A 10-year longitudinal follow-up study of a U.K. paediatric transplant population to assess for skin cancer.

BACKGROUND: Our earlier study, published in 2004,found no skin cancer in a cohort of paediatric organ transplant recipients (POTRs) 5-16 years post-transplantation. We re-evaluated the same cohort 10 years later. OBJECTIVES: To determine the prevalence of premalignant and malignant skin lesions and identify known risk factors associated with melanocytic naevi in a U.K. paediatric transplant population. METHODS: Ninety-eight POTRs from the original 2004 study were invited to participate in this longitudinal follow-up study. History of sun exposure, demographics and transplantation details were collected using face-to-face interviews, questionnaires and case note reviews. Skin examination was performed for regional count of malignant lesions, benign and atypical naevi. RESULTS: Of the 98 patients involved in the initial study, 45 POTRs (eight kidney, 37 liver), with a median follow-up of 19 years (range 15-26 years), agreed to participate. Neither skin cancer nor premalignant lesions were detected in these patients. When compared with the 2004 cohort, 41 patients in our current cohort had increased numbers of benign naevi (P < 0·001) with 11 patients having ≥ 50 benign naevi. Seventy-one per cent of benign naevi in our 2014 cohort occurred on sun-exposed sites (13% head/neck, 35% arms and 23% legs). Patients who regularly used sunscreen had more benign naevi on their arms (P = 0·008). CONCLUSIONS: Although skin cancer was not observed in our cohort, we identified a significant increase in the number of benign naevi, particularly in those reporting frequent sunburn and sunscreen use.

A diagnostic challenge: acute generalized exanthematous pustulosis or pustular psoriasis due to terbinafine.

A 72-year-old man developed a generalized erythematous pustular eruption 11 weeks after commencing terbinafine. Clinically and histologically, the appearance was that of acute generalized exanthematous pustulosis (AGEP), and the disease was managed with topical preparations. Initial improvement was marred by relapse of acute pustulosis, now more in keeping with terbinafine-induced pustular psoriasis (PP), which was successfully treated with acitretin. This case highlights the difficulty of differentiating between AGEP and PP.

Noncytotoxic antibodies to paternal antigens in maternal sera and placental eluates.

Noncytotoxic antibodies were detected in sera from 6 of 7 primigravid women during the first trimester of pregnancy. Such antibodies directed to antigens expressed on paternal B lymphocytes were detectable within the first 4-5 weeks of gestation. Antibody activity toward paternal B lymphocytes was also detected in 6 of 10 placental eluates, and in 3 of 10 predelivery and 2 of 10 postdelivery maternal serum samples. When B lymphocytes from umbilical cord blood were used as target cells, antibodies were detected in 5 of 7 placental eluates, and in 3 of 7 predelivery and 2 of 7 postdelivery serum samples. These antibodies also reacted with selected members of a normal B lymphocyte panel. The concept of an immunological enhancing mechanism in normal pregnancy is supported by these data.

The relationship between changing values of pregnancy-associated plasma protein-A in late pregnancy and the onset of labour.

The pattern of change of PAPP-A was established in three separate groups of patients. Day-to-day change from the 38th week was measured in six healthy patients whose pregnancies ended in spontaneous labour. The slow fluctuations of PAPP-A suggest that values found in labour are a consequence of events prior to the onset of labour. Increases of PAPP-A during the last few days of pregnancy and into labour were compared in patients going into labour spontaneously and patients who were induced. The induced patients showed a sharper increase in PAPP-A during this interval than the spontaneous onset group. A comparison at an earlier stage of pregnancy of PAPP-A increase was made between normal pregnancies going into labour on or before 280 days and those who went into labour later. Between 31 +/- 1 and 35 +/- 1 weeks, those who delivered in the earlier group showed a sharper rise in PAPP-A. It seems likely that the behaviour of PAPP-A in late pregnancy is the consequence of uterine activity and it seems unlikely that an increasing level of PAPP-A in itself has anything to do with the initiation of spontaneous labour.

High-dose azathioprine in children with inflammatory bowel disease.

