Changes to country-specific hepatitis A travel vaccination recommendation for UK travellers in 2017-responding to a vaccine shortage in the national context.

OBJECTIVES: A routine review of hepatitis A travel vaccination recommendations was brought forward in June 2017 due to hepatitis A vaccine shortages and a concurrent outbreak in men who have sex with men (MSM). There were three objectives: first, to document the review process for changing the recommendations for the UK travellers in June 2017. Second, to study the impact of these changes on prescribing in general practice in 2017 compared with the previous 5 years. Third, to study any changes in hepatitis A notifications in June-October 2017 compared with the previous 5 years. STUDY DESIGN: This is an observational study. METHODS: Travel vaccination recommendations for countries with either low-risk (<20%) or high-risk (>90%) status according to child hepatitis A seroprevalence were not changed. A total of 67 intermediate-risk countries with existing recommendations for most travellers and with new data on rural sanitation levels were shortlisted for the analysis. Data on child hepatitis A seroprevalence, country income status, access to sanitation in rural areas and traveller volumes were obtained. Information about the vaccine supply was obtained from Public Health England. Changes to the existing classification were made through expert consensus, based on countries' hepatitis A seroprevalence, sanitation levels, level of income, volume of travel and hepatitis A traveller cases. Data on the number of combined and monovalent hepatitis A-containing vaccines prescribed in England, 2012-2017, were obtained from the National Health Service Business Service Authorities. The number of monthly prescriptions for January-September 2017 was compared with the mean number of prescriptions for the same month in the previous 5 years (t-test, α = 5%, df = 4). The number of hepatitis A cases notified in June-October 2017 not related to the MSM outbreak was compared with the number of notifications in the same months in previous years. RESULTS: A total of 36 countries were downgraded based on good access (80+% of population) to sanitation in rural areas and the intermediate-risk status in terms of child hepatitis A seroprevalence. For these countries, vaccination would only be recommended to travellers staying long term, visiting friends and relatives or staying in areas without good sanitation. There was a significant decline in hepatitis A vaccine prescriptions in June-September 2017, and there was no increase in the number of notifications. CONCLUSIONS: Hepatitis A vaccination recommendations for travel were revised in 2017 following a systematic approach to maintain continuity of supply after a hepatitis A vaccine shortage and increased hepatitis A vaccine demand related to a large outbreak. Improved access to good sanitation in rural areas and low seroprevalence estimates among children have led to 36 countries to no longer require vaccination for most travellers. These changes do not seem to have impacted on hepatitis A notifications in England, although further research will be needed to quantify the impact more precisely.

Placental pathologic aberrations in cases of familial idiopathic spontaneous preterm birth.

OBJECTIVE: To test the hypothesis that placental histologic characteristics in familial spontaneous preterm birth (sPTB) differ by gestational age (GA) and reflect possible mechanisms of pathogenesis. STUDY DESIGN: Secondary analysis from prospective cohort study in women with sPTB <35 weeks and a first degree family member with PTB. Placental specimens (n = 79) were categorized by maternal and/or fetal inflammatory response (MIR, FIR) and compared among three preterm GA categories. RESULTS: Inflammatory changes were common. MIR was most frequent at the earliest GAs, 85% with PTB <28 weeks [(adj)OR 77.5 (95% CI 5, 1213.1)], and 57% at 28-32 weeks [(adj)OR 6.1 (0.8, 48.5)] compared to later PTBs occurring at 32-35 weeks (22%). FIR also occurred most frequently in the earliest cases of PTB <28 weeks. CONCLUSIONS: Placental inflammatory responses are common in women with familial sPTB. This data suggests that inflammation plays an important role in the onset of parturition in cases otherwise classified as idiopathic or spontaneous in nature, especially at the earliest GAs when neonatal outcomes are the poorest.

The genetics of birth timing: insights into a fundamental component of human development.

