A rare presentation of Klebsiella pneumoniae Endogenous Panophthalmitis with Optic Neuritis and Orbital Cellulitis from a Urinary Tract Infection

This case illustrates the rare presentation of endogenous Klebsiella pneumoniae endophthalmitis with concomitant orbital cellulitis from an acute pyelonephritis. A 59-year-old Caucasian female with type 2 diabetes mellitus was transferred from a regional hospital with decreased visual acuity, periorbital edema, photophobia, proptosis and pain of the right eye, as well as suprapubic discomfort. Initial ocular examination and B-scan ultrasonography were consistent with endophthalmitis and orbital cellulitis which lead to a vitreous tap and intravitreal antibiotics injection and systemic antibiotherapy. Vitreous and blood cultures confirmed Klebsiella pneumoniae as the causative organism. An orbital MRI showed a panophthalmitis with optic neuritis and further imaging confirmed a concomitant pyelonephritis secondary to a septic nephrolithiasis. The patient was given treatment with high-does intravenous antibiotics, oral and topical corticotherapy, and an early core pars plana vitrectomy (PPV), performed 5 days after presentation with repeat injections of antibiotics and dexamethasone. Unfortunately, two weeks following PPV, despite an initial stable postoperative course, the patient deteriorated and presented with purulent discharge from one of the vitrectomy port incision site. An emergency evisceration was performed in order to control the infection, revealing a large subretinal abscess and necrosed sclerotic tissue around the prior vitrectomy incision sites. Conclusion: This is the first case report of Klebsiella pneumoniae endophthalmitis or panophthalmitis presenting with orbital cellulitis and optic neuritis from an urinary tract infection. Prognosis is poor despite treatment including early vitrectomy

Multiple Promoters and Alternative Splicing: Hoxa5 Transcriptional Complexity in the Mouse Embryo

The genomic organization of Hox clusters is fundamental for the precise spatio-temporal regulation and the function of each Hox gene, and hence for correct embryo patterning. Multiple overlapping transcriptional units exist at the Hoxa5 locus reflecting the complexity of Hox clustering: a major form of 1.8 kb corresponding to the two characterized exons of the gene and polyadenylated RNA species of 5.0, 9.5 and 11.0 kb. This transcriptional intricacy raises the question of the involvement of the larger transcripts in Hox function and regulation.We have undertaken the molecular characterization of the Hoxa5 larger transcripts. They initiate from two highly conserved distal promoters, one corresponding to the putative Hoxa6 promoter, and a second located nearby Hoxa7. Alternative splicing is also involved in the generation of the different transcripts. No functional polyadenylation sequence was found at the Hoxa6 locus and all larger transcripts use the polyadenylation site of the Hoxa5 gene. Some larger transcripts are potential Hoxa6/Hoxa5 bicistronic units. However, even though all transcripts could produce the genuine 270 a.a. HOXA5 protein, only the 1.8 kb form is translated into the protein, indicative of its essential role in Hoxa5 gene function. The Hoxa6 mutation disrupts the larger transcripts without major phenotypic impact on axial specification in their expression domain. However, Hoxa5-like skeletal anomalies are observed in Hoxa6 mutants and these defects can be explained by the loss of expression of the 1.8 kb transcript. Our data raise the possibility that the larger transcripts may be involved in Hoxa5 gene regulation.Our observation that the Hoxa5 larger transcripts possess a developmentally-regulated expression combined to the increasing sum of data on the role of long noncoding RNAs in transcriptional regulation suggest that the Hoxa5 larger transcripts may participate in the control of Hox gene expression

Ephrin-B1 forward and reverse signaling are required during mouse development

Eph receptors and ephrin ligands are key players in many developmental processes including embryo patterning, angiogenesis, and axon guidance. Eph/ephrin interactions lead to the generation of a bidirectional signal, in which both the Eph receptors and the ephrins activate downstream signaling cascades simultaneously. To understand the role of ephrin-B1 and the importance of ephrin-B1-induced reverse signaling during embryonic development, we have generated mouse lines carrying mutations in the efnb1 gene. Complete ablation of ephrin-B1 resulted in perinatal lethality associated with a range of phenotypes, including defects in neural crest cell (NCC)-derived tissues, incomplete body wall closure, and abnormal skeletal patterning. Conditional deletion of ephrin-B1 demonstrated that ephrin-B1 acts autonomously in NCCs, and controls their migration. Last, a mutation in the PDZ binding domain indicated that ephrin-B1-induced reverse signaling is required in NCCs. Our results demonstrate that ephrin-B1 acts both as a ligand and as a receptor in a tissue-specific manner during embryogenesis