BACKGROUND: Azathioprine is widely used as maintenance therapy in children with moderate to severe inflammatory bowel disease (IBD). There is no data on safety at higher doses and its impact on growth and surgical morbidity in children. METHODS: This retrospective cohort study included all children treated with azathioprine and diagnosed with IBD between 1996-2001. Outcome measures included indications for azathioprine use, adverse-effects and reasons for treatment discontinuation. Height and weight at diagnosis, treatment onset and current follow-up was recorded, and Z scores for height standardised for time. RESULTS: 107 children received azathioprine at 3 mg/kg. 61% had Crohn's disease and 83% started azathioprine within 2 years of diagnosis. Only 2/107 children had to stop azathioprine because of persistent adverse effects and 16/107 required surgery. There was a trend toward better growth in a group of children with Crohn's disease following treatment with high dose azathioprine therapy (P = 0.08). CONCLUSIONS: Azathioprine is a safe and well-tolerated maintenance therapy at 3 mg/kg for children with IBD. The prevalence of surgery and growth failure in a cohort of children with moderate to severe IBD appears less than previously reported. In children with Crohn's disease, growth velocity may be maximised by an emphasis on nutritional therapy and the use of high dose azathioprine.

Low-dose intravenous azathioprine may be effective in the management of acute fulminant colitis complicating inflammatory bowel disease.

BACKGROUND: The management of acute fulminant colitis unresponsive to intravenous steroids is usually surgical. However, recent evidence suggests that intravenous administration of azathioprine at very high doses may allow more rapid onset of clinical efficacy, although its use has not previously been reported in the emergency situation. AIM: To report the successful use of intravenous azathioprine in the management of acute fulminant colitis complicating both Crohn's disease and ulcerative colitis. METHOD: We initially used intravenous azathioprine because of the refusal of the family of the first patient to accept surgery following failure of conventional medical management. Importantly the azathioprine was successful at the low dose of 3 mg/kg.day, equivalent to standard oral doses. Two subsequent patients demonstrated a similar resolution. All were weaned successfully to oral azathioprine and have remained in long-term endoscopic and histological remission. CONCLUSION: These preliminary data suggest that low-dose intravenous azathioprine may be helpful adjunct therapy in selected cases of severe fulminant colitis. However, the need for close monitoring and daily surgical assessment remains paramount, and a formal trial of low-dose intravenous azathioprine is required before it may be more widely recommended.

Spatial distribution of hippocampal-dentate theta rhythm following colchicine injection into the hippocampal formation of the rat.

This investigation confronts the basic question of dentate granule cell participation in the generation of superficial and/or deep theta recorded from the dorsal hippocampal formation in the ether-anesthetized rat. Granular cells were destroyed unilaterally by local injection of 2 micrograms of colchicine (COL) dissolved in 0.2 microliter of distilled water. Hippocampal EEG was recorded 8 days after the neurotoxin injection. The COL injection which destroyed most dentate granular cells but left nearby pyramidal cells of the hippocampal CA1 area virtually unaffected, failed to disrupt significantly either superficial or deep theta. In contrast, the COL injection which destroyed most dentate granular cells and, also, caused some damage to the nearby pyramidal cells of the CA1 area, resulted in a sharp alteration of both theta. These data strongly suggest that granular cells of the dentate gyrus may not be critically involved in theta production, at least in the ether-anesthetized rat. They also confirm a previous conclusion that the neuroanatomical integrity of the CA1 area of the dorsal hippocampus is necessary for the normal appearance and maintenance of both superficial and deep theta. These data are discussed in the context of the generally accepted notion that superficial and deep theta are produced by the rhythmic activity of CA1 pyramidal cells and dentate granular neurons respectively.

Hippocampal-dentate theta disturbance after selective CA1 pyramidal cell damage in the rat.

The contribution of the CA1 area of the dorsal hippocampus to both superficial and deep theta recorded from the dorsal hippocampal formation was assessed in rats anesthetized with ether. CA1 area cells were destroyed unilaterally by local injection of 2 micrograms of ibotenic acid dissolved in 0.1 microliters of phosphate buffer. Limited destruction of CA1 resulted in partial suppression of both superficial and deep theta, whereas extensive destruction resulted in almost total suppression of both theta's. A good correlation was found between the extent of the lesion and the theta disruption. Control preparations involving destructions by means of this neurotoxin of the hippocampal CA3 area or lower blade of the dentate gyrus failed to alter either superficial or deep theta. These data suggest that neuroanatomical integrity of the CA1 area of the dorsal hippocampus is a necessary condition for the normal appearance and maintenance of both superficial and deep theta as recorded from the dorsal hippocampal formation of the ether-anesthetized rat.

Temporal changes in hippocampal theta activity following twenty minutes of forebrain ischemia in the chronic rat.