The timing of birth necessitates the coupling of fetal maturation with the onset of parturition, and occurs at characteristic, but divergent gestations between mammals. Preterm birth in humans is an important but poorly understood outcome of pregnancy that uncouples fetal maturation and birth timing. The etiology of preterm birth is complex, involving environmental and genetic factors whose underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal models, although limited by differences with human physiology, have been crucial in exploring the role of various genetic pathways in mammalian birth timing. Studies in humans of both familial aggregation and racial disparities in preterm birth have contributed to the understanding that preterm birth is heritable. A significant portion of this heritability is due to polygenic causes with few true Mendelian disorders contributing to preterm birth. Thus far, studies of the human genetics of preterm birth using a candidate gene approach have met with limited success. Emerging research efforts using unbiased methods may yield promising results if concerns about study design can be adequately addressed. The findings from this frontier of research may have direct implications for the allocation of public health and clinical resources as well as spur the development of more effective therapeutics.

Burn Education Awareness Recognition and Support (BEARS): a community-based juvenile firesetters assessment and treatment program.

In response to the continued staggering statistics of fires set by juveniles and the devastating personal and property costs that are associated with these fires, the Burn and Shock Trauma Institute of Loyola University Medical Center, in collaboration with the State Fire Marshal's Office; the Illinois Fire Safety Alliance; and representatives from the firefighting community, law enforcement, emergency medicine and mental health, came together to create the Burn Education Awareness Recognition and Support Program. Through financial grant support from the International Association of Firefighters, the Illinois Fire Safety Alliance, and other private donations, the Burn Education Awareness Recognition and Support Program is able to provide a free resource to anyone who is concerned about a child playing with fire. Specially trained firefighters assess each child using the tool developed by the Federal Emergency Management Agency. In 2002, we assessed 42 children; 29 of those children were referred through the courts. So far, none of the children treated in our program have returned to fire-setting behaviors.

Fatal pediatric head injuries caused by short-distance falls.

Physicians disagree on several issues regarding head injury in infants and children, including the potential lethality of a short-distance fall, a lucid interval in an ultimately fatal head injury, and the specificity of retinal hemorrhage for inflicted trauma. There is scant objective evidence to resolve these questions, and more information is needed. The objective of this study was to determine whether there are witnessed or investigated fatal short-distance falls that were concluded to be accidental. The author reviewed the January 1, 1988 through June 30, 1999 United States Consumer Product Safety Commission database for head injury associated with the use of playground equipment. The author obtained and reviewed the primary source data (hospital and emergency medical services' records, law enforcement reports, and coroner or medical examiner records) for all fatalities involving a fall. The results revealed 18 fall-related head injury fatalities in the database. The youngest child was 12 months old, the oldest 13 years. The falls were from 0.6 to 3 meters (2-10 feet). A noncaretaker witnessed 12 of the 18, and 12 had a lucid interval. Four of the six children in whom funduscopic examination was documented in the medical record had bilateral retinal hemorrhage. The author concludes that an infant or child may suffer a fatal head injury from a fall of less than 3 meters (10 feet). The injury may be associated with a lucid interval and bilateral retinal hemorrhage.

Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat.

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathophysiological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Responses to QUIS-induced injury include an inflammatory component, as well as the development of spontaneous and evoked pain behaviors. We hypothesized that QUIS-induced inflammation and subsequent gene expression contribute to the development and progression of pain-related behaviors and that blockade of inflammation-related gene expression leads to the amelioration of these behaviors. Using the QUIS model of spinal cord injury, we examined whether interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is able to reduce mRNA levels of inflammatory and cell death-related genes leading to a reduction of pain behaviors. The results demonstrate that animals receiving systemic injection of IL-10, 30 minutes following QUIS-induced SCI, showed a significant delay in the onset of excessive grooming behavior, a significant reduction in grooming severity, and a significant reduction in the longitudinal extent of a pattern of neuronal loss within the spinal cord characterized as "grooming-type damage." QUIS injections also resulted in an increase in mRNA levels of interleukin-1 beta (IL-1 beta), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), CD95 ligand (CD95-L, also called FAS-L/APO-1L), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Results of QUIS injury plus IL-10 treatment resulted in a significant downregulation of IL1-beta and iNOS mRNA and these results were supported by Western blot analysis of protein levels following IL-10 treatment. These data suggest that IL-10 reduces inflammation and that targeting injury-induced inflammation is an effective strategy for limiting the extent of neuronal damage following excitotoxic SCI and thus the onset and progression of injury-induced pain behaviors.

Physiologic periosteal changes in infancy.

Surface modulation is part of normal bone growth. However, the radiologic appearance of physiologically growing bone in infancy may resemble changes secondary to trauma. This case report reviews bone remodeling in the postnatal infant and describes its unique radiologic and pathologic characteristics, allowing normal to be differentiated from healing and repair.

