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Mass spectrometry imaging (MSI) vows to enable simultaneous spatially-resolved investigation of hundreds of metabolites in tissue sections, but it still relies on poorly defined ion images for data interpretation. Here, we outline moleculaR, a computational framework in R, that introduces systematic probabilistic mapping and point-for-point statistical testing of metabolites in tissue to MSI. Beyond statistics, moleculaR allows for arithmetic operations within the same MS image and thereby, for instance, analysis and visualization of complex scores like the adenylate energy charge ([ATP]+0.5*[ADP])/ ([ATP]+[ADP]+[AMP]). moleculaR also enables collective molecular projections, for example of all potassium versus all sodium adducts for spatially-resolved investigation of ion milieus, or for surveys of lipid pathways or other user-defined biomolecular ensembles.

MRI enables detailed in vivo depiction of multiple sclerosis (MS) pathology. Localized areas of MS damage, commonly referred to as lesions, or plaques, have been a focus of clinical and research MRI studies for over four decades. A nonplaque MRI abnormality which is present in at least 25% of MS patients but has received far less attention is diffusely abnormal white matter (DAWM). DAWM has poorly defined boundaries and a signal intensity that is between normal-appearing white matter and classic lesions on proton density and T2 -weighted images. All clinical phenotypes of MS demonstrate DAWM, including clinically isolated syndrome, where DAWM is associated with higher lesion volume, reduced brain volume, and earlier conversion to MS. Advanced MRI metric abnormalities in DAWM tend to be greater than those in NAWM, but not as severe as focal lesions, with myelin, axons, and water-related changes commonly reported. Histological studies demonstrate a primary lipid abnormality in DAWM, with some axonal damage and lesser involvement of myelin proteins. This review provides an overview of DAWM identification, summarizes in vivo and postmortem observations, and comments on potential pathophysiological mechanisms, which may underlie DAWM in MS. Given the prevalence and potential clinical impact of DAWM, the number of imaging studies focusing on DAWM is insufficient. Characterization of DAWM significance and microstructure would benefit from larger longitudinal and additional quantitative imaging efforts. Revisiting data from previous studies that included proton density and T2 imaging would enable retrospective DAWM identification and analysis.

A Kriging surrogate model and a genetic algorithm are used to optimise the geometry of a ship wind assisted propulsion system (SWAP). The SWAP device is an actively controlled aerofoil mounted vertically on the deck of a ship in order to produce a forward propulsive force from the wind. The SWAP concept uses a circulation control system which employs both blowing from the leading edge and suction from the trailing edge. The aerodynamic parameters of the sail are found using a computational fluid dynamics (CFD) model validated against experimental data for a similar system, the coflow jet aerofoil. Further application of Kriging models is used to predict maximum lift coefficients for multiple freestream velocities, ensuring that the optimised device offers robust performance and low sensitivity to expected variations in wind speed. The maximum achievable lift coefficient was found to be 13.17% greater than for the baseline aerofoil over a range of wind speeds from 8–12 m/s.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by impaired and disordered language, decreased social interactions, stereotyped and repetitive behaviors, and impaired fine and gross motor skills. It has been well established that cerebellar abnormalities are one of the most common structural changes seen in the brains of people diagnosed with autism. Common cerebellar pathology observed in autistic individuals includes variable loss of cerebellar Purkinje cells (PCs) and increased numbers of reactive neuroglia in the cerebellum and cortical brain regions. The Lc/+ mutant mouse loses 100 % of cerebellar PCs during the first few weeks of life and provided a valuable model to study the effects of developmental PC loss on underlying structural and functional changes in cerebellar neural circuits. Lurcher (Lc) chimeric mice were also generated to explore the link between variable cerebellar pathology and subsequent changes in the structure and function of cerebellar neurons and neuroglia. Chimeras with the most severe cerebellar pathology (as quantified by cerebellar PC counts) had the largest changes in cFos expression (an indirect reporter of neural activity) in cerebellar granule cells (GCs) and cerebellar nucleus (CN) neurons. In addition, Lc chimeras with the fewest PCs also had numerous reactive microglia and Bergmann glia located in the cerebellar cortex. Structural and functional abnormalities observed in the cerebella of Lc chimeras appeared to be along a continuum, with the degree of pathology related to the number of PCs in individual chimeras.