The present study was designed to examine the temporal changes in the theta (theta) rhythm recorded from the dorsal hippocampal formation of the chronic rat following 20 min of cerebral ischemia. Recordings were made during both wakefulness and paradoxical sleep. The experimental results show that ischemia resulted in a drastic amplitude reduction in both superficial and deep theta. Amplitude reduction occurred between days 1 and 4 postischemia and was maintained across the subsequent survival period. This EEG alteration was associated with an excessive loss of pyramidal cells in the hippocampal CA1 area, as observed by light microscopy. The above data strongly support our previous conclusions that neural components of the CA1 area may be of fundamental importance for the appearance and the maintenance of not only superficial theta but also deep theta. Moreover, they suggest that the preparation used in the present study may be a useful model for investigations on the neuroanatomophysiological effects of transient cerebral ischemia.

Representation of vibrissae inputs through the climbing fiber pathway in lobule VII of the adult rat cerebellar vermis.

The present study gives a detailed description of the functional characteristics and of the topographic distribution of Purkinje cell (PC) responses, mediated through the climbing fiber pathway and elicited by mechanical stimulation of two different rows (A and C) of vibrissae in a circumscribed region of the posterior vermis of the rat cerebellum. Experiments were carried out on normal adult rats under barbiturate anesthesia. PCs were recorded in an area extending 1500 microns laterally to the midline in the vermal part of lobule VII contralateral to the stimulation. Using micromapping techniques and computer analysis, we located the cells on the map of the unfolded PC layer. Taking into account the mean latency of the responses and the probability of discharge of PCs, restricted areas of projection were found. For each row, these areas formed two longitudinal patches located between midline and plane 1100 microns and separated by a non-responsive plane at 500 microns. Cells having the best characteristics of responses to the stimulation of row C were located mainly in plane 200 microns. Cells giving the best responses to the stimulation of row A were located mainly in the posterior part of plane 200 microns which was therefore a zone of convergence for both rows.

Enlargement of olivo-cerebellar microzones in the agranular cerebellum of adult rats.

Previous work on normal adult rat showed that the vibrissae project, through the climbing fiber (CF) system, onto the Purkinje cells (PCs) of the contralateral cerebellar hemivermis of lobule VII. The highly elaborated CF projections from a given row of vibrissae delimit a narrow parasagittal zone which can be regarded as a functional olivo-cerebellar microzone. Interestingly, the adult one-to-one relationship between PCs and CFs is preceded by a transient phase during which each PC receives synaptic inputs from several CF collaterals which will be eliminated but one, when granule cells begin to establish synapses on PCs. Therefore, the question arose as to whether this synaptic elimination process could participate in the refinement of the topographical organization of CF projections and could contribute to the formation of such precise peripheral maps onto the cerebellum. In the present study, the topographical map of the CF-mediated projection of mystacial vibrissae onto the vermal PCs of lobule VII was determined in adult rats whose cerebellar PCs remain polyinnervated by olivary CFs due to degranulation by postnatal X-irradiation. Using intracellular recordings, we examined the responsiveness of PCs in lobule VII during mechanical stimulation of the 3rd row of contralateral vibrissae, and positioned cells responding to the stimulation on an averaged planar map of lobule VII. Comparison of the results to those obtained in our previous work on normal rats showed that the activated cells were more numerous and more diffusely distributed.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal ipsilateral functional vibrissae projection onto Purkinje cells multiply innervated by climbing fibers in the rat.

We have previously shown that synapse elimination occurring in the climbing fiber (CF)-Purkinje cell (PC) relationships during normal postnatal development is likely involved in the refinement of vibrissae projections onto the cerebellar cortex. In normal adult rats, CF-mediated vibrissae projections onto cerebellar Purkinje cells of the vermis of lobule VII are strictly contralateral and located in a narrow microzone whereas they are widely distributed in rats whose PCs remained multiply innervated by CFs due to postnatal irradiation. Given the proximity of this microzone to the midline, the question arose as to whether this synapse elimination process could participate in the segregation of ipsilateral and contralateral projections. In the present study, we compared the topographical map of the ipsilateral and contralateral CF-mediated projections of the third row of vibrissae onto the vermal PCs of lobule VII in adult normal rats and in polyinnervated rats. Using intracellular electrophysiological recordings, we examined the responsiveness of PCs to mechanical stimulation of vibrissae, and positioned responsive cells on an averaged planar map of lobule VII. In normal rats no ipsilateral responses were found, while in irradiated rats ipsilateral responses were distributed evenly from the midline to 700 microns apart. These results suggest that synapse elimination participates in the segregation of ipsi and contralateral mystacial inputs to the vermis.