Lumbar transplant of neurons genetically modified to secrete brain-derived neurotrophic factor attenuates allodynia and hyperalgesia after sciatic nerve constriction.

Chronic delivery of anti-nociceptive molecules by means of cell grafts near the pain processing centers of the spinal cord is a newly developing technique for the treatment of neuropathic pain. The rat neuronal cell line, RN33B, derived from E13 rat brainstem raphe and immortalized with the SV40 temperature-sensitive allele of large T antigen (tsTag), was transfected with rat brain-derived neurotrophic factor cDNA (BDNF), and the BDNF-synthesizing cell line, 33BDNF.4, was isolated. The 33BDNF.4 cells synthesized mature BDNF protein at permissive temperature (33 degrees C), when the cells were proliferating, and during differentiation at non-permissive temperature (39 degrees C) in vitro. The bio-active BDNF protein was also secreted by the cells during both growth conditions, as measured by ELISA analysis of BDNF content and secretion. The bio-activity of the BDNF in 33BDNF.4 cell conditioned media was assessed by neurite outgrowth from E15 dorsal root ganglion (DRG) cultures. A control cell line, 33V1, transfected with the vector alone, did not synthesize or secrete any significant BDNF at either growth condition. Both cell lines were used as grafts in a model of chronic neuropathic pain induced by unilateral chronic constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and thermal and tactile hyperalgesia, were evaluated after CCI in the affected hindpaw. When 33BDNF.4 and 33V1 cells were transplanted in the lumbar subarachnoid space of the spinal cord 1 week after CCI, they survived greater than 7 weeks on the pia mater around the spinal cord and the 33BDNF.4 cells continued to synthesize BDNF in vivo. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced during the 2-7 week period after grafts of 33BDNF.4 cells. The maximal effect on chronic pain behaviors with the BDNF grafts occurred 2-3 weeks after transplant and the anti-nociceptive effects of the BDNF cell grafts was permanent. Transplants of the control 33V1 cells had no effect on the allodynia and hyperalgesia induced by CCI and these cells did not synthesize BDNF in vivo. These data suggest that a chronically applied, low local dose of BDNF supplied by transplanted cells near the spinal dorsal horn was able to reverse the development of chronic neuropathic pain following CCI. The use of neural cell lines that are able to deliver anti-nociceptive molecules, such as BDNF, in a model of chronic pain offers a novel approach to pain management and such 'biologic minipumps' can be developed for safe use in humans.

Sudden death in an infant caused by rupture of a basilar artery aneurysm.

Ruptured aneurysms of the cerebrovasculature in infancy and early childhood, except for "giant" aneurysms and arteriovenous malformations, are rare. Seizures, loss of consciousness, and apnea are the usual presenting signs in infancy; symptoms such as headache or visual disturbances and signs such as cranial nerve compression or meningeal irritation commonly found in older children or adults are absent in infants. However, the morphologic findings (i.e., subarachnoid and retinal hemorrhage, and occasionally subdural hemorrhage) may be mistaken for inflicted trauma, especially if the aneurysm is not identified. Sudden death caused by rupture of a cerebral aneurysm has not been previously described in an infant. This report outlines the investigation and autopsy findings in a 7-month-old infant who died unexpectedly as a result of rupture of a complex basilar artery aneurysm.

Transplants of neuronal cells bioengineered to synthesize GABA alleviate chronic neuropathic pain.

