Nasogastric tube feeding in line with new dietetic guidelines for the treatment of anorexia nervosa in a specialist children and adolescent inpatient unit: a case series.

BACKGROUND: The present study reports a case series where three adolescent patients with anorexia nervosa (AN) (two cases with typical AN and one case atypical AN) received nasogastric tube feeding under restraint in line with new dietetic clinical guidelines. METHODS: Three cases were chosen out of 61 admitted patients over the period of 1 year who were fed via a nasogastric tube under restraint in a specialist eating disorders unit for children and adolescents. These cases were chosen to highlight a range of clinical scenarios that clinicians may encounter. They also represent clinical scenarios where decisions to feed patients under restraint were rendered more complex by additional concerns. RESULTS: Despite the complexity of the cases, all patients tolerated the feeds well and were discharged home eating solid food. CONCLUSIONS: The decision to feed a patient against their will is never an easy one. Sadly, there have been some recent high-profile deaths of adult patients on medical wards where treatment opinion was not considered, and the patient received no or minimal nutrition when awaiting specialist treatment. Dietetic guidelines have been published to help inform clinicians for whom feeding under restraint may be out of the scope of their daily practice. This case series highlights clinical scenarios that illustrate the utility of the guidelines, which we hope will support clinicians when making, potentially lifesaving decisions in children and young people.

Arterial stiffening, insulin resistance and acanthosis nigricans in a community sample of adolescents with obesity.

Acanthosis Nigricans (AN) is a common finding in adolescents with obesity. Little is known about its relevance for cardiovascular (CVS) risk, in particular arterial stiffening. We investigated associations between AN, conventional markers of CVS risk and carotid-radial pulse wave velocity (PWV) in a community sample of adolescents with obesity aged 12-19 recruited to an obesity trial. AN was present in 63% of subjects and 43% had severe grading. Presence of AN and severe AN were associated with z-score of body mass index (BMIz). Presence of AN (but not severity) was associated with abnormal or fasting hyperinsulinaemia but not after adjustment for BMIz. PWV data were available for 147 (84% of participants). Severe-grade AN was associated with PWV (co-efficient 0.51, 95% CI 0.13-0.89, P=0.01) but not when adjusted for BMIz, ethnic grouping and age. In our study presence and severity of AN offered little additional information on CVS risk beyond the degree of obesity itself. The relevance of AN for CVS risk should be interpreted with caution.

Alterations in neuronal gene expression profiles in response to experimental demyelination and axonal transection.

The main pathological features of multiple sclerosis, demyelination and axonal transection, are considered to cause reversible and irreversible neurological deficits, respectively. This study aimed to separately analyze the effects of these pathological hallmarks on neuronal gene expression in experimental paradigms. The pontocerebellar pathway was targeted with either lysolecithin-induced chemical demyelination or a complete pathway transection (axonal transection) in rats. Transcriptional changes in the pontocerebellar neurons were investigated with microarrays at days 4, 10 and 37 post-intervention, which was confirmed by immunohistochemistry on protein level. A common as well as unique set of injury-response genes was identified. The increased expression of activating transcription factor 3 (Atf3) and thyrotropin-releasing hormone (Trh) in both injury paradigms was validated by immunohistochemistry. The expression of Atf3 in a patient with Marburg's variant of multiple sclerosis was also detected, also confirming the activation of the Atf3 pathway in a human disease sample. It was concluded that this experimental approach may be useful for the identification of pathways that could be targeted for remyelinative or neuroprotective drug development.

Bone mineral density in Anorexia Nervosa versus Avoidant Restrictive Food Intake Disorder.