A number of experimental methods have been used to elicit metalinguistic judgments about syllable division, a good deal of which deals with the syllabification of English words. However the syllabification literature is largely silent on the issue of intratask reliability, that is, whether the tasks all yield the same kinds of intuitions from speakers. Cote and Kharlamov (2011) gathered data from Russian speakers who syllabified nonce words in four different experimental conditions. When the results were compared they observed widely different results in many instances. This suggests that syllabification preferences are highly influenced by the particular task used to elicit them, which in turn casts doubt on the intratask reliability of syllabification studies. In order to test the reliability of different experimental methods in English, syllable divisions of 120 English words were elicited with eight different experimental tasks. In a mixed-effects logistic regression, no main effect of experimental method was found, although the method showed some interaction with stress and the legality of the consonant cluster word-initially and word-finally. Reasons why these results differ from those of Cote and Kharlamov are discussed, some of which are due to methodological flaws in their analysis.

Despite relatively high medical expenditures, the United States performs poorly on population health indicators relative to many other countries. A key step in addressing this situation involves determining impactful and cost-effective interventions for at-risk populations. This requires an understanding of medical, social, behavioral health and safety domains of risk. Of immediate interest are those risks that are modifiable at the individual and family levels and could be reduced through intervention and broader care coordination efforts. Unfortunately, a comprehensive list of such risks does not exist in the published literature. Using multiple interrelated methods, including clinical, social, and care coordination experience, expert elaboration and validation, and reviews of existing assessments and literature, we present what we believe to be the most comprehensive listing of individually modifiable risk factors (IMRFs), relevant to care coordination, available for individuals aged 0–12 months. The list addresses IMRFs within four broad domains of risk (medical, social, behavioral health, and safety). Comprehensive risk registries such as the one presented here can enhance our collective efforts to identify and mitigate risks for specific populations. Such registries can also support research to build understandings of the impact of risks, individually and in interconnected signature combinations. The risk registry presented here and the enhanced understandings flowing from it may yield useful insights for clinicians, social service providers and researchers seeking a whole person approach to care, as well as for payers and policymakers seeking to enable health policy and payment reforms to improve population health.

All universities are seeking to develop their students’ skills. Typically, they deploy either or both an independent ‘skills’ offering, separate from disciplinary learning (‘bolt-on’); and/or individual academic staff embedding skills assessment in some modules (‘built-in’). What are the drawbacks of ‘bolt-on’ and ‘built-in’? To what extent does a partnership model, involving an integrated and longitudinal skills curriculum, resolve those drawbacks? Under what circumstances is this possible? What are the main barriers? We present a case study of a major curriculum development in the School of Law at the University of Sheffield to argue that the benefits of partnership probably outweigh either ‘bolt-on’ or ‘built-in’. However, some of the enablers and inhibitors associated with contemporary higher education (HE) may suggest that ‘built-in’ is more viable. This is not primarily because of the difficulties of engaging academic disciplinary specialists; rather it is better explained by structural and institutional rigidities. We therefore recommend courage to take a long view, to aim high, and to celebrate small successes.

The austerity agenda tries to establish a “new normal” in which working-class people must settle for less in all areas of life. This paper draws on focus group interviews with university students to investigate which elements of the austerity agenda seem to assimilate into common sense, which meet resistance, and why. I interpret contradictions within the interviews as expressions of “disaffected consent,” and speculate on the potential outcomes of this apparent shift in hegemony.