The use of cell lines utilized as biologic "minipumps" to provide antinociceptive molecules, such as GABA, in animal models of pain is a newly developing area in transplantation biology. The neuronal cell line, RN33B, derived from E13 brain stem raphe and immortalized with the SV40 temperature-sensitive allele of large T antigen (tsTag), was transfected with rat GAD67 cDNA (glutamate decarboxylase, the synthetic enzyme for GABA), and the GABAergic cell line, 33G10.17, was isolated. The 33G10.17 cells transfected with the GAD67 gene expressed GAD67 protein and synthesized low levels of GABA at permissive temperature (33 degrees C), when the cells were proliferating, and increased GAD67 and GABA during differentiation at nonpermissive temperature (39 degrees C) in vitro, because GAD67 protein expression was upregulated with differentiation. A control cell line, 33V1, transfected with the vector alone, contained no GAD67 or GABA at either temperature. These cell lines were used as grafts in a model of chronic neuropathic pain induced by unilateral chronic constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and thermal and tactile hyperalgesia, were evaluated after CCI in the affected hind paw. When 33G10.17 and 33V1 cells were transplanted in the lumbar subarachnoid space of the spinal cord 1 week after CCI, they survived greater than 7 weeks on the pia mater around the spinal cord. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced during the 2-7-week period after grafts of 33G10.17 cells. The maximal effect on chronic pain behaviors with the GABAergic grafts occurred 2-3 weeks after transplantation. Transplants of 33V1 control cells had no effect on the allodynia and hyperalgesia induced by CCI. These data suggest that a chronically applied, low local dose of GABA presumably supplied by transplanted cells near the spinal dorsal horn was able to reverse the development of chronic neuropathic pain following CCI. The use of neural cell lines that are able to deliver inhibitory neurotransmitters, such as GABA, in a model of chronic pain offers a novel approach to pain management.

Expression of Flt3 and c-kit during growth and maturation of human CD34+CD38- cells.

Studies of murine stem cells suggest that the cytokine receptors Flt3 and c-kit are expressed differentially on the earliest reconstitutional cells, such that Flt3 is not expressed until after stem cell activation. Much less is known about the expression of Flt3 and c-kit on primitive human cells, especially those mobilized into circulation for transplantation. In this study, early circulating precursors were analyzed for expression of Flt3 at the gene and protein levels. Flow cytometric studies showed that >90% of CD34+CD38- cells expressed Flt3 antigen (CD135). The proportion of fresh CD34+ cells expressing Flt3 decreased as CD38 staining increased. These results were confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) analyses, which showed that Flt3 gene expression generally was limited to the CD34+CD38- population. Because Flt3 ligand (FL) enhances the growth and/or maintenance of primitive cells, it was important to know how long early cells retain Flt3 receptor expression in expansion culture. Both RT-PCR analyses and functional tests demonstrated that primitive cells are capable of expressing Flt3 for as long as 2 weeks in liquid medium. During the first week of culture, FL enhanced the generation of cells and progenitors without causing a loss of primitive CD34+CD38-Flt3+ cells. Flt3 expression in cell cultures was limited to precursors retaining a CD34+CD38(-/lo) phenotype. Because the most primitive human precursors are believed to express c-kit at a low level, we examined the FL responsiveness of CD34+CD38-c-kit(-/lo) cells and CD34+CD38-c-kit+ cells. CD34+CD38-c-kit(-/lo), cells constituted a small fraction (12%) of the CD34+CD38- population. Whereas both c-kit(-/lo) and c-kit+ subsets were stimulated by FL, cell expansion (p < 0.01) and colony formation (p < 0.01) were greater and maintained longer with CD34+CD38-c-kit(-/lo) cells. Furthermore, the rapid response to FL suggests that primitive CD34+CD38-c-kit(-/lo) cells express Flt3 at the time of isolation or shortly thereafter. These results demonstrate the presence of Flt3 on CD34+CD38 blood cells and suggests that Flt3 also may be present on a c-kit(-/lo) subset, among the most primitive in circulation. Flt3 is lost during maturation to committed (CD34+CD38+) lineages. Addition of FL to primitive cell cultures stimulates cell expansion while maintaining early CD34+CD38-Flt3+ precursors for at least 7 days. The possible existence of a more primitive CD34+CD38-c-kit(-/lo) Flt3(-/lo) precursor remains to be determined.

Shaken baby syndrome and the death of Matthew Eappen: a forensic pathologist's response.

Subdural hemorrhage, retinal hemorrhage, and cerebral edema have been considered diagnostic for a "shaken infant" since the syndrome was described almost 30 years ago. However, the specificity of these findings has been disputed by defense witnesses in recent U.S. criminal prosecutions. This review examines the scientific basis for the shaken baby syndrome.

Sudden death in an infant caused by rupture of a basilar artery aneurysm.