Extent of multiple innervation of cerebellar Purkinje cells by climbing fibers in adult X-irradiated rats. Comparison of different schedules of irradiation during the first postnatal week.

The multiple innervation of cerebellar Purkinje cells (PCs) by climbing fibers (CFs) that is transient in normal developing rats can be experimentally maintained in cerebella which have been degranulated by repetitive postnatal X-irradiation restricted to the first postnatal week. Since the involution of redundant CFs occurs essentially between postnatal days 5 and 10, and given that postirradiation effects last 2-3 days, the question arose to know whether it is possible to further delimit a 'critical period' of irradiation within the first week. An estimate of the extent of multiple innervation of PCs by CFs was made in adult rats that had been irradiated according to 5 different schedules: in two groups, rats received X-rays applied repetitively during the first postnatal week (PN0-7 groups); in the 3 other groups, X-rays were delivered either during the first part of the week (early group PN1-3) or during the last part of the week (late groups PN4-7). In addition, two daily doses were tested (150 and 200 r). The CF pathway was electrically stimulated in anesthetized rats at the level of the inferior olive or in the cerebellar white matter. Intracellular recordings of spontaneous and evoked CF responses in PCs allowed to estimate the number of afferent CFs and to calculate the mean value (m) per PC for each group. The majority of recorded cells was located in lobules VII and VIII and similar results were obtained in these two lobules.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammon's horn commissural responses in young rabbits.

Different responses evoked by stimulation of contralateral hippocampus at various levels are examined in new-born rabbits up to 1 month of age. Commissural fibres coming from the CA3-CA4 reach the contralateral regio superior (CA1) essentially at the st. oriens levels. CA1 responses elicited by stimulation of the contralateral CA1 in the st. oriens (commissural CA3 fibres) or in the st. radiatum (Schaffer's collaterals) are present at any age. For the regio inferior (CA3-CA4), the distribution of commissural fibres is more diffuse. Before 5--6 days, CA3-CA4 fields do not respond to a contralateral stimulation and do not give contralateral responses, showing that fibres and cells are not yet organized.

Human placenta--an antibody sponge?

Maternal IgG antibodies in sera and placenta eluates were studied by a cellular enzyme-linked immunosorbent assay (CELISA) method. Antibodies were not detectable in any of the serum samples obtained before or after delivery from nine normal primigravid women. Antibody activity was, however, present in five of nine placental eluates and two of nine neonatal sera tested in CELISA. Lymphocytotoxic antibodies were not detected in any of the samples tested. These results support the concept that the absence of antibody activity in maternal sera may be caused by the immunosorbent effect of the placenta.

Persistent wheezing and gastroesophageal reflux in infants.

We have evaluated the presence of gastroesophageal reflux (GER) and the effect of its treatment in 12 infants (mean age, 7 months; range, 4-11 months) with persistent wheezing not responding to bronchodilators and anti-inflammatory asthma medications. All patients had GER on cineradiography and significant acid reflux on 24 hour pH monitoring (percentage of time pH < 4 ranged from 6.1 to 47%). All infants were initially treated with prokinetic agents and with receptor histamine antagonists in addition to aggressive pulmonary therapy. Six patients treated medically had substantially decreased use of asthma medications, completely discontinuing them within 2-4 months. Two patients, though significantly improved, require intermittent asthma therapy. Four patients responding poorly to GER and asthma treatment for 2 months to 2 years had fundoplications. These had an excellent outcome over 1-4.5 years follow-up; only one patient required further asthma medications. Pulmonary function testing was done in six patients before and after 6-8 weeks of therapy indicating significant improvement in peripheral airflow: terminal flow/peak tidal expiratory flow (TEF25/PTEF), and percentage of total expiratory time to reach peak tidal expiratory flow (Tp/Te or Tme/Te). Our experience suggests that evaluation for GER should be considered in infants with persistent wheezing. Aggressive medical and possibly surgical therapy for GER may resolve persistent wheezing.

Treatment of traveller's diarrhoea. Economic aspects.