BACKGROUND: Avoidant Restrictive Food Intake Disorder (ARFID) and Anorexia Nervosa (AN) cause significant underweight in children and young people (CYP). The association of low bone mineral density (BMD) and underweight CYP in AN is well established, but less is known about BMD in ARFID. METHODS: Retrospective case-note review and analysis of BMD measures by DXA on underweight patients referred to a paediatric clinic for eating disorders between 2014 and 2019. Indications for BMD measurement were age > 5 years and underweight for at least 6 months. RESULTS: Of 134 cases where BMD was measured, 118 (88%) had AN and 16 (12%) ARFID. Age range was 6-19 years. 19% were males. ARFID cases were more likely to be male, have lower Body Mass Index (BMI), BMI z-score (BMIz), and longer underweight duration. For all cases, BMI and BMIz were positively associated with BMD z-score (BMI: coefficient 0.13,95%CI 0.04 to 0.22, p = 0.01; BMIz: coefficient 0.34, 95%CI 0.17 to 0.51, p < 0.001) and bone mineral areal density z-score (BMI: coefficient 0.12, 95% CI 0.01 to 0.23, p = 0.04 and BMIz: coefficient 0.27, 95% CI 0.05 to 0.49, p = 0.02). However, there were no associations of BMD with diagnosis (ARFID vs AN). Paired t-testing of 13 age, sex and pubertally matched pairs from AN and ARFID cases also showed no difference in standardized BMD scores. CONCLUSION: Low BMD in our sample of underweight AN and ARFID cases was associated with BMI but not diagnosis. BMD may be as important in ARFID as AN. Further research should examine mechanisms and potential interventions.

The initial events in myelin synthesis: orientation of proteolipid protein in the plasma membrane of cultured oligodendrocytes.

Proteolipid protein (PLP) is the most abundant transmembrane protein in myelin of the central nervous system. Conflicting models of PLP topology have been generated by computer predictions based on its primary sequence and experiments with purified myelin. We have examined the initial events in myelin synthesis, including the insertion and orientation of PLP in the plasma membrane, in rat oligodendrocytes which express PLP and the other myelin-specific proteins when cultured without neurons (Dubois-Dalcq, M., T. Behar, L. Hudson, and R. A. Lazzarini. 1986. J. Cell Biol. 102:384-392). These cells, identified by the presence of surface galactocerebroside, the major myelin glycolipid, were stained with six anti-peptide antibodies directed against hydrophilic or short hydrophobic sequences of PLP. Five of these anti-peptide antibodies specifically stained living oligodendrocytes. Staining was only seen approximately 10 d after PLP was first detected in the cytoplasm of fixed and permeabilized cells, suggesting that PLP is slowly transported from the RER to the cell surface. The presence of PLP domains on the extracellular surface was also confirmed by cleavage of such domains with proteases and by antibody-dependent complement-mediated lysis of living oligodendrocytes. Our results indicate that PLP has only two transmembrane domains and that the great majority of the protein, including its amino and carboxy termini, is located on the extracellular face of the oligodendrocyte plasma membrane. This disposition of the PLP molecule suggests that homophilic interactions between PLP molecules of apposed extracellular faces may mediate compaction of adjacent bilayers in the myelin sheath.

Surfactant chemical composition and biophysical activity in acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung injury and damage to the alveolar type II cells. This study sought to determine if endogenous surfactant is altered in ARDS. Bronchoalveolar lavage was performed in patients at-risk to develop ARDS (AR, n = 20), with ARDS (A, n = 66) and in normal subjects (N, n = 29). The crude surfactant pellet was analyzed for total phospholipids (PL), individual phospholipids, SP-A, SP-B, and minimum surface tension (STmin). PL was decreased in both AR and A (3.48 +/- 0.61 and 2.47 +/- 0.40 mumol/ml, respectively) compared to N (7.99 +/- 0.60 mumol/ml). Phosphatidylcholine was decreased in A (62.64 +/- 2.20% PL) compared to N (76.27 +/- 2.05% PL). Phosphatidylglycerol was 11.58 +/- 1.21% PL in N and was decreased to 6.48 +/- 1.43% PL in A. SP-A was 123.64 +/- 20.66 micrograms/ml in N and was decreased to 49.28 +/- 21.68 micrograms/ml in AR and to 29.88 +/- 8.49 micrograms/ml in A. SP-B was 1.28 +/- 0.33 micrograms/ml in N and was decreased to 0.57 +/- 0.24 micrograms/ml in A. STmin was increased in AR (15.1 +/- 2.53 dyn/cm) and A (29.04 +/- 2.05 dyn/cm) compared to N (7.44 +/- 1.61 dyn/cm). These data demonstrate that the chemical composition and functional activity of surfactant is altered in ARDS. Several of these alterations also occur in AR, suggesting that these abnormalities occur early in the disease process.

