Syndemic anemia in British Malaya: An early global health encounter with hookworm and malaria co-infections in plantation workers.

With the establishment of the International Health Commission in 1913, the Rockefeller Foundation sought governmental partnerships overseas to combat hookworm disease and improve feces disposal practices. In the Madras Presidency in British India, the India Research Fund Association carried out hookworm surveys but failed in its educational efforts to improve feces disposal practices. In British Malaya, the Uncinariasis [Hookworm] Commission to the Orient discovered a syndemic of anemia among Tamil plantation laborers from the Madras Presidency and Chinese laborers from southern China who suffered from hookworm and malarial co-infections. Confronted with the apparent infeasibility of improving feces disposal practices and the obdurate fact of re-infection with hookworm after purgative treatment, the Rockefeller Foundation ended its hookworm initiative in British Malaya without advocating for programmatic intervention against syndemic anemia. The essay concludes with a reflection on the engagement of historians with the syndemic paradigm.

Specialized cytonemes induce self-organization of stem cells.

Spatial cellular organization is fundamental for embryogenesis. Remarkably, coculturing embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) recapitulates this process, forming embryo-like structures. However, mechanisms driving ESC-TSC interaction remain elusive. We describe specialized ESC-generated cytonemes that react to TSC-secreted Wnts. Cytoneme formation and length are controlled by actin, intracellular calcium stores, and components of the Wnt pathway. ESC cytonemes select self-renewal-promoting Wnts via crosstalk between Wnt receptors, activation of ionotropic glutamate receptors (iGluRs), and localized calcium transients. This crosstalk orchestrates Wnt signaling, ESC polarization, ESC-TSC pairing, and consequently synthetic embryogenesis. Our results uncover ESC-TSC contact-mediated signaling, reminiscent of the glutamatergic neuronal synapse, inducing spatial self-organization and embryonic cell specification.

Wnt ligand presentation and reception: from the stem cell niche to tissue engineering.

Stem cells reside in niches where spatially restricted signals maintain a delicate balance between stem cell self-renewal and differentiation. Wnt family proteins are particularly suited for this role as they are modified by lipids, which constrain and spatially regulate their signalling range. In recent years, Wnt/ß-catenin signalling has been shown to be essential for the self-renewal of a variety of mammalian stem cells. In this review, we discuss Wnt-responsive stem cells in their niche, and mechanisms by which Wnt ligands are presented to responsive cells. We also highlight recent progress in molecular visualization that has allowed for the monitoring of Wnt signalling within the stem cell compartment and new approaches to recapitulate this niche signalling in vitro Indeed, new technologies that present Wnt in a localized manner and mimic the three-dimensional microenvironment of stem cells will advance our understanding of Wnt signalling in the stem cell niche. These advances will expand current horizons to exploit Wnt ligands in the rapidly evolving fields of tissue engineering and regenerative medicine.

The use of CRP within a clinical prediction algorithm for the differentiation of septic arthritis and transient synovitis in children.

Clinical prediction algorithms are used to differentiate transient synovitis from septic arthritis. These algorithms typically include the erythrocyte sedimentation rate (ESR), although in clinical practice measurement of the C-reactive protein (CRP) has largely replaced the ESR. We evaluated the use of CRP in a predictive algorithm. The records of 311 children with an effusion of the hip, which was confirmed on ultrasound, were reviewed (mean age 5.3 years (0.2 to 15.1)). Of these, 269 resolved without intervention and without long-term sequelae and were considered to have had transient synovitis. The remaining 42 underwent arthrotomy because of suspicion of septic arthritis. Infection was confirmed in 29 (18 had micro-organisms isolated and 11 had a high synovial fluid white cell count). In the remaining 13 no evidence of infection was found and they were also considered to have had transient synovitis. In total 29 hips were categorised as septic arthritis and 282 as transient synovitis. The temperature, weight-bearing status, peripheral white blood cell count and CRP was reviewed in each patient. A CRP > 20 mg/l was the strongest independent risk factor for septic arthritis (odds ratio 81.9, p < 0.001). A multivariable prediction model revealed that only two determinants (weight-bearing status and CRP > 20 mg/l) were independent in differentiating septic arthritis from transient synovitis. Individuals with neither predictor had a < 1% probability of septic arthritis, but those with both had a 74% probability of septic arthritis. A two-variable algorithm can therefore quantify the risk of septic arthritis, and is an excellent negative predictor.

