS: Despite differences in geographic location, ethnicity, and predominance of infratentorial lesions in the Canadian group, the RR-MS phenotypes were similar although the Saudi cohort displayed a more severe disease course.

Disability progression in multiple sclerosis is associated with plasma neuroactive steroid profile.

BACKGROUND: Neuroactive steroids (NASs) exert multiple biological effects on development and inflammation. The effects of NASs on disease progression in multiple sclerosis (MS) are uncertain, prompting analyses of NAS profiles during the transition from clinically isolated syndrome (CIS) to relapsing-remitting (RR) MS. METHODS: Subjects with CIS or RRMS and healthy controls (HCs) were recruited; demographic and clinical data as well as disability scores measured by the Expanded Disability Status Scale (EDSS) were recorded. Matched plasma NAS and amino acid (AA) concentrations were measured. RESULTS: HC (n = 17), CIS (n = 31), and RRMS (n = 33) groups showed similar ages and sex distribution although disability scores were higher in the RRMS group. The conversion rate of CIS to RRMS group was 51.6% (n = 16) during a mean follow-up period of 1.85 years. The RRMS group showed significantly higher mean allopregnanolone, aspartate, and taurine concentrations with lower epiallopregnanolone concentrations than CIS patients, and higher L-serine-O-phosphate and lower alanine, arginine, and glutamine concentrations than the HC group. Among CIS and RRMS groups, multivariate hierarchical regressions revealed that higher concentrations of plasma tetrahydrodeoxycorticosterone (THDOC) may predict disability worsening. CONCLUSIONS: RRMS and CIS patients exhibited differing concentrations of both NASs and AAs in plasma while both THDOC and pregnanolone might serve as biomarkers of disability worsening.

First Measurement of the Total Neutron Cross Section on Argon between 100 and 800 MeV.

We report the first measurement of the neutron cross section on argon in the energy range of 100-800 MeV. The measurement was obtained with a 4.3-h exposure of the Mini-CAPTAIN detector to the WNR/LANSCE beam at LANL. The total cross section is measured from the attenuation coefficient of the neutron flux as it traverses the liquid argon volume. A set of 2631 candidate interactions is divided in bins of the neutron kinetic energy calculated from time-of-flight measurements. These interactions are reconstructed with custom-made algorithms specifically designed for the data in a time projection chamber the size of the Mini-CAPTAIN detector. The energy averaged cross section is 0.91±0.10(stat)±0.09(syst) b. A comparison of the measured cross section is made to the GEANT4 and FLUKA event generator packages, where the energy averaged cross sections in this range are 0.60 and 0.68 b, respectively.

Allopregnanolone reversion of estrogen and progesterone memory impairment: interplay with serotonin release.

Previously, we found out that in ovariectomized female rats, estrogen and progesterone produce a memory deficit which is reverted by the intrahippocampal administration of allopregnanolone. Here, we study the possible interplay between allopregnanolone and hippocampal serotonergic activity. Ovariectomized rats injected subcutaneously with estrogen and progesterone were subsequently injected in the dorsal hippocampus with vehicle, allopregnanolone alone or allopregnanolone shortly after 8OH-DPAT, a predominantly 5HT1A-7 receptor agonist. Then, the subjects were sequentially tested in: (1) an inhibitory avoidance task and (2) K+-evoked [3H]-serotonin ex vivo release through superfusion experiments. Allopregnanolone increased the K+-evoked [3H]-serotonin release compared to control. 8OH-DPAT infusions reversed the effects of allopregnanolone on memory and K+-evoked [3H]-serotonin release. These results suggest that allopregnanolone memory improvement could be mediated, at least in part, through modulation of the hippocampal serotonergic system reactivity.

RAS testing of liquid biopsy correlates with the outcome of metastatic colorectal cancer patients treated with first-line FOLFIRI plus cetuximab in the CAPRI-GOIM trial.