In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis

Integration of diverse signaling pathways is essential in development and homeostasis for cells to interpret context-dependent cues. BMP and MAPK signaling converge on Smads, resulting in differential phosphorylation. To understand the physiological significance of this observation, we have generated Smad1 mutant mice carrying mutations that prevent phosphorylation of either the C-terminal motif required for BMP downstream transcriptional activation (Smad1(C) mutation) or of the MAPK motifs in the linker region (Smad1(L) mutation). Smad1(C/C) mutants recapitulate many Smad1(-/-) phenotypes, including defective allantois formation and the lack of primordial germ cells (PGC), but also show phenotypes that are both more severe (head and branchial arches) and less severe (allantois growth) than the null. Smad1(L/L) mutants survive embryogenesis but exhibit defects in gastric epithelial homeostasis correlated with changes in cell contacts, actin cytoskeleton remodeling, and nuclear β-catenin accumulation. In addition, formation of PGCs is impaired in Smad1(L/L) mutants, but restored by allelic complementation in Smad1(C/L) compound mutants. These results underscore the need to tightly balance BMP and MAPK signaling pathways through Smad1

: un maître d’oeuvre à multiples facettes

Les gènes Hox représentent une vaste famille de facteurs de transcription qui interagissent avec l’ADN par le biais d’un motif protéique de 60 acides aminés, l’homéodomaine. Chez les mammifères, 39 gènes Hox sont distribués en quatre complexes, HoxA, B, C et D, chacun situé sur un chromosome différent. Ces gènes Hox sont organisés en 13 groupes paralogues sur la base de la conservation de leurs séquences codantes et de leur position le long des complexes. Les conséquences phénotypiques de leur invalidation chez la souris, caractérisées par des phénomènes d’antériorisation ou de postériorisation du squelette axial, des anomalies du système nerveux et des défauts lors des processus d’organogenèse, suscitent l’intérêt de la communauté scientifique depuis près de 20 ans. Une certaine redondance fonctionnelle existe entre les gènes Hox et les phénotypes observés ont permis d’établir l’action concertée des gènes Hox au sommet de hiérarchies moléculaires contrôlant la spécification de l’identité cellulaire le long des axes de l’embryon et orchestrant le développement global de l’organisme. Malgré la démonstration des fonctions essentielles de ces gènes au cours du développement, la compréhension de leur mode d’action et des mécanismes de leur régulation demeure toujours incomplète. Le gène Hoxa5 appartient à cette grande famille et les souris invalidées pour ce gène présentent un large spectre d’anomalies affectant ses différents sites d’expression au cours du développement

Correlates of disrupted sleep-wake variables in patients with advanced cancer

Objectives : High rates of sleep difficulties have been found in patients with advanced cancer. However, not much is known about factors that are associated with sleep impairments in this population and that could constitute their potential risk factors or consequences. This study conducted in patients with cancer receiving palliative care aimed to evaluate the relationships of subjective (sleep diary; Insomnia Severity Index, ISI) and objective (actigraphy) sleep–wake variables with several physical and psychological symptoms, maladaptive sleep behaviours, erroneous beliefs about sleep, quality of life, time to death and environmental factors. Methods : The sample was composed of 57 community-dwelling patients with cancer receiving palliative care and with an Eastern Cooperative Oncology Group Scale score of 2 or 3. Actigraphic, light and sound recording and a daily sleep and pain diary were completed for seven consecutive days. A battery of self-report scales was also administered. Results : Greater disruptions of subjective and objective sleep–wake variables were more consistently associated with worse physical symptoms than with psychological variables. Disrupted objective sleep–wake parameters were also associated with a greater frequency of maladaptive sleep behaviours. Finally, a greater nocturnal noise in the bedroom was correlated with more impairments in subjective and objective sleep–wake variables while a lower 24-hour light exposure was associated with more disruption of subjectively assessed sleep only. Conclusions : Although longitudinal studies are needed to establish the etiology of sleep–wake difficulties in patients with advanced cancer, our findings suggest that physical symptoms, maladaptive sleep behaviours and environmental factors can contribute to their development or their persistence and need to be adequately addressed