The first large-scale use of synthetic insecticide for malaria control in tropical Africa: lessons from Liberia, 1945-1962.

In 1945, a United States Public Health Service team in Monrovia, Liberia, began the use of synthetic insecticides for indoor residual spraying (IRS) and as a larvicide, with the goal of controlling malaria in the Liberian capital. In the early 1950s, the project was "scaled up" to reach the surrounding areas, and in 1953, the World Health Organization (WHO) launched an antimalaria program in the upcountry region of Central Province, Liberia. It was initially based solely upon IRS, as it was one of a series of pilot projects whose goal was to determine the feasibility of malaria eradication in tropical Africa. The malaria control project in Monrovia constituted the first large-scale use of synthetic insecticide to combat malaria in tropical Africa, and the WHO pilot project in Central Province was one of a first cluster of projects initiated to explore the efficacy of IRS in a variety of African ecological zones. These projects encountered a spate of difficulties that foreshadowed the general retreat from malaria eradication efforts across tropical Africa by the mid-1960s.

The association between clubfoot and developmental dysplasia of the hip.

The association between idiopathic congenital talipes equinovarus (CTEV) and developmental dysplasia of the hip is uncertain. We present an observational cohort study spanning 6.5 years of selective ultrasound screening of hips in clubfoot. From 119 babies with CTEV there were nine cases of hip dysplasia, in seven individuals. This suggests that 1 in 17 babies with CTEV will have underlying hip dysplasia. This study supports selective ultrasound screening of hips in infants with CTEV.

Outcome of the scarf osteotomy in adolescent hallux valgus.

PURPOSE: We have reported the radiological and clinical outcome of scarf osteotomy in the treatment of moderate to severe hallux valgus among adolescent children. METHOD: Data were collected retrospectively between April 2001 and June 2006. The pre- and post-operative intermetatarsal angle (IMA), hallux valgus angle (HVA) and distal metatarsal articular angle (DMAA) were determined. Patients were followed up for a mean of 37.6 months. RESULTS: Thirteen patients with 19 operated feet were available at the time of the latest follow-up. There was significant improvement in the mean post-operative IMA, which was maintained to the last follow-up. There was statistically significant improvement in the 6-week post-operative HVA and DMAA. However, this was lost at the final follow-up. The mean American Orthopaedic Foot and Ankle Society score for the whole group was 80 (54-100). CONCLUSION: This study indicates that scarf osteotomy should be used with caution in symptomatic adolescent hallux valgus, as there is a high recurrence rate.

Microbiological culture results for the femoral head. Are they important to the donor?

We determined the rate of contamination of donated femoral heads at primary hip arthroplasty within a single region between July 1992 and July 2001. We established the null hypothesis that culture results played no role in predicting early failure of the joint because of infection. The rate of contamination was 9%. A positive culture, at the time of retrieval, was found in 367 of 4045 femoral heads. Coagulase-negative staphylococcus was isolated in 77% of the positive cases. At a minimum follow-up of one year, there was no statistically significant difference in the rate of complications or of revision of age-matched patients whose femoral heads had a positive culture compared with those whose femoral heads were sterile. Our findings confirm that culture of the femoral head plays no part in determining future failure of joint replacement in the donor.

Identification of recurrent regions of chromosome loss and gain in vestibular schwannomas using comparative genomic hybridisation.

