Familial rare EGFR-mutant lung cancer syndrome: Review of literature and description of R776H family.

BACKGROUND: Interest in hereditary lung cancer is increasing, in particular germline mutations in the Epidermal Growth Factor Receptor (EGFR) gene. We review the current literature on this topic, discuss risk of developing lung cancer, treatment and screening options and describe a family of 3 sisters with lung cancer and their unaffected mother all with a rare EGFR germline mutation (EGFR p.R776H). METHODS: We searched PubMed, Medline, Embase, the Cochrane Library, Google Scholar and scanned reference lists of articles. Search terms included "EGFR germline" and "familial lung cancer" or "EGFR familial lung cancer". We also describe our experience of managing a family with rare germline EGFR mutant lung cancer. RESULTS: Although the numbers are small, the described cases in the literature show several similarities. The patients are younger and usually have no or light smoking history. 50% of the patients were treated with a tyrosine kinase inhibitor (TKIs) with OS over six months. CONCLUSION: Although rare, germline p.R776H EGFR lung cancer mutations are over-represented in light or never smoking female patients who often also possess an additional somatic EGFR mutation. Treatment with TKIs appears suitable but further research is needed into the appropriate screening regime for unaffected carriers or light/never smokers.

Transmission of canine transmissible venereal tumour between two dogs in the UK.

Canine transmissible venereal tumour (CTVT) is a contagious cancer spread by transfer of living cancer cells. Occasional cases are observed in the UK in dogs imported from endemic regions. Here, we report a case of imported canine transmissible venereal tumour that was transmitted to a second dog within the UK. Transmission of genital canine transmissible venereal tumour occurred despite neutered status of the second dog. The aggressive course of disease in both cases, which included metastasis, resistance to therapeutic interventions and ultimate euthanasia of both dogs, is described. The diagnosis of canine transmissible venereal tumour was made using a combination of cytology, histology, immunohistochemistry and PCR to detect the LINE-MYC rearrangement. Practitioners unfamiliar with canine transmissible venereal tumour are reminded of this disease of concern, particularly when imported dogs are placed in multi-dog households, irrespective of neuter status.

Testing spatial working memory in pigs using an automated T-maze.

Pigs are an important large animal model for translational clinical research but underutilized in behavioral neuroscience. This is due, in part, to a lack of rigorous neurocognitive assessments for pigs. Here, we developed a new automated T-maze for pigs that takes advantage of their natural tendency to alternate. The T-maze has obvious cross-species value having served as a foundation for cognitive theories across species. The maze (17' × 13') was constructed typically and automated with flanking corridors, guillotine doors, cameras, and reward dispensers. We ran nine pigs in (1) a simple alternation task and (2) a delayed spatial alternation task. Our assessment focused on the delayed spatial alternation task which forced pigs to wait for random delays (5, 60, 120, and 240 s) and burdened spatial working memory. We also looked at self-paced trial latencies, error types, and coordinate-based video tracking. We found pigs naturally alternated but performance declined steeply across delays (R2 = 0.84). Self-paced delays had no effect on performance suggestive of an active interference model of working memory. Positional and head direction data could differentiate subsequent turns on short but not long delays. Performance levels were stable over weeks in diverse strains and sexes, and thus provide a benchmark for future neurocognitive assessments in pigs.

Optogenetic silencing of a corticotropin-releasing factor pathway from the central amygdala to the bed nucleus of the stria terminalis disrupts sustained fear.

The lateral central nucleus of the amygdala (CeAL) and the dorsolateral bed nucleus of the stria terminalis (BNSTDL) coordinate the expression of shorter- and longer-lasting fears, respectively. Less is known about how these structures communicate with each other during fear acquisition. One pathway, from the CeAL to the BNSTDL, is thought to communicate via corticotropin-releasing factor (CRF), but studies have yet to examine its function in fear learning and memory. Thus, we developed an adeno-associated viral-based strategy to selectively target CRF neurons with the optogenetic silencer archaerhodopsin tp009 (CRF-ArchT) to examine the role of CeAL CRF neurons and projections to the BNSTDL during the acquisition of contextual fear. Expression of our CRF-ArchT vector injected into the amygdala was restricted to CeAL CRF neurons. Furthermore, CRF axonal projections from the CeAL clustered around BNSTDL CRF cells. Optogenetic silencing of CeAL CRF neurons during contextual fear acquisition disrupted retention test freezing 24 h later, but only at later time points (>6 min) during testing. Silencing CeAL CRF projections in the BNSTDL during contextual fear acquisition produced a similar effect. Baseline contextual freezing, the rate of fear acquisition, freezing in an alternate context after conditioning and responsivity to foot shock were unaffected by optogenetic silencing. Our results highlight how CeAL CRF neurons and projections to the BNSTDL consolidate longer-lasting components of a fear memory. Our findings have implications for understanding how discrete amygdalar CRF pathways modulate longer-lasting fear in anxiety- and trauma-related disorders.