Ruptured aneurysms of the cerebrovasculature in infancy and early childhood, except for "giant" aneurysms and arteriovenous malformations, are rare. Seizures, loss of consciousness, and apnea are the usual presenting signs in infancy; symptoms such as headache or visual disturbances and signs such as cranial nerve compression or meningeal irritation commonly found in older children or adults are absent in infants. However, the morphologic findings (i.e., subarachnoid and retinal hemorrhage, and occasionally subdural hemorrhage) may be mistaken for inflicted trauma, especially if the aneurysm is not identified. Sudden death caused by rupture of a cerebral aneurysm has not been previously described in an infant. This report outlines the investigation and autopsy findings in a 7-month-old infant who died unexpectedly as a result of rupture of a complex basilar artery aneurysm.

Lumbar transplant of neurons genetically modified to secrete galanin reverse pain-like behaviors after partial sciatic nerve injury.

The use of cell lines as biologic "minipumps" to chronically deliver antinociceptive molecules such as the peptide galanin near the pain processing centers of the spinal cord after nerve injury is a newly developing technology for the treatment of neuropathic pain. The neuronal rat cell line, RN33B, derived from E13 brainstem raphe and immortalized with the SV40 temperature-sensitive allele of large T antigen (tsTag), was transfected with rat preprogalanin (GAL) cDNA and the galanin-synthesizing and -secreting cell line, 33GAL.19, was isolated [1]. The 33GAL.19 cells transfected with the GAL gene expressed immunoreactivity (ir) for the GAL protein and synthesized low levels of GAL-ir at permissive temperature (33 degrees C), when the cells were proliferating, and increased GAL-ir during terminal differentiation at non-permissive temperature (39 degrees C) in vitro. A control cell line, 33V.1, RN33B cells transfected with the pCEP4 vector alone and similarly isolated by subcloning, contained no detectible GAL-ir at either temperature in vitro. These cell lines were used as grafts in a model of chronic neuropathic pain induced by unilateral chronic constriction injury (CCI) of the sciatic nerve. Pain-related behaviors, including cold and tactile allodynia and thermal and mechanical hyperalgesia, were evaluated in the affected hindpaw after CCI and transplants. The 33GAL.19 and 33V.1 cells transplanted in the lumbar subarachnoid space near the spinal cord one week after CCI, survived at least seven weeks on the pial surface around the spinal cord and only the 33GAL.19 cells expressed GAL-ir in vivo after transplant. Furthermore, the tactile and cold allodynia and tactile and thermal hyperalgesia induced by CCI was significantly reduced or eliminated during the two to seven week period after grafts of 33GAL.19 cells. The maximal effect on chronic pain behaviors with the GAL grafts occurred one to three weeks after transplantation. Transplants of 33V.1 control cells had no effect on the allodynia and hyperalgesia induced by CCI. These data suggest that a chronically applied, low local dose of galanin supplied by transplanted cells near the lumbar spinal dorsal horn was able to reverse the development of chronic neuropathic pain following CCI. The use of transplants of genetically modified neural cell lines that are able to deliver antinociceptive molecules, such as galanin, offers a safe and novel approach to pain management.

Differential regulation of synaptic vesicle protein genes by target and synaptic activity.

Differentiation of presynaptic nerve terminals involves changes in gene expression; these may be regulated by synaptic transmission and/or by contact with the target muscle. To gain insight into the control of presynaptic differentiation, we examined the regulation by target and synaptic activity of synaptic vesicle protein (SVP) genes in the chick ciliary ganglion (CG). In the CG, two SVP genes, synaptotagmin I (syt I) and synaptophysin II (syp II), are coordinately upregulated at the time of target contact. To test the hypothesis that this upregulation is induced by target contact, we examined mRNA levels of syt I and syp II in CGs from embryos in which one eye had been removed before axon outgrowth. As expected, target removal prevented the normal upregulation of syt I mRNA in the deprived ganglion. In contrast, and unexpectedly, syp II mRNA upregulation was not affected. The target dependence of syt I upregulation was not attributable to nerve-muscle transmission, because blockade of this transmission had no effect on SVP mRNA levels. Surprisingly, blockade of synapses onto CG neurons from the brain also did not affect syt I mRNA levels but increased levels of syp II mRNA. We conclude that contact with target induces upregulation of syt I mRNA, which is the case for spinal motor neurons. However, the normal upregulation of syp II mRNA is not controlled by the same signal(s). Instead, our results suggest that these two SVP genes are differentially regulated, both by target contact and by blockade of synaptic transmission.