Traveller's diarrhoea (TD) is an enteric infective disease seen in 30 to 50% of the 30 million people who travel annually from the developed world to developing countries. It is the commonest disorder affecting international travellers. Although usually trivial, a significant minority of patients may develop a more protracted disease with an attendant increase in morbidity. This may then incur financial costs to the travellers themselves and to the healthcare systems of the host and origin countries. Advice regarding risk avoidance has so far proved ineffective in altering the behaviour of travellers and consequently the incidence of TD among them. Hard data are lacking on the cost effectiveness and cost benefit of prophylaxis and treatment of TD. Thus, we have attempted to quantify, as far as is possible, the total cost of TD and to set this against the potential savings from avoiding TD if prophylaxis or treatment options were universally employed. It must be noted that the financial benefit-cost ratio of an intervention may not be the most suitable measure of its desirability. However, such concepts as the success of travel are inherently difficult to quantify in economic terms. This analysis applies to travellers from the UK and economic variations between countries will after the outcomes obtained. Nevertheless, given these necessary constraints, all possible treatment options have a more favourable benefit-cost ratio than prophylaxis. In conclusion, the case for prophylaxis is not strong except in selected high risk groups, and limited self-treatment seems economically justified.

Nutritional growth retardation is associated with defective lung growth in cystic fibrosis: a preventable determinant of progressive pulmonary dysfunction.

Evidence for a relationship between nutritional growth retardation in cystic fibrosis (CF) and progressive pulmonary dysfunction was evaluated by a prospective longitudinal study of changes in nutritional growth parameters, in relation to changes in pulmonary function data, in 61 moderately affected CF patients, aged 5-17 yr, during the equilibrated phase of lung growth. Age, sex, initial and serial weight and height Z scores, body cell mass (BCM) by total-body potassium (TBK) analysis, and changes in forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), excluding data during pulmonary exacerbations, were analyzed by multiple regression analyses. The only significant predictor of change in FVC (best-fit model) was change in BCM, expressed as TBK (g/yr), TBK for age (percentage predicted), and TBK for height (percentage predicted) (p < 0.01). Standard anthropometric variables were not predictive. No reliable predictive model emerged for changes in FEV1. Relative decline in TBK for age was strongly predictive of decline in FVC (percentage predicted) accounting for 23% of this change. Patients with normal growth of the BCM had significantly less decline in FVC than those with retarded growth of the BCM (a fall of 2.5 vs. 6.8%/yr, p < 0.01). Impaired growth of the metabolically active BCM appears to be associated with progressive lung dysfunction in CF, possibly mediated by impaired lung growth. Achieving optimal nutrition and growth may minimize the progressive decline in pulmonary function commonly seen in this disease.

Efficacy of electromyographic biofeedback compared with conventional physical therapy for upper-extremity function in patients following stroke: a research overview and meta-analysis.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the efficacy of electromyographic biofeedback compared with conventional physical therapy for improving upper-extremity function in patients following a stroke. SUBJECTS AND METHODS: A literature search was done for the years 1976 to 1992. The selection criteria included single-blinded randomized control trials. Study quality was assessed for nine criteria. For functional (disability index or stage of recovery) and impairment outcomes, meta-analyses were performed on odds ratios for improvement versus no improvement. Mann-Whitney U-Test probability values were combined across studies. RESULTS: Six studies were selected, and outcome data were obtained for five studies. The common odds ratio was 2.2 for function and 1.1 for impairments in favor of biofeedback. The estimate of the number needed to treat to prevent a nonresponder was 11 for function and 22 for impairments. None of the meta-analyses were statistically significant. CONCLUSIONS AND DISCUSSION: The results do not conclusively indicate superiority of either form of therapy. Although there is a chance of Type II error, the estimated size of the effect is small. Given this estimate of little or no difference, therapists need to consider cost, ease of application, and patient preference when selecting these therapies.

Effect of station examination item sampling on generalizability of student performance.

This article may be of interest to physical therapy educators who are responsible for structuring station or practical examinations used to evaluate physical therapy students. The global intent of the article is to provide information that may be useful in selecting test items. Specifically, the purposes of this study were 1) to examine how two item-sampling strategies (one based on different diagnostic concepts, or diagnostic probes, and the other based on different anatomical sites) influenced the generalizability of a station examination, 2) to determine the interrater reliability during the station examination, and 3) to determine whether the status of the rater (that of observer or simulated patient) influenced the rating. Using a nested study design, 24 physical therapy students were assessed by eight raters. The raters were randomly and equally assigned to four teams. Each team assessed six students. One rater acted as the simulated patient for the first three students in each group, and the other rater acted as observer. This order was reversed for the last three students. Each student performed nine mini-diagnostic patient cases consisting of three diagnostic probes reproduced at three different anatomical sites. The results demonstrate that 1) similar diagnostic concepts can be generalized across anatomical sites, although different concepts or skills cannot be generalized at a given anatomical site or across sites; 2) interrater reliability was excellent; and 3) the status of the raters (ie, simulated patient or observer) did not bias the ratings.(ABSTRACT TRUNCATED AT 250 WORDS)