A Summer School for Special Children,September 1991

A summer school for seven children provided a therapeutic environment in which emotional needs could be addressed. This approach led to gains in development and reductions in severe behaviour disturbance. The scheme utilised finance from the health authority and the Mental Health Foundation, staff on short-term contracts and a variety of help from existing resources. The combined effort ensured a crisis-free summer and presented evidence of a way of working that is beneficial to some very disturbed children.     

Cytomegalovirus-induced pathology in human temporal bones with congenital and acquired infection

ObjectivePublications on histopathology of human temporal bones with cytomegalovirus (CMV) infection are limited. We aim to determine histopathology of the inner ears and the middle ears in human temporal bones with congenital and acquired CMV infections.MethodsTemporal bones from 2 infants with congenital and 2 adults with acquired CMV infection were evaluated by light microscopy.ResultsTwo infants with congenital CMV infection showed striking pathological changes in the inner ear. There was a hypervascularization of the stria vascularis in the cochlea of the first infant, but no obvious loss of outer and inner hair cells was seen in the organ of Corti. However, cytomegalic cells and a loss of outer hair cells were found in the cochlea of the second infant. The vestibular organs of both infants showed cytomegalic cells, mostly located on dark cells. There was a loss of type I and type II hair cells in the macula of the saccule and utricle. Loss of hair cells and degeneration of nerve fibers was also seen in the semicircular canals. Both infants with congenital infection showed abundant inflammatory cells and fibrous structures in the middle ear cavity. No evidence of cytomegalic cells and hair cell loss was found in the cochlea or vestibular labyrinth in acquired CMV infection.ConclusionsIn two infants with congenital CMV infection, the cochlea, vestibule, and middle ear were highly affected. Temporal bones of adult donors with acquired viral infection showed histological findings similar to donors of the same age without ear disease.     

Neurobehavioral effects of chronic halothane exposure during developmental and juvenile periods in the rat

Chronic exposure of rats to the surgical anesthetic agent halothane during development has been found to cause both neural and behavioral impairment. Among the halothane-induced deficits are retarded synaptogenesis and impaired spontaneous alternation. It is unclear how long after birth the susceptibility to the neurotoxic effects of halothane persists. The present study compared in rats the effects of halothane exposure on synaptic density and spontaneous alternation during early and late periods of maturation. All three experimental groups were exposed to 100 parts per million of halothane for 8 h/day, 5 days/week. One group (early exposure) was exposed from day 2 of conception until 30 days after birth. The second group (late exposure) was exposed to the same amounts from day 31 until day 90 after birth. The third group (continued exposure) received both periods. The control group was treated in the same way, but was not exposed to halothane. As found in the previous study, there were greater effects of halothane on synaptogenesis than on spontaneous alternation; impairment of spontaneous alternation behavior was found only with the early exposure. Deficits in synaptic density were found with both early and late exposure, although the early exposure had more severe effects. Halting the exposure to halothane on day 30 reinstated control-like rates of synaptogenesis, but the deficit in synaptic density from the early exposure persisted into adulthood. The potent neurotoxic effect of halothane in suppressing synaptogenesis highlights not only its potential as a hazard but also its potential as an experimental tool for manipulating the rate of synaptogenesis and examining the relationship between synaptic development and behavioral maturation.     

Solvent-free synthesis of 3,5-isoxazoles via 1,3-dipolar cycloaddition of terminal alkynes and hydroxyimidoyl chlorides over Cu/Al2O3 surface under ball-milling conditions

Scalable, solvent-free synthesis of 3,5-isoxazoles under ball-milling conditions has been developed. The proposed methodology allows the synthesis of 3,5-isoxazoles in moderate to excellent yields from terminal alkynes and hydroxyimidoyl chlorides, using a recyclable Cu/Al₂O₃ nanocomposite catalyst. Furthermore, the proposed conditions are reproducible to a 1.0-gram scale without further milling time variations.

A practical and scalable mechanochemical 1,3-dipolar cycloaddition between hydroxyimidoyl chlorides and terminal alkynes catalyzed by Cu/Al₂O₃ allows a quick access to 3,5-isoxazole derivatives.