Background: Liquid biopsy is an alternative to tissue for RAS testing in metastatic colorectal carcinoma (mCRC) patients. Little information is available on the predictive role of liquid biopsy RAS testing in patients treated with first-line anti-EGFR monoclonal antibody-based therapy. Patients and methods: In the CAPRI-GOIM trial, 340 KRAS exon-2 wild-type mCRC patients received first-line cetuximab plus FOLFIRI. Tumor samples were retrospectively assessed by next generation sequencing (NGS). Baseline plasma samples were analyzed for KRAS and NRAS mutations using beads, emulsion, amplification, and magnetics digital PCR (BEAMing). Discordant cases were solved by droplet digital PCR (ddPCR) or deep-sequencing. Results: A subgroup of 92 patients with available both NGS data on tumor samples and baseline plasma samples were included in this study. Both NGS analysis of tumor tissue and plasma testing with BEAMing identified RAS mutations in 33/92 patients (35.9%). However, 10 cases were RAS tissue mutant and plasma wild-type, and additional 10 cases were tissue wild-type and plasma mutant, resulting in a concordance rate of 78.3%. Analysis of plasma samples with ddPCR detected RAS mutations in 2/10 tissue mutant, plasma wild-type patients. In contrast, in all tissue wild-type and plasma mutant cases, ddPCR or deep-sequencing analysis of tumor tissue confirmed the presence of RAS mutations at allelic frequencies ranging between 0.15% and 1.15%. The median progression-free survival of RAS mutant and wild-type patients according to tissue (7.9 versus 12.6 months; P = 0.004) and liquid biopsy testing (7.8 versus 13.8 moths; P < 0.001) were comparable. Similar findings were observed for the median overall survival of RAS mutant and wild-type patients based on tissue (22.1 versus 35.8 months; P = 0.016) and plasma (19.9 versus 35.8 months; P = 0.013) analysis. Conclusion: This study indicates that RAS testing of liquid biopsy results in a similar outcome when compared with tissue testing in mCRC patients receiving first-line anti-EGFR monoclonal antibodies.

The antepartum stillbirth syndrome: risk factors and pregnancy conditions identified from the INTERGROWTH-21st Project.

OBJECTIVES: To identify risk factors for antepartum stillbirth, including fetal growth restriction, among women with well-dated pregnancies and access to antenatal care. DESIGN: Population-based, prospective, observational study. SETTING: Eight international urban populations. POPULATION: Pregnant women and their babies enrolled in the Newborn Cross-Sectional Study of the INTERGROWTH-21st Project. METHODS: Cox proportional hazard models were used to compare risks among antepartum stillborn and liveborn babies. MAIN OUTCOME MEASURES: Antepartum stillbirth was defined as any fetal death after 16 weeks' gestation before the onset of labour. RESULTS: Of 60 121 babies, 553 were stillborn (9.2 per 1000 births), of which 445 were antepartum deaths (7.4 per 1000 births). After adjustment for site, risk factors were low socio-economic status, hazard ratio (HR): 1.6 (95% CI, 1.2-2.1); single marital status, HR 2.0 (95% CI, 1.4-2.8); age ≥40 years, HR 2.2 (95% CI, 1.4-3.7); essential hypertension, HR 4.0 (95% CI, 2.7-5.9); HIV/AIDS, HR 4.3 (95% CI, 2.0-9.1); pre-eclampsia, HR 1.6 (95% CI, 1.1-3.8); multiple pregnancy, HR 3.3 (95% CI, 2.0-5.6); and antepartum haemorrhage, HR 3.3 (95% CI, 2.5-4.5). Birth weight <3rd centile was associated with antepartum stillbirth [HR, 4.6 (95% CI, 3.4-6.2)]. The greatest risk was seen in babies not suspected to have been growth restricted antenatally, with an HR of 5.0 (95% CI, 3.6-7.0). The population-attributable risk of antepartum death associated with small-for-gestational-age neonates diagnosed at birth was 11%. CONCLUSIONS: Antepartum stillbirth is a complex syndrome associated with several risk factors. Although small babies are at higher risk, current growth restriction detection strategies only modestly reduced the rate of stillbirth. TWEETABLE ABSTRACT: International stillbirth study finds individual risks poor predictors of death but combinations promising.

Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): a randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX.

BACKGROUND: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. PATIENTS AND METHODS: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. RESULTS: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. CONCLUSIONS: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.

Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial.

BACKGROUND: Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information. PATIENTS AND METHODS: In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer. RESULTS: Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect. CONCLUSIONS: This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.

Implementation of the INTERGROWTH-21st Project in Italy.

Turin, Italy, was one of the two European sites for the INTERGROWTH-21(st) Project. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two obstetric hospitals that together account for 79% of the city's approximately 12,000 births per year. Women were recruited for the Fetal Growth Longitudinal Study (FGLS) from ten antenatal clinics serving the city's largest obstetric hospital, Azienda Ospedaliera OIRM-S. Anna. Special activities to encourage participation and raise awareness of the project in this population included obtaining an endorsement from the coordinator of the city's antenatal care service, and disseminating information about the project to women through posters and leaflets in antenatal clinics. One of the major challenges at this site was the low recruitment rate in the early phase of FGLS because of the high prevalence of smoking and of women >35 years old in the population. The addition of six extra recruiting clinics served to increase the pool of potentially eligible women who could be screened and led to a marked improvement in the recruitment rate.

Implementation of the INTERGROWTH-21st Project in the UK.

There are approximately 10,000 births per year in the county of Oxfordshire in the UK, which is one of the two European sites for the International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) Project. The samples for both components of the project--the Fetal Growth Longitudinal Study (FGLS) and Newborn Cross-Sectional Study (NCSS)--were drawn from the John Radcliffe Hospital, a major university hospital with a large regional role that covers more than 75% of deliveries in the county. Special activities to encourage participation in this population included the formation of a research coalition to streamline recruitment in the Maternity Unit and the distribution of study information leaflets to women using the hospital's antenatal care service. This was a demanding project and several challenges were overcome to reach recruitment targets and to maintain high standards of data quality. Amongst the major challenges for FGLS at this study site was the level of ineligibility because of maternal age, smoking and body mass index (BMI) ≥ 30. The major challenge for the NCSS field teams was to ensure that all anthropometric data were collected before the early discharge of uncomplicated deliveries, often within 6 hours of birth. It is evident from our experience in implementing this project that, when large-scale clinical studies are meticulously planned and avoid major disruption to routine clinical care, they are well received by hospital staff and can contribute to the improvement of the overall standard of clinical care.

Standardisation of neonatal clinical practice.

The International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) is a large-scale, population-based, multicentre project involving health institutions from eight geographically diverse countries, which aims to assess fetal, newborn and preterm growth under optimal conditions. Given the multicentre nature of the project and the expected number of preterm births, it is vital that all centres follow the same standardised clinical care protocols to assess and manage preterm infants, so as to ensure maximum validity of the resulting standards as indicators of growth and nutrition with minimal confounding. Moreover, it is well known that evidence-based clinical practice guidelines can reduce the delivery of inappropriate care and support the introduction of new knowledge into clinical practice. The INTERGROWTH-21(st) Neonatal Group produced an operations manual, which reflects the consensus reached by members of the group regarding standardised definitions of neonatal morbidities and the minimum standards of care to be provided by all centres taking part in the project. The operational definitions and summary management protocols were developed by consensus through a Delphi process based on systematic reviews of relevant guidelines and management protocols by authoritative bodies. This paper describes the process of developing the Basic Neonatal Care Manual, as well as the morbidity definitions and standardised neonatal care protocols applied across all the INTERGROWTH-21(st) participating centres. Finally, thoughts about implementation strategies are presented.

Detection of bovine alpha-S1-casein in term and preterm human colostrum with proteomic techniques.

Due to increased social awareness of allergens and population hyper-sensitization, the reported incidence of allergic reactions to food allergens has increased over the past two decades. Cow's milk proteins (CMPs) are among the most common food allergens. The aim of this study was to use proteomics techniques to investigate cow's milk allergens in both full-term human colostrum and in preterm newborns mothers where both groups showed no prior allergen detection -- in order to understand whether cows milk allergens could be a cause of sensitization established through lactation. The most relevant finding was the detection of the intact bovine alpha-S1-casein in both term and preterm colostrum. Using techniques detailed in this paper and which allowed for direct protein identification, beta-lactoglobulin was not detected in any of the colostrum samples. According to our results, bovine alpha 1 casein is considered a major cow's milk allergen, is readily secreted in human milk, and so could be considered a possible cause of sensitization in exclusively breastfed infants.