Novel member of the zinc finger superfamily: A C2-HC finger that recognizes a glia-specific gene.

A novel member of the zinc finger superfamily was cloned by virtue of its binding to cis-regulatory elements of a glia-specific gene, the myelin proteolipid protein (PLP) gene. Named MyTI (myelin transcription factor I), this gene is most highly transcribed in the developing nervous system, where expression precedes induction of its presumptive target, PLP. Low levels of MyTI transcripts can be detected in nonneural tissues only by polymerase chain reaction analysis. Zinc is a necessary cofactor for DNA binding of MyTI, as the zinc-chelating agent 1,10-orthophenanthroline eliminates binding activity. Zinc may stabilize the DNA-binding domain of MyTI by coordinating three cysteine and one histidine residue in a Cys-X5-Cys-X12-His-X4-Cys (C2-HC) arrangement. The MyTI protein has six fingers of the C2-HC class arranged in two widely separated clusters. These two domains of DNA binding can function independently and recognize the same DNA sequence, suggesting that MyTI may contribute to the higher-order structure of a target promoter by simultaneously binding both proximal and distal sites. The six fingers are highly conserved, suggesting that they arose from successive duplication events, while the linker regions diverge in size and sequence. Both amino acid sequence comparisons and secondary-structure predictions indicate that the C2-HC fingers of MyTI do not resemble the zinc-mediated loops of C2-H2 fingers, C2-C2 fingers, or Cx clusters. MyTI may therefore be the prototype of a new structural family of zinc-stabilized DNA binding proteins.

Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta).

To determine the physiological roles of peroxisome proliferator-activated receptor beta (PPARbeta), null mice were constructed by targeted disruption of the ligand binding domain of the murine PPARbeta gene. Homozygous PPARbeta-null term fetuses were smaller than controls, and this phenotype persisted postnatally. Gonadal adipose stores were smaller, and constitutive mRNA levels of CD36 were higher, in PPARbeta-null mice than in controls. In the brain, myelination of the corpus callosum was altered in PPARbeta-null mice. PPARbeta was not required for induction of mRNAs involved in epidermal differentiation induced by O-tetradecanoylphorbol-13-acetate (TPA). The hyperplastic response observed in the epidermis after TPA application was significantly greater in the PPARbeta-null mice than in controls. Inflammation induced by TPA in the skin was lower in wild-type mice fed sulindac than in similarly treated PPARbeta-null mice. These results are the first to provide in vivo evidence of significant roles for PPARbeta in development, myelination of the corpus callosum, lipid metabolism, and epidermal cell proliferation.

Disseminated Nocardia caviae with positive blood cultures.

Disseminated Nocardia caviae infection with multiple positive blood cultures occurred in a bone marrow transplant recipient. Positive blood cultures are unusual in disseminated Nocardia infections and N caviea is an unusual species of Nocardia to cause infections in man, although its virulence in laboratory animals is similar to N asteroides. Multiple positive blood cultures in this case suggest a continuous or recurrent bacteremia rather than a transient bacteremia as previously has been thought to occur in disseminated Nocardia infections. The marked immunosuppressed state of the patient and an indwelling venous line could also have accounted for the recurrent bacteremia.

Subcutaneous and mediastinal emphysema. Pathophysiology, diagnosis, and management.