BACKGROUND: Schwannomas are benign tumours of the nervous system that are usually sporadic but also occur in the inherited disorder neurofibromatosis type 2 (NF2). The NF2 gene is a tumour suppressor on chromosome 22. Loss of expression of the NF2 protein product, merlin, is universal in both sporadic and NF2 related schwannomas. The GTPase signalling molecules RhoA and Rac1 regulate merlin function, but to date only mutation in the NF2 gene has been identified as a causal event in schwannoma formation. METHODS: Comparative genomic hybridisation (CGH) was used to screen 76 vestibular schwannomas from 76 patients (66 sporadic and 10 NF2 related) to identify other chromosome regions that may harbour genes involved in the tumorigenesis. RESULTS: The most common change was loss on chromosome 22, which was more frequent in sporadic than in NF2 related tumours. Importantly, eight tumours (10%) showed gain of copy number on chromosome 9q34. Each of the two NF2 patients who had received stereotactic radiotherapy had non-chromosome 22 changes, whereas only one of eight non-irradiated NF2 patients had any chromosome changes. Three tumours had gain on 17q, which has also been reported in malignant peripheral nerve sheath tumours that are associated with neurofibromatosis type 1. Other sites that were identified in three or fewer tumours were regions on chromosomes 10, 11, 13, 16, 19, 20, X, and Y. CONCLUSIONS: These findings should be verified using techniques that can detect smaller genetic changes, such as microarray-CGH.

Parachuting: a sport of chance and expense.

This paper seeks to determine the cost to the NHS associated with treating parachute-related injuries. More specifically, it compares the training received by civilians to that received by military personnel together with the types of parachutes used or the type of jump. It also reviews the information given to civilian jumpers prior to their first jump. Fifty-three jumpers suffered injuries in the period under review. Of these, 32 cases with 41 injuries were transferred to Accident and Emergency Department for treatment. Injuries involved most of the musculoskeletal system. Twenty-six (n=32) patients were admitted for treatment, with an average length of hospital stay of 6.8 days. Post-discharge, the length of time lost from work was 42.8 days. The cost to the NHS was calculated at pound 4026.50 per patient treated. This did not include time lost from work, subsequent follow up or any other secondary procedures. Civilian parachute jumpers were trained for 6.5h compared to 31.5h for military personnel. Twenty-seven patients used rectangular rather than circular parachutes. Thirty of the 41 injuries occurred during static line jumps, with 7 occurring during tandem jumps and only 5 during free-fall jumps. Twenty-three of the 32 jumpers sustained the injury during their first jump. First-time civilian jumpers were given a minimum of information regarding risks and injuries prior to their jump and were inadequately insured against potential injuries. The cost of caring for these patients is substantial when compared to the money that is raised for charity during some of the jumps. Private insurance, with the NHS legally able to claim expenses would help to offset these medical costs. It is also possible that by increasing civilian training, there may be a reduction in the number of injuries sustained by first-time civilian jumpers from 1.1 to 1.2% (11% in charity jumps) to the military figures of 0.22-0.89%.

The clinical significance of femoral head culture results in donors after hip arthroplasty: a preliminary report.

The aim of this study is to determine whether a link exists between clinical wound problems and positive bacterial culture of the femoral head after primary hip arthroplasty. Clinical data were retrieved for 24 culture-positive and 26 culture-negative patients. Coagulase-negative Staphylococcus was the commonest pathogen, cultured in 19 of the 24 culture-positive femoral heads donated to a regional bone bank. Wound problems occurred in 2 of the patients from the culture-positive group and 4 of the patients from the culture-negative group. The relative risk of wound problems was 0.54 in the culture-positive group. Based on the available evidence in this preliminary short-term retrospective review, positive microbiology from donated femoral heads has no clinical implication in the donors. The practice of reporting culture-positive femoral heads should be continued.

Effects of maternal iron restriction on placental vascularization in the rat.