This article analyses representations of bourgeois femininity in early twentieth century newspaper coverage of the ceremonial Opening of the Legislature in Ontario, Canada's largest and most populous province. Building on theories that shed light upon the complex processes of material and symbolic reproduction required to reproduce “the idea of the reality of the state,” I argue that mass mediated representations of women's bodies and fashions during this key civic ritual contributed to state formation. The article demonstrates the ways in which newspaper coverage of a particular type of gendered performance reflected and reinforced an imperialist and patriarchal provincial state-building project.

Background: IPF is a progressive fibrotic lung disease with significant unmet medical needs. Mast cell density is increased in IPF lung tissue, however the relevance to disease pathophysiology & progression remains poorly understood. Aims: To combine vasculature, airways & mast cells identified on immunohistochemistry with corresponding microCT of IPF distal lung tissue, segmenting them for individual visualisation. To investigate relationships between mast cells and structural elements of lung. Method: A formalin fixed, paraffin embedded IPF lung biopsy was scanned using microCT (resolution:8μm, X-ray tube potential peak:55kVp). It was then sectioned. Slides were stained with Russell Movat9s Pentachrome or immunostained against mast cell tryptase. Blood vessels and airways were semi-automatically segmented & mast cells were manually segmented using 3D visualisation software with reference to immunostaining. Results: The positions of 21767 mast cells were integrated with segmentation of airways, pleural surface & vasculature on the microCT dataset allowing visualisation & analysis of the relationship between them. Using 3D distance maps, distances between large numbers of mast cells & other structures can be measured & analyzed. Conclusion: Mapping mast cell locations in microCT of fibrotic lung is feasible, with the potential to provide new understanding of the 3D distribution and interrelationships of mast cells, blood vessels & airways in IPF. The approach used here will be applicable to other cell types & tissue structures. For small, numerous features such as mast cells, automatic segmentation would further aid analysis & should be investigated.

This article focuses on the Canadian Parliamentary Coalition to Combat Antisemitism (CPCCA): a self-appointed group of parliamentarians dedicated to extinguishing what it calls “the new antisemitism.” Working from a Gramscian perspective, we identify key discursive strategies in coalition publications and testimony and argue that despite the CPCCA’s pretence to being a forum for liberal-pluralist debate, in fact it is engaged in an ideological reframing of human rights designed to restrict political debate. It does so, paradoxically, by drawing on the language of left-liberalism, which contrasts with recent ideological interventions aiming to secure the priorities of the neo-liberal state. RESUME Cet article porte sur la Coalition parlementaire canadienne de lutte contre l’antisemitisme, un groupe de parlementaires auto-designes qui se consacrent a supprimer ce qu’ils appellent le « nouvel antisemitisme ». Dans cet article, nous avons recours a une perspective gramscienne pour identifier des strategies discursives cles dans les publications et les temoignages de la Coalition et nous soutenons que, bien qu’elle se veuille un forum pour des debats liberaux-pluralistes, la Coalition s’engage au fait dans un recadrage ideologique des droits humains ayant pour consequence la restriction de debats politiques. Elle le fait, paradoxalement, en empruntant le langage du liberalisme de gauche, qui offre un contraste par rapport a des interventions ideologiques recentes dont le but est d’assurer les priorites de l’etat neoliberal.