Subcutaneous emphysema and pneumomediastinum occur frequently in critically ill patients in association with blunt or penetrating trauma, soft-tissue infections, or any condition that creates a gradient between intra-alveolar and perivascular interstitial pressures. A continuum of fascial planes connects cervical soft tissues with the medlastinum and retroperitoneum, permitting aberrant air arising in any one of these areas to spread elsewhere. Diagnosis is made in the appropriate clinical setting by careful physical examination and inspection of the chest roentgenogram. While the presence of air in subcutaneous or mediastinal tissue is not dangerous in itself, prompt recognition of the underlying cause is essential. Certain trauma-related causes may require surgical intervention, but the routine use of chest tubes tracheostomy, or mediastinal drains is not recommended.

Pulmonary function of marrow transplant patients. I. Effects of marrow infusion, acute graft-versus-host disease, and interstitial pneumonitis.

The pulmonary function of patients receiving marrow transplants was studied during a two-year period. The 81 patients studied before transplantation showed a slight reduction in average lung volumes and diffusing capacity (DLCO). Studies were repeated within 48 h after marrow infusion to look for evidence of fat embolism syndrome. There was no change in the DLCO, but there was a 4% decrease in the lung volumes. Sixty-three patients (20 with aplastic anemia, 43 with hematologic malignancies) completed studies on admission and every other week during hospitalization (mean of six studies per patient). When categorized by diagnosis or conditioning regimen (including with and without total body irradiation), no differences were seen. The patients developing interstitial pneumonitis (IP) had restrictive ventilatory changes and decreases in the DLCO. The patients not developing IP remained unchanged. The patients developing IP averaged a 20% decrease in the DLCO before the clinical diagnosis of pneumonia, but a decrease in the DLCO lacked specificity for predicting occurrence of IP. Among 18 patients developing graft-versus-host disease, there was no evidence of air-flow obstruction. We conclude that patients developing IP have restrictive ventilatory changes, but in the absence of complicating IP, the marrow transplant regimen (including marrow infusion and total body irradiation) leaves pulmonary function largely unchanged.

High-grade human brain tumors exhibit increased expression of myelin transcription factor 1 (MYT1), a zinc finger DNA-binding protein.

Detection and characterization of distinct central nervous system (CNS) tumor cell types is clinically important since distinct tumor types are associated with different prognoses and treatments. However, there is currently a lack of markers to identify certain glioma types and insufficient understanding as to which cells give rise to different glioma cell types. In the present study, biopsy specimens from human brain tumors were analyzed for expression of Myelin Transcription Factor 1 (MYT1) to explore the extent to which glioma cells reflect characteristic expression of MYT1 in developing glial progenitor cells. Immunostaining with an antibody against MYT1 revealed widespread immunoreactivity that was most prominent in high-grade oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas as well as in a dysembryoplastic neuroepithelial tumor. MYT1 immunoreactivity in tumor regions generally correlated with the prevalence of cells exhibiting nuclear immunolabeling with an antibody against Ki-67, suggesting an association of MYT1 with cell proliferation that was also observed in normal adult human and rat brain in the germinal subependymal zone. The MYT1 immunoreactivity was frequently nuclear, appearing as dotted or punctate, but in some cases it was localized to the cytoplasm. In combination with histopathological studies and analysis of Ki-67 immunoreactivity, examination of MYT1 immunolabeling may provide additional information to aid in the detection and diagnosis of CNS tumors.

Chronic relapsing experimental autoimmune encephalomyelitis: effects of insulin-like growth factor-I treatment on clinical deficits, lesion severity, glial responses, and blood brain barrier defects.