The Equine Movement Disorder "Shivers" Is Associated With Selective Cerebellar Purkinje Cell Axonal Degeneration.

"Shivers" is a progressive equine movement disorder of unknown etiology. Clinically, horses with shivers show difficulty walking backward, assume hyperflexed limb postures, and have hind limb tremors during backward movement that resembles shivering. At least initially, forward movements are normal. Given that neither the neurophysiologic nor the pathologic mechanisms of the disease is known, nor has a neuroanatomic locus been identified, we undertook a detailed neuroanatomic and neuropathologic analysis of the complete sensorimotor system in horses with shivers and clinically normal control horses. No abnormalities were identified in the examined hind limb and forelimb skeletal muscles nor the associated peripheral nerves. Eosinophilic segmented axonal spheroids were a common lesion. Calretinin-positive axonal spheroids were present in many regions of the central nervous system, particularly the nucleus cuneatus lateralis; however, their numbers did not differ significantly from those of control horses. When compared to controls, calretinin-negative, calbindin-positive, and glutamic acid decarboxylase-positive spheroids were increased 80-fold in Purkinje cell axons within the deep cerebellar nuclei of horses with shivers. Unusual lamellar or membranous structures resembling marked myelin decompaction were present between myelin sheaths of presumed Purkinje cell axons in the deep cerebellar nuclei of shivers but not control horses. The immunohistochemical and ultrastructural characteristics of the lesions combined with their functional neuroanatomic distribution indicate, for the first time, that shivers is characterized by end-terminal neuroaxonal degeneration in the deep cerebellar nuclei, which results in context-specific hypermetria and myoclonus.

Posture and movement characteristics of forward and backward walking in horses with shivering and acquired bilateral stringhalt.

REASONS FOR PERFORMING STUDY: To investigate and further characterise posture and movement characteristics during forward and backward walking in horses with shivering and acquired, bilateral stringhalt. OBJECTIVES: To characterise the movement of horses with shivering (also known as shivers) in comparison with control horses and horses with acquired bilateral stringhalt. STUDY DESIGN: Qualitative video analysis of gait in horses. METHODS: Owners' and authors' videos of horses with shivering or stringhalt and control horses walking forwards and backwards and manually lifting their limbs were examined subjectively to characterise hyperflexion, hyperextension and postural abnormalities of the hindlimbs. The pattern and timing of vertical displacement of a hindlimb over one stride unit was evaluated among control, shivering and stringhalt cases. RESULTS: Gait patterns of shivering cases were characterised as follows: shivering-hyperextension (-HE, n = 13), in which horses subjectively showed hyperextension when backing and lifting the limb; shivering-hyperflexion (-HF, n = 27), in which horses showed hindlimb hyperflexion and abduction during backward walking; and shivering-forward hyperflexion (-FHF, n = 4), which resembled shivering-HF but included intermittent hyperflexion and abduction with forward walking. Horses with shivering-HF, shivering-FHF and stringhalt (n = 7) had a prolonged swing phase duration compared with control horses and horses with shivering-HE during backward walking. With the swing phase of forward walking, horses with stringhalt had a rapid ascent to adducted hyperflexion of the hindlimb, compared with a rapid descent of the hindlimb after abducted hyperflexion in horses with shivering-FHF. CONCLUSIONS: Shivering affects backward walking, with either HE or HF of hindlimbs, and can gradually progress to involve intermittent abducted hyperflexion during forward walking. Shivering-HF and shivering-FHF can look remarkably similar to acquired bilateral stringhalt during backward walking; however, stringhalt can be distinguished from shivering-HF by hyperflexion during forward walking and from shivering-FHF by an acute onset of a more consistent, rapidly ascending, hyperflexed, adducted hindlimb gait at a walk.

Epidemiology of shivering (shivers) in horses.