This article analyzes the postwar emergence of liberal-pluralist symbolism in newspaper coverage of the ceremonial Opening of the Legislature in Ontario. It argues that in the era of Social Celebration (1900 to 1940s), Ontario newspapers framed the legislative opening as a spectacular festival of provincial unity through colonial identity; whereas, by contrast, in the era of Social Deliberation (1950s to the present), the same civic ritual is depicted as a province-wide policy debate among competing politicians, interest groups, and citizens. Viewing Social Deliberation news coverage as a specific moment that contributes to the reproduction of liberal-pluralist democracy as a whole, the author concludes that, like liberal-pluralist politics in general, liberal-pluralist symbolism encompasses contradictions, normalizes systemic inequalities, and restricts the range of legitimate forms of political action. RESUME Cet article analyse l’emergence pendant l’apres guerre d’un symbolisme liberalpluraliste dans la couverture par les journaux de l’ouverture ceremonielle de l’Assemblee legislative en Ontario. Il soutient que, dans l’ere de la Celebration sociale (de 1900 jusqu’aux annees 40), les journaux ontariens ont presente l’ouverture de l’Assemblee comme etant un festival spectaculaire qui pronait l’unite de la province en soulignant l’identite coloniale. Par contraste, dans l’ere de la Deliberation sociale (des annees 50 jusqu’a aujourd’hui), le meme rituel civique s’est vu depeindre comme un debat provincial entre politiciens, groupes d’interets et citoyens rivaux. L’auteur interprete la couverture mediatique de la Deliberation sociale comme refletant un moment particulier qui a contribue a la reproduction integrale de la democratie liberale-pluraliste. Il conclut a cet egard que le symbolisme liberal-pluraliste, comme la politique liberale-pluraliste en general, englobe des contradictions, normalise des inegalites systemiques et restreint l’eventail de formes legitimes d’action politique.

Answer When the mother is an ultra-rapid metabolizer of cytochrome 2D6, she produces much more morphine than most people. Considering limiting codeine administration to no more than a few days and staying aware of potential opioid toxicities are two management points discussed in this article. Codeine is commonly used in the postpartum period for pain associated with episiotomy and caesarean section. As most new mothers initiate breast-feeding, the safety of codeine itself, and its pharmacologically active metabolite, morphine, are of primary concern in breast-fed infants. The American Academy of Pediatrics and major authoritative texts list codeine as compatible with breast-feeding, despite the lack of sufficient published data to support this recommendation. To illustrate the need for further assessment of codeine/morphine transfer into breast milk, we use the case of a full-term, breast-fed infant who died with a picture consistent with morphine overdose. 3 The pharmacogenetic assessment of maternal drug biotransformation was consistent with an enhanced formation of the pharmacologically active opioid, morphine.

Sympathetic ophthalmia is a rare and potentially visually devastating bilateral panuveitis, typically following non-surgical penetrating injury to one eye. Three patients are presented where sympathetic ophthalmia developed after repeated vitreoretinal surgery. Prompt and effective management with systemic immunosuppressive agents permitted control of their disease and retention of good visual acuity in their remaining eye. Vitreoretinal surgery is an important risk factor in sympathetic ophthalmia. Informed consent for vitreoretinal surgery (especially in the re-operation setting) should now include the risk of sympathetic ophthalmia (approximately 1 in 800). Diverse clinical presentations are possible in sympathetic ophthalmia and any bilateral uveitis following vitreoretinal surgery should alert the surgeon to the possibility of sympathetic ophthalmia. Modern immunosuppressive therapy with systemic steroids and steroid-sparing agents such as cyclosporin A and azathioprine have improved the prognosis. This is particularly so in cases where early diagnosis is made and prompt and suitable immunotherapy is commenced.

In Zambia, free health care is not sustainable, so the community must participate actively in the operation of health services. A well-operated district hospital and health centers within the community must cooperate. A successful cost-effective health system depends on effective leadership of the health care team; use of appropriate technology; delegation of much responsibility to paramedical, nursing, and ancillary staff; and use of the district hospital and its district for postgraduate teaching programs for district health specialists. The health care team consists of medical officers, who are generalists; nurses and midwives; administrators; and an engineer to maintain equipment. Examples of appropriate or intermediate technology include Perkin's traction for most fractures, dynamic skin traction for fracture/dislocations of the elbow in adults or olecranon traction, split skin grafting, musculo-cutaneous or axial flaps, suturing of tendons, spinal anesthesia, draw-over anesthesia, and IV ketamine. In some African countries, including Zambia, medical assistants are trained to deal with some types of general anesthesia. Nurses can be trained to become children's nurses, organizing preventive clinics and being responsible for diagnosis and treatment of all conditions except the most serious. Both medical assistants and nurses can become ophthalmic assistants. Dental therapists can handle many activities usually handled by dentists (e.g., fillings and extractions). Operating nurses can be trained to perform some surgery. In many countries, the training ability of the good district hospital is not used to its potential. The district hospital can form important links by teaching medical students at university centers and the districts. Improvement of health problems in developing countries depends on persons willing to work with the poor and to sacrifice material gain.