Chronic relapsing experimental autoimmune encephalomyelitis (crEAE), a model for multiple sclerosis, was used to test 2 regimens of insulin-like growth factor-I (IGF-I) treatment. We induced crEAE by injecting 3x10(7) myelin basic protein-(MBP) sensitized lymph node cells into adult female SJL/J mice. Fifty-one mice, divided randomly into 4 groups, were used in the first trial. Two groups received IGF-I (a gift of Cephalon, Inc.) 0.6 mg/kg/d subcutaneously from day 7 to day 16 and the other two groups received placebo injections. IGF-I treatment reduced clinical deficits during the first attack and during 2 subsequent relapses. Image analysis of immunostained and histological sections showed that IGF-I treatment reduced BBB defects and both the numbers and sizes of inflammatory, demyelinating, and demyelinated lesions. Twelve mice that had recovered from their first attack were used in our second trial to evaluate possible adverse effects of prolonged treatment with a higher dose of IGF-I. Six received 1.2 mg/kg/d for 6 weeks (days 19-63). No adverse effects of IGF-I treatment were identified. The eyes, hearts, livers, and kidneys of IGF-I-treated mice were normal histologically and their spleens also appeared normal except for mild to moderate microscopic increases in lymphopoesis. Our results suggest that prolonged IGF-I treatment is well tolerated and that the anti-inflammatory effects of IGF-I have a major role in reducing clinical deficits and lesion severity in crEAE. These effects, if present in multiple sclerosis, may benefit patients with this disease.

Effect of diazepam on ventilatory responses.

To investigate the effects of diazepam on ventilatroy control, hypoxic and hypercapnic ventilatory responses were studied in 8 normal subjects before and after 10 mg of intramuscular diazepam. There was no significant change in either resting minute ventilation or resting end-tidal CO2 tension, but depression of hypoxic ventilatory response was observed 15 (60% of control) and 30 min (53% of control) after diazepam (p less than 0.05). No significant depression of hypercapnic ventilatory response was noted 70 to 130 min after diazepam. In view of the depression of hypoxic ventilatory response by diazepam in normal subjects, adverse responses along these lines should be considered in patients with impaired ventilatory function, such as chronic airways obstruction, and in those encountering acute hypoxemia.

Pulmonary responses to smoke inhalation: morphologic changes in rabbits exposed to pine wood smoke.

Inhalation of smoke can adversely affect pulmonary function; however, the lack of detailed knowledge of exposure conditions and the overall complexity of ensuing clinical problems generally preclude an understanding of the specific role played by smoke in human victims. Using controlled exposures of rabbits to white pine wood smoke, an animal model of smoke inhalation has been created. Light and electron microscopic examinations of injured respiratory tissues from these animals have revealed a reproducible, necrotizing tracheobronchial epithelial cell injury. By six hours after injury, the epithelium remains largely intact but is infiltrated by inflammatory cells; by 24 hours its ciliated and secretory lining cells are largely destroyed, the inflammatory reaction is maximal, but basal epithelial cells retain their normal structural appearances; by 72 hours, its surfaces are largely covered by a nonciliated, stratified reparative epithelium, apparently derived from proliferating and migrating basal cells. The acute injury and early reactions to injury resemble lesions observed in the lungs of human smoke-injured victims, and suggest several physiologic consequences that would provide likely explanations for some of the disabilities observed in these victims.

Severe precocious emphysema in intravenous methylphenidate (Ritalin) abusers.

Intravenous (IV) drug abuse is known to cause pulmonary tale granulomatosis. Reports have documented a syndrome of pulmonary vascular sclerosis in long-term IV methylphenidate users. Although this would be expected to produce restrictive lung disease, we hereby report six patients who have severe obstructive lung disease. All had used IV methylphenidate for at least four years. One of these patients died of progressive respiratory insufficiency and the others are clinically disabled. Their symptoms and airflow obstruction are more severe than those of most patients with chronic obstructive pulmonary disease. In these individuals, we cannot say that precocious obstructive lung disease is not due to a combination of smoking and other factors, nor can we be certain that methylphenidate is the offending agent. However, this cluster of cases among methylphenidate abusers suggests that long-term IV exposure to this drug might lead to early severe obstructive lung disease.

Hospitalization needs during an outpatient rehabilitation program for severe chronic airway obstruction.