To investigate the effects of maternal iron deficiency and anaemia on the placenta the composition and vascularization of the placental labyrinth was investigated in iron-restricted rats. Rats in the experimental groups were placed on iron-restricted diets either 1 or 2 weeks before mating and continued on these diets throughout gestation. Placentae were studied at day 21 of gestation. Tissue sections were stained with lectin to allow identification of fetal capillaries and analyzed using stereological techniques. Capillary surface area density and total capillary surface area were decreased in both iron-restricted groups compared with the control group. Capillary length density was decreased in both iron-restricted groups compared with the control group. Total capillary length was significantly reduced in the 1-week, but not in the 2-week, iron-restricted group compared with the control group. Endothelial cell volume was increased in both iron-restricted groups compared to the controls. There were no significant differences in the volume of fetal capillaries, the volume of the maternal blood spaces or the surface area of the maternal-fetal interface between the control and iron-restricted groups. Labyrinthine volume, labyrinthine tissue volume and the surface area of the maternal fetal interface were increased in the 2-week group when compared with the 1-week group. These changes in placental vascularization may contribute to the fetal growth retardation observed in iron-restricted litters.

Timing of operative intervention in the management of acutely fractured ankles and the cost implications.

A study of the length of the time between the diagnosis of an ankle fracture and operative intervention and the length of subsequent hospital stay was undertaken. The delay in operative fixation beyond 24 h from injury was associated with a lengthening of stay. The cost implication of a longer stay was assessed. Eighty-seven patients with 87 fractures fulfilled the inclusion criteria of having an acute closed fracture of the ankle requiring open reduction and internal fixation (ORIF). There were 34 unimalleolar, 35 bimalleolar and 18 trimalleolar fractures. Only 47 (54%) of the patients were operated on within 24 h of injury, even though 74 had presented by 6 h and a further five by 24 h. The mean inpatient stay was 9.6 days for this early operation group. The patients who had their operation delayed were in hospital for a mean of 14 days, a significant difference (P<0.0001) (using Wilcoxon's Signed Rank test). The cost per patient per day of an acute trauma bed is estimated at pound sterlings 225. This translates into an average cost of pound sterlings 990 more per patient whose operation is delayed. We recommend that policies be put in place to provide early operative intervention for patients with fractured ankles as this would result in significant financial savings.

Effects of maternal iron restriction in the rat on hypoxia-induced gene expression and fetal metabolite levels.

The mechanism by which maternal Fe deficiency in the rat causes fetal growth retardation has not been clearly established. This study compared the effects on the fetuses from dams fed a control diet with two groups of dams fed Fe-restricted diets. One Fe-restricted group was fed the Fe-restricted diet for 1 week prior to mating and throughout gestation and the second Fe-restricted group was fed the Fe-restricted diet for 2 weeks prior to mating and throughout gestation. On day 21 of gestation Fe-restricted dams, and their fetuses, were anaemic. Fetal weight was reduced in both Fe-restricted groups compared with controls. Expression of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) are induced by hypoxia. The levels of HIF-1alpha mRNA were highest in placenta, then in kidney, heart and liver but were not different between the groups. Levels of plasma VEGF were not different between the groups. Maternal plasma triacylglycerol was decreased in the 1-week Fe-restricted dams compared with controls. Maternal plasma cholesterol and free fatty acid levels were not different between the groups. In fetal plasma, levels of triacylglycerol and cholesterol were decreased in both Fe-restricted groups. In maternal plasma, levels of a number of amino acids were elevated in both Fe-restricted groups. In contrast, levels of a number of amino acids in fetal plasma were lower in both Fe-restricted groups. Fetal plasma lactate was increased in Fe-restricted fetuses but fetal plasma glucose and beta-hydroxybutyrate were not affected. These changes in fetal metabolism may contribute to fetal growth retardation in this model. This study does not support the hypothesis that the Fe-restricted fetus is hypoxic.

Genomic alterations associated with loss of heterozygosity for TP53 in Li-Fraumeni syndrome fibroblasts.