One hundred and one of 255 recipients of a plasma-derived hepatitis B vaccine were evaluated in 1990, 9 years after the first vaccine dose in a study in Zambia to evaluate the efficacy of one, two, or three doses. In 1983, 2 years after the first vaccine dose, antibody to the hepatitis B surface antigen (anti-HBs) had been detectable in 90 of these 101 participants (89%). In 1990, anti-HBs was still detectable in 72 of 101 (71%), and was present at a protective level ( ≥ 10 mlU ml) in 68 of 101 (67%). Although the original vaccine study elicited a protective level of antibody in a greater percentage of children and adolescents than in adults, there were no significant differences among the three groups at 9 years. (In 1990, anti-HBs was still detectable in 52 of 70 [74%] who had had no serologic markers of the hepatitis B virus in 1981, and a protective level was detected in 47 of 70 [67%].) A protective level of anti-HBs was detected in 1990 in 26 of 36 (72%) recipients of three doses and in 23 of 31 (74%) recipients of two doses; the slightly lower prevalence among recipients of one dose (19 of 34 [56%]) was not statistically significant. However, between the years 1983–1990, hepatitis B virus infections had occurred in one of 36 (3%) of those who had been vaccinated with three doses, one of 31 (3%) vaccinated with two doses, and eight of 34 (24%) of those vaccinated with one dose (P < .02 for either two or three doses compared with one dose). These data support the long-term immunogenicity and protective efficacy of a two- or three-dose regimen of the hepatitis B vaccine in a rural African setting. © 1993 Wiley-Liss, Inc.

A seven-month-old infant was admitted to hospital with vomiting and abdominal distention. His past history revealed that he was born at term. There were difficulties establishing oral feedings. The infant was managed with total parenteral nutrition, and discharged home at nine days of age. At five months of age, the baby was seen with a history of intermittent vomiting of bile-stained fluid during the previous two to three weeks. An abdominal x-ray showed distended loops of bowel. A barium enema was performed to rule out intussusception. This investigation showed the cecum to be in a “high lying medial position”. Two days later, an upper gastrointestinal series showed a “spiral appearance to the proximal jejunum descending in the midline”. The radiologist expressed concern: “There was a malrotation at the mid gut. The radiological appearance suggested nonfixation of the mesentery and that the patient may be predisposed at some stage to a mid gut volvulus”. The infant was in hospital for four days and discharged. Over the next 44 days, the baby had repeated visits to doctors’ offices and to the emergency department with a complaint of recurrent vomiting of bile-stained fluid and, at times, constipation. During that time he was seen in consultation by three paediatricians, a general surgeon, a paediatric surgeon and three different family physicians. A repeat barium enema was performed in a facility outside the hospital and showed the same findings. On the final admission, the infant was admitted because of vomiting, constipation and lethargy. Over the next 8 h, his heart rate increased from 136 to 156 to 180 beats/min and, finally, to 200 beats/min 8 h after admission. Blood pressures were never recorded. The abdomen became increasingly distended, and the child was brought to the x-ray department for another barium enema to rule out intussusception. During the procedure, the baby regurgitated, aspirated and died. At autopsy, the infant was found to have a malrotation of the gut, with a volvulus and infarction of the entire small bowel. At the subsequent inquest, the jury expressed concern that each of the physicians who saw this child did not appear to have reviewed the entire record to get a total picture of the infant’s illness. Concern was also expressed that when x-rays are performed in two different settings, they should be compared. Expert testimony suggested that intermittent vomiting of bile in the neonatal period should be considered malrotation with volvulus until proven otherwise. This baby clearly had intermittent volvulus from which he recovered each time, except for the final admission. The baby’s vital signs clearly indicated an infant who was going into shock. Despite this, intravenous access was not established, and appropriate fluid resuscitation was not implemented. The jury recommended that physicians gain expertise in the insertion of intraosseous needles and maintain Pediatric Advanced Life Support certification. The failure to measure blood pressure, the failure to recognize increasing tachycardia and the failure to initiate appropriate fluid replacement are frequent themes observed by Ontario’s Paediatric Death Review Committee. The committee encourages physicians who assess children who have seen many other physicians to review comprehensively the children’s entire history – all assessments, consultations, and laboratory and x-ray reports.