Hormone and cytokine circadian alteration in non-small cell lung cancer patients.

Alterations in hormone secretion and cytokine levels have been evidenced in many neoplastic diseases. In this study we have evaluated the circadian profile of growth hormone (GH), insulin-like growth factor-1 (IGF-1), interleukin-2 (IL2), melatonin (MEL) and cortisol (COR) serum levels in non-small cell lung cancer patients. Blood was sampled every 4 h for 24 h in 11 healthy (H) men (ages 35-53 years) and 9 men with stage 2, 3 or 4 non-small cell lung cancer (C) (ages 43-63 years). Serum GH, total IGF1, IL2, MEL and COR were measured and examined for group differences, trends, and rhythm characteristics. 24-h means were significantly higher in C234 vs H for GH, GH/IGF1, IL2 and COR, and lower for IGF1, but IL2 and COR were not different for C23 vs H. A linear regression across 4 groups (H, C2, C3, C4) found a positive trend for COR, GH, GH/IGF1 and IL2, and a negative trend for IGF1. A linear regression run between the 24-h mean levels of GH, IGF1, COR, MEL and IL2 in healthy subjects evidenced a statistically significant positive trend between MEL and GH (R = 0.281, p = 0.022) and in cancer patients showed a statistically significant negative trend between GH and IGF1 (R = 0.332, p = 0.01), COR and IGF1 (R=0.430, p=0.001), and a statistically significant positive trend between the 24-h mean of COR and GH (R = 0.304, p = 0.02). Rhythms in MEL and COR (peaks near 01:00h and 08:00h, respectively) indicated identical synchronization to the light-dark cycle for both groups. A circadian rhythm was detected in GH and GH/IGF1 for C23 and H, with IGF1 and IL2 non-rhythmic in any group. In conclusion, an increasing trend and progressive loss of circadian rhythmicity in GH and GH/IGF1, an increasing trend in cortisol and IL2, and a decreasing trend in IGF1 in C, reflect a complex chain of events that could be involved in progression of neoplastic disease. A therapeutic strategy needs to take into account circadian patterns and complex interactions of the multiple functions that characterize the hormone and cytokine levels in the frame cancer progression.

Update of adjustable fortification regimen for preterm infants: a new protocol.

Preterm infants fed fortified human milk in standard fashion receive less protein than they need due to customary assumptions. Protein is limiting for growth and neurocognitive development,and shortfalls of protein are not acceptable. Adjustable fortification regimen has been proven as an effective way to provide adequate protein intakes and appropriate growth in this group of infants. Italian Association of Human Milk Banks (AIBLUD) has promoted and implemented this Adjustable fortification regimen in neonatal intensive care units (NICUs) with success. This paper presents an update of Adjustable fortification regimen; a new protocol already utilized in several italian NICUs.

Biological, nutritional and clinical aspects of feeding preterm infants with human milk.

Benefits of breastfeeding are widely recognized, during the last decades human milk has been identified as the normative standard for infant feeding and nutrition. Recent evidence focused on specific bioactive and immunomodulatory factors, such as oligosaccharides, lactose, glycosaminoglycans of human milk and the variability of their concentrations during lactation in both term and preterm milk. Human milk should be fortified with proteins, minerals and vitamins to ensure optimal nutrient intake for preterm VLBWI infants. Best fortification strategies as well as the optimal composition of fortifiers are still object of research. Short and long-term clinical, metabolic, immunologic and neurodevelopmental advantages of breastfeeding ndividualizes fortification - particulary adjustable fortification- has proven to be effective when compared to formula are well documented. Moreover several non-experimental studies observed that clinical feeding tolerance is improved and the attainment of full enteral feeding is quicker by a diet of human milk. In addition, benefits of breastfeeding on psychological and relational aspects have to be considered. Mother’s own milk remains the first choice for all neonates, when it is not available or not sufficient despite significant lactation support, donor milk represents the second best alternative and although some nutritional elements are inactivated by the pasteurization process, it still has documented advantages compared to formula.