The addition of oxygen or nitrogen-containing heterocycles in drug candidates has become a common feature of the recently approved drugs by the FDA.^1,2 In particular, isoxazoles are common molecular scaffolds employed in medicinal chemistry due to the non-covalent interactions such as hydrogen bonding (through the N) and π–π stacking (by the unsaturated 5-membered ring).^3–6 Within the isoxazole family, 3,5-isoxazoles (1) are regularly utilized as pharmacophores in medicinal chemistry.^2,5,6 Selected examples including muscimol (GABA_a agonist), isocarboxazib (antidepressant), isoxicam (anti-inflammatory), berzosertib (ATR kinase inhibitor), and sulfamethoxazole (antibiotic) are highlighted in Fig. 1.^7–10Open in a separate windowFig. 1Examples of isoxazoles with pharmacological activity.Various methodologies to synthesize 3,5-isoxazoles have been developed over the years.^7,9,11–13 Specifically, 1,3-dipolar cycloaddition between terminal alkynes (2) and nitrile oxides (4) formed in situ by deprotonation of hydroxyimidoyl chlorides (3) is a standard route to access 3,5-isoxazoles (1) (Fig. 2).^7,9,14 Recent reports have sought to mitigate the environmental impact of this reaction by performing 1,3-dipolar cycloaddition under solvent-free conditions, using green solvents such as water or ionic liquids, under metal-free conditions, or using mild oxidants.^14–28 However, these methodologies have a low atom economy, have a higher hazardous waste production, and are less energy efficient. Therefore, developing a greener methodology that enables rapid and efficient access to these scaffolds is highly desirable.Open in a separate windowFig. 21,3-Dipolar cycloaddition of terminal alkynes and nitrile oxides.Mechanochemistry has been recognized as an environmentally friendly technique as reactions can be performed under solvent-free conditions. Additionally, in some instances, work-up and purification are simplified or absent from procedures, and the process consumes less energy than other solution-based techniques.^29–33 The use of mechanochemical techniques to synthesize isoxazoles is limited. Sherin et al. reported a synthesis of 3,5-isoxazoles (7) by grinding in a mortar and pestle curcumin derivatives (5), hydroxylamine (6), and sub-stoichiometric amounts of acetic acid to form the 3,5-isoxazole (7) in short times and excellent yields (Fig. 3a).³⁴ Likewise, Xu et al. studied the synthesis of trisubstituted isoxazoles (10) via 1,3-dipolar cycloaddition of N-hydroxybenzimidoyl chlorides (8) and N-substituted β-enamino carbonyl (9) compounds by ball-milling (Fig. 3b) in high yields, short reaction times, in the absence of catalyst and liquid additives.³⁵ To our knowledge, mechanochemical synthesis of 3,5-isoxazoles (1) from terminal alkynes (2) and hydroxyimidoyl chloride (3) has not been reported (Fig. 3c). The proposed methodology employs a planetary ball-milling technique that provides a route to access in large scale, short reaction times, and high atom economy the corresponding 3,5-isoxazoles (1). Additionally, it utilizes synthetically accessible or commercially available motifs such as terminal alkynes (2) and hydroxyimidoyl chlorides (3) that are recurrent or easily installed in many substrates. Herein, we report a mechanochemical 1,3-dipolar cycloaddition using the planetary ball-mill to synthesize a wide range 3,5-isoxazoles from a broad library of alkynes and (E,Z)-N-hydroxy-4-nitrobenzimidoyl chloride (3a), ethyl (E,Z)-2-chloro-2-(hydroxyimino)acetate (3b), hydroxycarbonimidic dibromide (3c), or (E,Z)-N-hydroxy-4-methoxybenzimidoyl chloride (3d) in moderate to excellent yields, in short reaction time, and with less waste production than in solution based reactions (Fig. 3c).Open in a separate windowFig. 3Previously reported synthesis of isoxazoles.We began our investigation by performing an optimisation of the 1,3-dipolar cycloaddition reaction between alkyne 2a and hydroxyimidoyl chlorides 3a by milling the selected substrates in a stainless-steel (SS) jar in the planetary ball-mill to obtain 3,5-isoxazole 1a (36,37Optimization of reaction conditions^a