To identify factors contributing to methadone-related deaths in Ontario in 2004, demographic factors, methadone blood levels, evidence of concurrent drug use, the source of methadone (prescribed or illicit), and its contribution in exacerbating preexistent disease were studied to identify users at risk for methadone toxicity and death. This retrospective study reviewed postmortem data, autopsy reports, police reports, hospital data, and postmortem toxicological analyses available in the Ontario Chief Coroner's Information System. There were 54 cases with methadone detected in postmortem blood samples. Of total, 9 cases were not included in the study because of incomplete documentation. About 11 deaths were due to methadone toxicity alone; 25 deaths were due to combined methadone and other drug toxicity (notably cocaine and alcohol); 7 deaths were due to the exacerbation of a preexisting disease by methadone; 1 death was due to disease alone, and 1 death was due to trauma sustained in a motor vehicle collision. A significant number of methadone-related deaths were due to illicit methadone ingestion, which exceeded the opioid tolerance level. The source of methadone in these cases was unknown. Drug addicts, unaware of the hazard of consuming other illicit or prescription drugs concurrently, are at risk. This study demonstrated that methadone toxicity is enhanced by underlying disease, especially in individuals with underlying cardiac and pulmonary pathology.

A field trial of a plasma-derived hepatitis B vaccine in five rural villages in Zambia was analyzed to determine if adults in a rural African setting respond to this vaccine as well as adults in Western countries and to determine the immunogenicity of fewer than the recommended three doses; 255 residents, including 171 who were susceptible to hepatitis B, were vaccinated. Among those who received three vaccine doses, protective levels of antibody to hepatitis B surface antigen (anti-HBs) developed in 67% of adults (ages 21 to 70 years), 87% of adolescents (ages 12 to 19 years), and 100% of children (ages 0 to 11 years). The 67% of vaccinated adults who developed anti-HBs at the protective level was lower than the 96% reported among adults receiving the same vaccine at the same dose and dosage schedule in studies in Western countries. No difference was seen in the response of those receiving two doses compared with those receiving three doses among adults and adolescents, suggesting that a two-dose regimen may be acceptable in these age groups in developing countries to reduce costs and improve compliance. Use of hepatitis B vaccine in a region where prevaccination hepatitis B serologic screening was not available did not appear to increase the number of severity of adverse reactions.

The author responds, The purpose of our case report was to alert readers to the death of a child related to complications of a circumcision and to stimulate discussion that morbidity associated with this procedure may be higher than we think. The comment that “local anaesthetic was not used” was to rule this out as a contributing factor to the septicemia and cellulitis that led to this child’s death. We agree with Dr McMillan’s comments regarding pain relief for this procedure.