Studies of Li-Fraumeni syndrome fibroblasts heterozygous for germline TP53 mutations have shown that loss of heterozygosity (LOH) occurs during passaging and is associated with genomic instability, such as chromosomal aberrations and aneuploidy to investigate the genomic changes associated with LOH in Li-Fraumeni (LF) fibroblasts, we have analysed cell strains at increasing population doublings (PD) using Comparative Genomic Hybridization (CGH). We have looked at three groups of cell strains: LF mutation-carrying strains which showed LOH for TP53, LF mutation-carrying strains which did not show LOH, and strains from normal individuals. Using CGH, we have detected loss of distinct chromosomal regions associated with LOH in 4 out of 5 mutation-carrying strains. In particular we have found loss of chromosomal regions containing genes involved in cell cycle control or senescence, including loss of 9p and 17p in these strains. Other recurrent changes included loss of chromosomes 4q and 6q, regions shown to contain one or more tumour suppressor genes. No genomic alterations were detected at cumulative PD in the normal strains or in the LF mutation-carrying strains which did not show LOH for TP53. We have also analysed the three groups of strains for microsatellite instability and somatic TP53 mutations, and have found genetic alterations in only one strain.

Multiple endocrine neoplasia type 1: clinical and genetic features of the hereditary endocrine neoplasias.

MEN1 is a syndrome of parathyroid adenomas, gastrinomas, prolactinomas, and other endocrine tumors. Collagenomas and facial angiofibromas are newly recognized but common skin expressions. Many tumors in MEN1 are benign; however, many entero-pancreatic neuroendocrine tumors and foregut carcinoid tumors are malignant. MEN1 is thus the expression of a cancer gene but without available prevention or cure for malignancy. Hereditary (as compared to sporadic) endocrine tumors show early onset age and multiplicity, because each cell of the body has "one hit" by inheritance. Multiple neoplasia syndromes with endocrine tumor(s) all include nonendocrine components; their known defective genes seem mainly to disturb cell accumulation. Hereditary neoplasia/hyperplasia of one endocrine tissue reflects a defect that is tissue selective and directed at cell secretion. Though the hereditary endocrine neoplasias are rare, most of their identified genes also contribute to common sporadic endocrine neoplasms. Hereditary tumors may be caused by activation of an oncogene (e.g., RET) or, more often, by inactivation of a tumor suppressor gene (e.g., P53, MEN1). Recently, MEN1 was identified by positional cloning. This strategy included narrowing the gene candidate interval, identifying many or all genes in that interval, and testing the newly identified candidate genes for mutation in MEN1 cases. MEN1 was identified because it showed mutation in 14 of 15 MEN1 cases. NIH testing showed germline MEN1 mutations in 47 of 50 MEN1 index cases and in seven of eight cases with sporadic MEN1. Despite proven capacity to find germline MEN1 mutation, NIH testing found no MEN1 mutation among five families with isolated hyperparathyroidism, suggesting that this often arises from mutation of other gene(s). Analogous studies in Japan found that familial isolated pituitary tumors also did not show MEN1 germline mutation. MEN1 mutation testing can now be considered for cases of MEN1 and its phenocopies and for asymptomatic members of families with known MEN1 mutation. Germline MEN1 testing does not have the urgency of RET testing in MEN2a and 2b, as MEN1 testing does not commonly lead to an important intervention. Somatic MEN1 mutation was found in sporadic tumors: parathyroid adenoma (21%), gastrinoma (33%), insulinoma (17%), and bronchial carcinoid (36%). For each of these, MEN1 was the known gene most frequently mutated. MEN1 has a widely expressed mRNA that encodes a protein (menin) of 610 amino acids. The protein sequence is not informative about domains or functions. The protein was mainly nuclear. Menin binds to JunD, an AP-1 transcription factor, inhibiting JunD's activation of transcription. Most of the germline and somatic MEN1 mutations predict truncation of menin, a likely destructive change. Inactivating MEN1 mutations in germline and in sporadic neoplasms support prior predictions that MEN1 is a tumor suppressor gene. Germline MEN1 mutation underlies all or most cases of MEN1 (familial or sporadic). Somatic MEN1 mutation is the most common gene mutation in many sporadic endocrine tumor types.