Acute surgical wound‐dressing procedure: Description of the steps involved in the development and validation of an observational metric

The aim of this study was to develop an observational metric that could be used to assess the performance of a practitioner in completing an acute surgical wound‐dressing procedure using aseptic non‐touch technique (ANTT). A team of clinicians, academics, and researchers came together to develop an observational metric using an iterative six‐stage process, culminating in a Delphi panel meeting. A scoping review of the literature provided a background empirical perspective relating to wound‐dressing procedure performance. Video recordings of acute surgical wound‐dressing procedures performed by nurses in clinical (n = 11) and simulated (n = 3) settings were viewed repeatedly and were iteratively deconstructed by the metric development group. This facilitated the identification of the discrete component steps, potential errors, and sentinel (serious) errors, which characterise a wound dressing procedure and formed part of the observational metric. The ANTT wound‐dressing observational metric was stress tested for clarity, the ability to be scored, and interrater reliability, calculated during a further phase of video analysis. The metric was then subjected to a process of cyclical evaluation by a Delphi panel (n = 21) to obtain face and content validity of the metric. The Delphi panel deliberation verified the face and content validity of the metric. The final metric has three phases, 31 individual steps, 18 errors, and 27 sentinel errors. The metric is a tool that identifies the standard to be attained in the performance of acute surgical wound dressings. It can be used as both an adjunct to an educational programme and as a tool to assess a practitioner's performance of a wound‐dressing procedure in both simulated and clinical practice contexts.     

Survival of patients with chronic-phase chronic myeloid leukaemia on imatinib after failure on interferon alfa

Until the recent introduction of imatinib, interferon alfa was the standard treatment for patients in the chronic phase of chronic myeloid leukaemia. We compared survival of 143 such patients, who did not respond to interferon alfa and were treated with imatinib, with that of 246 historical controls who received conventional treatment. Patients on imatinib showed an overall survival advantage (relative risk 0.54, 95% CI 0.31-0.93). However, although patients on imatinib who achieved at least some degree of cytogenetic response after 6 months had better survival than controls (0.13, 0.05-0.39), those with no cytogenetic response to imatinib had significantly worse survival (1.69, 1.09-2.64). Our findings suggest that cytogenetic responders obtain benefit from imatinib but patients who show no cytogenetic response should be given alternative treatment without delay. We confirmed these results in a case-matched analysis.     

Autoimmune chronic active hepatitis in Down''s syndrome

Hashimoto's thyroiditis, autoimmune adrenalitis, pernicious anaemia, and diabetes mellitus are all recognised associations with Down's syndrome. In addition chronic active hepatitis (CAH) resulting from chronic hepatitis B antigenaemia is known to occur in these patients, but an association of autoimmune CAH and Down's syndrome has not previously been described. We report a case in which Down's syndrome was associated with autoimmune CAH, Hashimoto's thyroiditis, and alopecia areata.     

Immunoelectron microscopic analysis of a novel carbohydrate differentiation antigen (CDA-3C2) in the developing rat olfactory and otic systems

A carbohydrate differentiation antigen (CDA-3C2) exhibits a highly specific and restricted pattern of expression during rat embryogenesis. In the periphery of the embryo, this antigen is associated transiently with the lateral ectoderm but is retained only in the olfactory and otic epithelium throughout morphogenesis. At the light microscopic level, CDA-3C2 immunoreactivity appears mostly along cell periphery and in the extracellular matrix. The aim of the present study was to determine the specific cellular and subcellular distribution of CDA-3C2 in vivo in order to identify potential sites of cellular and tissue function of the antigen during embryogenesis. There was a strikingly similar subcellular distribution of CDA-3C2 in the developing otic and olfactory systems, found mostly along cell membranes, microvillar projections and acellular secretions of the epithelium. Mature sensory components of the epithelia were not immunoreactive, whereas supportive cells and their secreted structures were densely stained. The highly coincident nature of CDA-3C2 in both sensory epithelia suggests that this carbohydrate epitope, and possibly its carrier macromolecule, participate in a morphogenetic function common to these two sensory epithelia. © Wiley-Liss, Inc.