An 18-month-old child presented at a community hospital emergency room at 18:00 with a history of “vomiting and diarrhea all day”. No attempt was made to quantify or semiquantify the number of stools or vomiting episodes, and there is no record regarding the passage of urine. The child’s weight was 9 kg and body temperature 37.7°C, but the pulse, blood pressure and respiratory rate were not recorded. The child was given 12.5 mg of Gravol (CarterHorner, Canada) intramuscularly and sent home on oral Gravol (2.5 cc every 4 h for two doses). At the inquest, the mother recalled that she was told only “to give clear fluids”. The physician involved stated that he “gave an order for fluids to be given over the next day”. He was unable to recall which fluids and had made no notation in this regard. The child returned to the emergency room 25 h after discharge. The triage nurse noted that his “lips were blue and eyes sunken”. His temperature was 38.4°C and, once again, no other vital signs were recorded. A physician assessed the child 30 min later and, confirming the nurses observation, ordered an immediate complete blood cell count and electrolytes to be drawn. While this was being attempted 50 min after presentation, the child arrested. Attempts at starting an intravenous infusion were unsuccessful, and an intraosseous line was not established until 10 min after the child arrested. An autopsy determined the cause of death to be dehydration secondary to gastroenteritis. The Pediatric Death Review Committee of Ontario made the following recommendations. A full set of vital signs is crucial in the assessment of a child who is potentially dehydrated. If vital signs have not been recorded by the nursing staff, the physician has a responsibility to ensure that vital signs are taken and recorded. Oral rehydration therapy (ORT) was probably the appropriate response during the child’s first presentation at the hospital. Printed handouts for parents about oral rehydration are far more effective than verbal advice. Furthermore, it is easier to note that “ORT handout given” than it is to note the verbal advice that may have been provided. The child was clearly in shock during the second presentation, at which point immediate volume expansion with normal saline or Ringer lactate should have taken priority over laboratory investigations. Oxygen administration would have been valuable. These may appear to be simple, basic and unnecessary recommendations; however, Ontario’s Pediatric Death Review Committee continues to review the deaths of children from dehydration in urban Canada in the 21st century. Paediatricians have an obligation to educate their family physician and emergency medicine colleagues in the ABC’s of the management of gastroenteritis.

This study aimed to assess the impact of adopting the WHO case management protocol for childhood pneumonia in a district hospital in rural Zambia. The subjects were children under 5 years of age with a diagnosis of pneumonia, admitted in the 9-month period following introduction of the WHO protocol. Management and outcome were compared with a historical control group admitted during the same period in the previous year. There were 158 children in the intervention group and 135 controls with similar age and sex distribution. Both groups were malnourished (mean weight-for-age Z score in subjects = -1.91, in controls = -1.83). There was no significant difference in the numbers receiving parenteral antibiotics or supplementary fluids in each group. However, children in the intervention group were significantly more likely to receive oxygen (odds ratio 4.7, 95% confidence interval 2.8-8.1, p0.0001). Mortality was significantly greater in the control group (case fatality rate, 25%) compared with the intervention group (case fatality rate, 15%; chi 2 = 4.6; p = 0.032). The introduction of the WHO protocol for management of childhood pneumonia and training of staff in its use was accompanied by a fall in mortality from this condition in a rural hospital. The improved survival rate may be related to the more frequent use of oxygen.

To the Editor.— It has been suggested that the worldwide epidemics of human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type I (HTLV-I) could have originated in Africa 1,2 and that HTLV-I was carried to the endemic region in southern Japan from Africa in the 16th century. 2 However, few serological studies of stored serum samples have been conducted to evaluate these suggestions. We conducted a study to determine whether antibodies to HIV-1 (anti-HIV-1) or HTLV-I (anti-HTLV-I) were present in Zambia before (in 1976, 1977, 1978, and 1979) and at the beginning (in 1981) of the recognized worldwide epidemics of these viruses. Study.— Three hundred forty-nine serum samples, stored at—20°C, were obtained from 226 apparently healthy villagers (from five rural villages located 500 km east of Lusaka; preinoculation samples in a hepatitis B vaccine trial in 1981) 3,4 and from 123 patients with hepatocellular carcinoma who