REASONS FOR PERFOMING STUDY: Investigating the epidemiology of shivering in horses. OBJECTIVES: The purpose of this study was to characterise the signalment, clinical signs and management factors associated with shivering (also known as shivers), a relatively rare, poorly defined movement disorder in horses. STUDY DESIGN: Web-based case series survey and case-control study. METHODS: A Web-based survey was used to obtain information from owners, worldwide, who suspected that their horse had shivering. Survey respondents were asked to answer standardised questions and to provide a video of the horse. Authors reviewed the surveys and videos, and horses were diagnosed with shivering if they displayed normal forward walking, with difficulty during manual lifting of the hoof and backward walking due to hyperflexion or hyperextension of the pelvic limbs. Cases confirmed by video were designated 'confirmed shivering', while those with compatible clinical signs but lacking video confirmation were designated 'suspected shivering'. Owners of confirmed shivering horses were asked to provide information on 2 horses without signs of shivering (control group). RESULTS: Three hundred and five surveys and 70 videos were received; 27 horses were confirmed shivering (50 controls), 67 were suspected shivering and the rest had a variety of other movement disorders. Suspected shivering horses resembled confirmed shivering cases, except that the suspected shivering group contained fewer draught breeds and fewer horses with exercise intolerance. Confirmed shivering signs often began at <5 years of age and progressed in 74% of cases. Owner-reported additional clinical signs in confirmed cases included muscle twitching (85%), muscle atrophy (44%), reduced strength (33%) and exercise intolerance (33%). Shivering horses were significantly taller (confirmed shivering, mean ∼173 cm; control horses, ∼163 cm) with a higher male:female ratio (confirmed shivering, 3.2:1 vs. control, 1.7:1). No potential triggering factors or effective treatments were reported. CONCLUSIONS: Shivering is a chronic, often gradually progressive movement disorder that usually begins before 7 years of age and has a higher prevalence in tall male horses.

Pituitary null cell adenoma in a domestic llama (Lama glama).

Pituitary gland neoplasia has been reported rarely in camelids. A 12-year-old neutered male llama (Lama glama) presented with lethargy, inappetence and neurological signs. On physical examination, the llama was mentally dull and exhibited compulsive pacing and circling to the left. Complete blood count and serum biochemistry revealed haemoconcentration, mild hypophosphataemia, hyperglycaemia, hypercreatininaemia and hyperalbuminaemia. Humane destruction was elected due to rapid clinical deterioration and poor prognosis. Post-mortem examination revealed a pituitary macroadenoma and bilateral internal hydrocephalus. Microscopically, the pituitary tumour was composed of neoplastic chromophobic pituitary cells. Ultrastructural studies revealed similar neoplastic cells to those previously described in human null cell adenomas. Immunohistochemically, the neoplastic cells were strongly immunoreactive for neuroendocrine markers (synaptophysin and chromogranin A), but did not exhibit immunoreactivity for epithelial, mesenchymal, neuronal and all major pituitary hormone markers (adrenocorticotropic hormone, follicle stimulating hormone, growth hormone, luteinizing hormone, melanocyte-stimulating hormone, prolactin and thyroid stimulating hormone), consistent with the diagnosis of a pituitary null cell adenoma. This is the first report of pituitary neoplasia in a llama.

Qualitative research in nutrition and dietetics: data collection issues.

The wide scope of qualitative enquiry presents the researcher with a number of choices regarding data collection and sampling. Selecting data collection and sampling techniques can therefore be somewhat daunting, particularly because, often, there is no single, universally accepted 'correct' option. Appropriate research methods are, however, crucial to ensure high-quality research. This review, the second in the series, provides an overview of the principal techniques of data collection and sampling that may be used for qualitative research in nutrition and dietetics. In addition, it describes a process for choosing appropriate data collection and sampling methods that considers the extent to which they provide data that answers the research question(s) and are compatible with the philosophical assumptions about ontology, epistemology and methodology that underpin the overall design of a study. Finally, it discusses the central role that the researcher plays in qualitative data collection and encourages researchers to acknowledge and reflect upon their impact on the data. Other reviews in this series provide a model for embarking on a qualitative research project in nutrition and dietetics, an overview of the principal techniques of data analysis and quality assessment of this kind of research, and some practical advice relevant to nutrition and dietetics, along with glossaries of key terms.

Association of the melioidosis agent Burkholderia pseudomallei with water parameters in rural water supplies in Northern Australia.

We analyzed water parameters and the occurrence of the melioidosis agent Burkholderia pseudomallei in 47 water bores in Northern Australia. B. pseudomallei was associated with soft, acidic bore water of low salinity but high iron levels. This finding aids in identifying water supplies at risk of contamination with this pathogenic bacterium.