The number of days of hospitalization for respiratory disease following entry into an outpatient pulmonary rehabilitation program was reviewed for 44 patients with chronic airway obstruction whose hospitalization records were available for the year prior to entry into the program. A significant reduction in the number of days of hospitalization occurred in patients for each of the four years following entry into the program, compared to the year prior to therapy.

Expression of the tissue specific splicing protein SmN in neuronal cell lines and in regions of the brain with different splicing capacities.

The SmN protein is closely related to the ubiquitously expressed SmB and B' RNA splicing proteins but is expressed in only a limited range of tissues and cell types. The expression of SmN in a range of neuronal and non-neuronal cell lines correlates with their ability to splice the calcitonin/CGRP transcript to produce the mRNA encoding CGRP rather than that encoding calcitonin. Moreover, the SmN mRNA shows a widespread distribution within the brain and spinal ganglia being present in neuronal cells in all regions which naturally produce CGRP as well as in those areas which do not naturally express the calcitonin/CGRP gene but which can correctly splice the CGRP mRNA in transgenic mice expressing the calcitonin/CGRP gene in all cell types. Interestingly however the mRNA encoding SmN is also found in a few areas of the brain which can only carry out calcitonin-specific splicing in transgenic mice, such as the Purkinje layer of the cerebellum and the inferior colliculus. The possible role of SmN in the regulation of splicing in neuronal cells is discussed in the light of these results.

Total lung capacity. An insensitive measure of impairment in patients with asbestosis and chronic obstructive pulmonary disease?

The total lung capacity (TLC) is frequently used as a measure of respiratory impairment in patients with asbestosis. Because asbestosis and chronic obstructive pulmonary disease (COPD) exert opposite effects on the TLC, it may be an insensitive measure of impairment in patients with both abnormalities. To assess this, we compared asbestos-exposed patients with functional evidence of COPD and radiographic evidence of interstitial fibrosis (group 1) to those with interstitial fibrosis alone (group 2). Despite the two groups being comparable in degree of radiographic "fibrosis," no case of restrictive impairment (reduced TLC) was identified among those with both interstitial fibrosis and COPD (group 1), compared to 33 percent of those with interstitial fibrosis alone (group 2). In addition, those patients with both interstitial fibrosis and COPD, compared to those with interstitial fibrosis alone, were found to have greater impairment as measured by alveolar-arterial oxygen difference and diffusing capacity. We conclude that the TLC is an insensitive measure of impairment due to asbestosis in patients with the common setting of coexistent asbestosis and COPD.

Variability of arterial blood gas values in stable patients in the ICU.

To establish guidelines for the interpretation of changes in arterial blood gas (ABG) values, we studied 29 clinically stable ICU patients for spontaneous variability in PaO2, PaCO2 and pH. ABGs were sampled six times over a 50-minute period, during which all patients received a fixed FIO2 of 0.5 via endotracheal tube and underwent no therapeutic interventions. Each sample was analyzed in duplicate with careful attention to method of collection and measurement. The range separating the lowest and highest PaO2 varied from 1 to 45 mm Hg (16.2 +/- 10.9 mm Hg [mean +/- SD] ). For PaCO2 this range was from 1 to 8 mm Hg (3.0 +/- 1.9 mm Hg). Coefficient of variation for PaO2 and PaCO2 averaged 5.1 +/- 3.2 percent (mean +/- SD) and 3.0 +/- 1.5 percent respectively. pH varied within 0.03 +/- 0.02 units. Percentage change in PaO2 between sequential intrapatient samples averaged 5.3 +/- 2.8 percent (mean +/- SD) and 7.1 +/- 7.9 percent over ten- and 50-minute intervals, respectively. Various clinical features were analyzed by multiple regression analysis for their relation to PaO2 variation. Only leukocyte count and mean arterial oxygen content were statistically significant associations (p less than 0.05), but together explained less than 35 percent of the variation observed. Because considerable spontaneous variation occurs, even in stable patients, clinicians should base therapeutic decisions on trends in PaO2 values rather than on isolated changes interpreted without appropriate clinical correlation.