In April, 2005, a full-term healthy male infant, delivered vaginally, showed intermittent periods of diffi culty in breastfeeding and lethargy starting on day 7. During a well-baby paediatric visit on day 11, the paediatrician noted that the baby had regained his birthweight. On day 12, however, he had grey skin and his milk intake had fallen. He was found dead on day 13. Postmortem analysis showed no anatomical anomalies. Blood concentration of morphine (the active metabolite of codeine) was 70 ng/mL by gas chromatography-mass spectrometry (GC-MS)— neonates breastfed by mothers receiving codeine typically have morphine serum concentrations of 0–2·2 ng/mL. The mother had been prescribed a combination preparation of codeine 30 mg and paracetamol 500 mg after birth for episiotomy pain (initially two tablets every 12 h, reduced to half that dose from day 2 because of somnolence and constipation). She continued the tablets for 2 weeks. Because of poor neonatal feeding, she stored milk on day 10, which was later assayed for morphine by GC-MS. A morphine concentration of 87 ng/mL was found—the typical range of milk concentrations after repeated maternal codeine is 1·9–20·5 ng/mL at doses of 60 mg every 6 h. Genotype analysis was done for cytochrome P450 2D6 (CYP2D6), the enzyme catalysing the O-demethylation of codeine to morphine. The mother was heterozygous for a CYP2D6*2A allele with CYP2D6*2×2 gene duplication, classifi ed as an ultra-rapid metaboliser. This genotype leads to increased formation of morphine from codeine, consistent with the somnolence and constipation she experienced. The maternal grandfather, the father, and the infant had two functional CYP2D6 alleles (CYP2D6*1/ *2 genotypes), classifi ed as extensive metabolisers. The maternal grandmother was an ultra-rapid metaboliser. The clinical and laboratory picture is consistent with opioid toxicity leading to neonatal death. Most of the analgesic and central-nervous-system depressant eff ects of codeine are secondary to its metabolism to morphine by CYP2D6. Neonates invariably have impaired capacity to metabolise and eliminate morphine. Codeine is a commonly used analgesic after labour for pain associated with episiotomy and caesarean section. The American Academy of Pediatrics lists codeine as compatible with breastfeeding, despite lack of suffi cient published data to support this recommendation. This case shows that polymorphism of CYP2D6 can be life threatening for some breastfed babies. Given that the frequency of CYP2D6 ultra-rapid metaboliser genotypes ranges from 1% in Finland and Denmark to 10% in Greece and Portugal, and 29% in Ethiopia, this polymorphism is clinically important. Several strategies can be considered to prevent life-threatening neonatal toxicity (table). Careful follow-up of breastfeeding mothers using codeine, and their infants, may be a useful approach. Testing of mother–child pairs when the mother or neonate is experiencing symptoms consistent with opioid toxicity may be necessary—eg somnolence, or poor milk intake. The facilities to measure morphine concentrations are not routine in most hospitals; in any suspicious case, naloxone can reverse, and, therefore, corroborate opioid toxicity. Above all, avoidance of codeine use during breastfeeding, with its use being retained as second or third line for uncontrolled pain, could also avert this situation. Whatever clinical approach is taken, codeine cannot be considered as a safe drug for all infants during breastfeeding.

EDITOR,--Rajendra Kale's article on traditional healers in South Africa commends traditional medicine for its holistic approach but acknowledges that “unfortunately there have been no studies of the efficacy of traditional remedies.”1 Some traditional remedies used in Africa are effective—for instance, simple purgatives in constipation. Others use the placebo effect and are used in illnesses recognised by traditional healers as self limiting or due to anxiety states. …

A phase advance of the circadian rhythm of rapid eye movement (REM) sleep propensity relative to the sleep-wake cycle has been hypothesized to account for the abnormalities of REM sleep in depression. One implication of this hypothesis is that an acute phase delay of sleep in normal subjects should produce the same abnormalities of REM sleep. A further implication is that changes in REM sleep that occur in normal subjects with delay shifts of sleep of progressively greater magnitude describe those that occur during the course of a depressive episode. This hypothesis was tested by computer simulation using two equations which, given the data derived from normal subjects experiencing phase delays of sleep, generated the REM latencies expected during successive stages of a depressive episode. For severely depressed patients, the computer-generated data matched those found empirically. The known correlation between severity of depression and REM latency, and the REM latencies of recovered patients, are consistent with the hypothesis.