Dual sensitization to rat and mouse urinary allergens reflects cross-reactive molecules rather than atopy.

BACKGROUND: Sensitization to rats and mice can develop in laboratory animal workers exposed to only one species. Reasons for this dual sensitization are unclear but may reflect a genetic predisposition to developing allergy (atopy) or alternatively cross-reactivity between rat and mouse urinary allergens. We examined cross-reactivity between rat and mouse urine and the effect atopy has on dual sensitization in laboratory animal workers. METHODS: In a cross-sectional study the frequency of sensitization to rat and/or mouse was analysed in 498 employees exposed to both rat and mouse at work and 220 to rat only. RAST inhibitions, western blots and blot inhibitions were carried out on a subset of five individuals to assess cross-reactivity. RESULTS: Fourteen per cent of workers were sensitized to rats and 9% to mouse. Over half (62%) of rat sensitized individuals were also mouse sensitized and the majority (91%) of mouse sensitized individuals were also rat sensitized. IgE cross-reactivity was demonstrated between rat and mouse urine using RAST inhibitions. Rates of atopy did not differ between rat only sensitized individuals compared with those sensitized to both species. Sensitization to cats and rabbits was more common amongst those with dual sensitization. CONCLUSIONS: Dual sensitization to rat and mouse reflects IgE cross-reactivity rather than atopy. Individuals with dual sensitization are more likely to be sensitized to other animal allergens. These findings will have implications for individuals working with only one rodent species who develop sensitization and symptoms to be aware of the potential for allergy to other species.

The nutritional vulnerability of older Guyanese in residential homes / Vulnerabilidad nutricional de los ancianos guyaneses en los hogares de ancianos

OBJECTIVE: To assess the nutritional status, functional ability and food intake of older Guyanese in residential care. METHODS: Eighty-four residents of one public and two private homes underwent an anthropometric and functional ability assessment including height, weight, armspan, arm and calf circumferences and handgrip strength. Food intake in two private homes was measured over seven days by direct weighing and the use of consumption units. RESULTS: The overall prevalence of underweight was 26.2% and of overweight was 17.8% but the prevalence of underweight was higher in the public home (29.3% underweight and 17.2% overweight in the public home, and 19.2% underweight and 19.2% overweight in the private home). Mean handgrip strength was 26 kg in males and 17.7 kg in females. The nutritional adequacy of the diet provided by one of the homes was poor with the food providing less than 50% of the required amount of zinc and vitamins A, D and C. Neither home met the requirement for energy. CONCLUSION: A high prevalence of malnutrition exists in a public home for the elderly and, to a lesser degree, in two private homes. In the context of a rapidly ageing population and tight financial constraints, the challenge of providing an adequate diet must be given priority.

Objetivo: Evaluar el estatus nutricional, la capacidad funcional, y la ingestión de alimentos de ancianos guyaneses en el cuidado residencial. Métodos: Ochenta y cuatro residentes de dos hogares privados y uno público fueron sometidos a una evaluación antropométrica y de su capacidad funcional, que incluyó altura, peso, medida de la distancia de los brazos abiertos, brazos, circunferencias de la pantorrilla, y fuerza del puño. La ingestión de alimentos en dos hogares privados fue medida durante siete días mediante el peso directo y el uso de unidades de consumo. Resultados: La prevalencia general del bajo peso corporal fue de 26.2% y la del peso corporal excesivo de 17.8%, pero la prevalencia del bajo peso fue más alta en el hogar público (29.3% de bajo peso frente a 17.2% de peso excesivo en el hogar público, y 19.2% de bajo peso frente a 19.2% de peso excesivo en el hogar público). La fuerza media del puño fue 26 kg en los hombres y 17.7 kg en las mujeres. La adecuación nutricional de la dieta suministrada por uno de los hogares fue pobre, formada por alimentos que proveían menos del 50% de las cantidades requeridas de zinc y vitaminas A, D, y C. Ninguno de los hogares satisfacía los requerimientos energéticos. . Conclusion: En el hogar público para los ancianos, la prevalencia de la malnutrición es alta en grado alarmante, y lo mismo ocurre, en menor grado, en los dos hogares privados. En el contexto de una población que se avejenta rápidamente y que experimenta serias limitaciones financieras, hay que dar prioridad al reto de suministrar una dieta adecuada.