Donor human milk versus mother's own milk in preterm VLBWIs: a case control study.

As for term infants, over the past decades there has been increasing evidence of the benefits of human milk in the feeding of Very Low Birth Weight Infants (VLBWI), influencing not only short-term health outcomes but also long-term neurodevelopmental, metabolic outcomes, and growth. Mother's own milk is the first choice for all neonates including preterm infants, when it is unavailable or in short supply, pasteurized donor breast milk offers a safe alternative and is considered the next best choice. The main aim of this case-control retrospective analysis was to evaluate short term advantages of mother's own milk as a sole diet compared to donor milk as a sole diet, in terms of growth, antiinfectious properties, feeding tolerance, NEC and ROP prevention in a population of VLBWI born in a tertiary center. We did not find significant differences in clinical outcome from mother's own milk compared with pasteurized donor milk. Only a slight and statistically not significant difference in growth could be observed, in favour of maternal milk. We conclude that the maximum effort should always be put in supporting and promoting breastfeeding and donor milk used not only as an alternative to mother's milk but also as a breastfeeding promotion and support strategy.

Communication in NICUs.

In a Neonatal Intensive Care Unit (NICU) counseling should be a shared culture for all the care givers: it should be developed by all the professionals, to face up to parents' needs of information, explanations, facility of decisions, finding of resources, agreement, help, reassurance, attention. The first essential aspect is the training in counseling skills, by periodic courses for all professionals of the department (physicians, nurses, and physiotherapists). In our department, a professional counselor is present, assisting the medical staff in direct counseling. The counselor's intervention allows a better parent orientation in the situation. A more effective sharing of these rules also facilitates the communication among parents and medical staff. Periodic meetings are established among the medical staff, in which the professional counselor discusses difficult situations to share possible communicative strategies. We wanted to have not only a common communicative style, but also common subjects, independent from the characteristics of each of us. Individuals are often faced with different situations. For every setting that we more frequently face in communication (for example the first interview with a parent of a very preterm infant) we have built an 'algorithm' that follows a pattern: (1) information always given; (2) frequent questions from parents; and (3) frequent difficulties in the communication. Counselling is also a tool to face some critical issue, such as the decision to open the department to parents 24 h on 24, or the promotion of mother's milk use in Very Low Birth Weight Infants (VLBWI).

Auxological evaluation of newborns.

Auxological evaluation of the newborn should be based on accurate anthropometry at birth and a reliable estimate of gestational age (GA). However, a comprehensive evaluation of the neonate should consider not only anthropometric traits at birth, but also fetal ultrasound biometry and Doppler velocimetry. Many charts have been proposed, but they are hardly comparable with each other, due to numerous methodological problems. The Italian Societies of Neonatology, of Pediatric Endocrinology and Diabetology and the Italian Society of Medical Statistics and Clinical Epidemiology promoted a multicenter survey with the aim to produce an Italian neonatal anthropometric reference (Italian Neonatal Study [INeS] charts) fulfilling the set of the criteria that a reliable neonatal chart should possess. In order to construct an international standard, an international project (INTERGROWTH-21st) has started a study aiming to create a prescriptive standard. Until an international standard is developed, the use of national updated reference charts is recommended.

Medication and breastfeeding.

It is well accepted that the best feeding method for infants is breastfeeding, due to its numerous biological and clinical effects on child and maternal health. The use of medication by the nursing mother and the physician's advice to stop nursing are the most common reasons for the cessation of breastfeeding. The physician plays an extremely delicate role and should be able to assess risks and benefits for both mother and child. The main factors that must be taken into account include pharmacokinetics, the duration of maternal therapy, the age of the infant and the general health of the infant. All physicians should have access to reliable and updated information on medication safety during breastfeeding (reference books, online medical literature). Few drugs have been demonstrated to be absolutely contraindicated during breastfeeding. Nevertheless clear, safe and reliable information is still lacking for most drugs and it would be desirable to improve the knowledge about mechanisms and consequences of infant exposure to drug present in milk.