The nutritional vulnerability of older Guyanese in residential homes.

OBJECTIVE: To assess the nutritional status, functional ability and food intake of older Guyanese in residential care. METHODS: Eighty-four residents of one public and two private homes underwent an anthropometric and functional ability assessment including height, weight, armspan, arm and calf circumferences and handgrip strength. Food intake in two private homes was measured over seven days by direct weighing and the use of consumption units. RESULTS: The overall prevalence of underweight was 26.2% and of overweight was 17.8% but the prevalence of underweight was higher in the public home (29.3% underweight and 17.2% overweight in the public home, and 19.2% underweight and 19.2% overweight in the private home). Mean handgrip strength was 26 kg in males and 17.7 kg in females. The nutritional adequacy of the diet provided by one of the homes was poor with the food providing less than 50% of the required amount of zinc and vitamins A, D and C. Neither home met the requirement for energy. CONCLUSION: A high prevalence of malnutrition exists in a public home for the elderly and, to a lesser degree, in two private homes. In the context of a rapidly ageing population and tight financial constraints, the challenge of providing an adequate diet must be given priority.

Determination of the T cell epitopes of the lipocalin allergen, Rat n 1.

BACKGROUND: Laboratory animal allergy (LAA) is an important cause of occupational sensitization and asthma. Rats are a frequent cause of LAA and the major rat allergen, Rat n 1, is a member of the lipocalin protein family, which includes several other animal allergens such as the cow allergen, Bos d 2. To date, Bos d 2 is the only mammalian lipocalin allergen to have been studied in detail. OBJECTIVE: We undertook a cross-sectional study of a large population of individuals exposed to laboratory rats to determine the proliferative responses of peripheral blood mononuclear cells (PBMCs) to the major rat allergen, Rat n 1. METHODS: Eighty-three cases (defined by a positive skin prick test (SPT) > or =3 mm and/or a positive RAST > or =2% binding) and 274 referents without specific IgE to rats were tested for their proliferative responses of PBMCs to rat allergen. Cytokine release to rat urinary protein was examined in 28 sensitized and 42 non-sensitized exposed individuals. RESULTS: Proliferation to rat urinary protein was weak in all individuals. Four regions within Rat n 1 were identified as containing potential immunodominant T cell epitopes and three of these co-localized within the conserved regions of the lipocalin molecule. All four regions within Rat n 1 overlapped considerably with the characterized epitopes of the lipocalin allergen, Bos d 2. IL-5 and ratios of IL-5/IFN-gamma were significantly increased in cases. CONCLUSION: The response to Rat n 1 is remarkably similar to the cow lipocalin allergen Bos d 2. T cell epitopes within lipocalins appear to co-localize with the conserved regions of the molecule. LAA is characterized by an increased production of IL-5. Investigation of other lipocalin allergens will provide further information about the allergenicity of this group of proteins.

Non-invasive ventilation to avoid tracheal intubation in a patient with Guillain-Barré syndrome.

A 72-yr-old man presented with respiratory failure secondary to Guillain-Barré syndrome. Although the criteria for mechanical ventilation were satisfied, the absence of weakness of the bulbar muscles allowed the safe use of non-invasive ventilation for 2 weeks in this patient. Invasive ventilation and tracheostomy were avoided and the patient made a good recovery.

Estimating the incidence of occupational asthma and rhinitis from laboratory animal allergens in the UK, 1999-2000.

We report a survey of the number of persons handling laboratory animals in the UK in 1999-2000. This estimate has allowed us to calculate annual incidence rates of allergic asthma and rhinitis attributable to laboratory animals, insects, and birds using numerators derived from cases reported to a national surveillance scheme (SWORD). The number of exposed employees has almost halved since the early 1980s. From these data, the estimated annual incidence rate of occupational asthma among persons working with small mammals is 1.56/1000 employees. Although reported cases are rare, estimated incidence rates of asthma attributable to birds (23.9/1000/year) and insects (2.35/1000/year) are high.

Occupational asthma from fungicides fluazinam and chlorothalonil.

We report two cases of occupational asthma caused by sensitisation to powdered fungicides fluazinam and chlorothalonil, from the same fungicide formulation plant. Both developed work related lower respiratory symptoms after a latent interval of asymptomatic exposure. The diagnosis in each case was confirmed with a serial peak flow record in the workplace followed by specific inhalation tests. These fungicides are known to cause dermatitis; this report indicates that these compounds can induce specific immunological reactions in the airways as well as skin.