Recurrent and De Novo Toxoplasmosis Retinochoroiditis following Coronavirus Disease 2019 Infection or Vaccination

This study reports three cases of toxoplasmosis retinochoroiditis following coronavirus disease 2019 (COVID-19) infection or vaccination from the national Canadian COVID-19 Eye Registry between December 2020 and September 2021. A 56-year-old male presented 15 days after a positive COVID-19 test with toxoplasmosis retinochoroiditis. He later relapsed 8 days following a first Pfizer-BioNTech vaccine dose. Two patients presented with toxoplasmosis retinochoroiditis following COVID-19 vaccination: A 58-year-old female presenting 4 days following a first Pfizer-BioNTech vaccine dose with anterior uveitis and a posterior pole lesion discovered 3 months later and a 39-year-old female presenting 17 days after a first Moderna vaccine dose. Resolution was achieved with oral clindamycin, oral trimethoprim/sulfamethoxazole, and topical prednisolone acetate 1%. Patients were offered prophylactic trimethoprim/sulfamethoxazole for subsequent doses without relapse. Following COVID-19 infection or vaccination, patients may be at risk for toxoplasmosis retinochoroiditis. Prophylactic antibiotics for future doses may be offered to patients with known ocular toxoplasmosis to prevent recurrence

Feasibility of a cognitive-behavioral and environmental intervention for sleep-wake difficulties in community-dwelling cancer patients receiving palliative care

Abstract BACKGROUND: High rates of sleep-wake difficulties have been found in patients with cancer receiving palliative care. Pharmacotherapy is the most frequently used treatment option to manage these difficulties despite numerous adverse effects and the absence of empirical evidence of its efficacy and innocuity in palliative care. OBJECTIVE: This pilot study aimed to assess the feasibility and acceptability of a cognitive-behavioral and environmental intervention (CBT-E) to improve insomnia and hypersomnolence in patients with a poor functioning level and to collect preliminary data on its effects. METHODS: Six patients with cancer receiving palliative care (Eastern Cooperative Oncology Group score 2-3), who had insomnia and/or hypersomnolence, received 1 CBT-E individual session at home. They applied the strategies for 3 weeks. Patients completed the Insomnia Severity Index, the Epworth Sleepiness Scale, a daily sleep diary, and a 24-hour actigraphic recording (7 days) at pretreatment and posttreatment, in addition to a semistructured interview (posttreatment). RESULTS: Participants found strategies easy to apply most of the time, and none was rated as impossible to use because of their health condition. However, their adherence and satisfaction toward CBT-E were highly variable. Results on the effects of CBT-E were heterogeneous, but improvements were observed in patients with a persistent insomnia disorder. CONCLUSIONS: The CBT-E protocol tested among this highly selected sample was fairly well received and suggested positive outcomes in some patients, particularly those with an insomnia complaint alone. IMPLICATIONS: Efforts should be pursued to adapt CBT-E and develop other nonpharmacological interventions, in order to provide an alternative to pharmacotherapy for sleep-wake difficulties in this population

Early Postnatal Lethality inHoxa-5Mutant Mice Is Attributable to Respiratory Tract Defects

AbstractTo uncover roles for theHoxa-5gene during embryogenesis, we have focused on identifying structural and functional defects in organ systems underlying the perinatal lethality inHoxa-5homozygous mutants. Analysis of the mutant phenotype shows thatHoxa-5is essential for normal organogenesis and function of the respiratory tract. In homozygous newborn mutants, improper tracheal and lung morphogenesis can lead to tracheal occlusion, and to respiratory distress associated with a marked decrease in the production of surfactant proteins. Collectively, these defects likely underlie the pronounced mortality of homozygous mutant pups. Furthermore, the loss ofHoxa-5function results in alteredTTF-1, HNF-3β,and N-mycgene expression in the pulmonary epithelium. Since expression ofHoxa-5is confined to the mesenchymal component of the developing trachea and lung, the effects observed in epithelial cells may result from a disruption of normal epithelial–mesenchymal interactions

Sleep-wake difficulties in community-dwelling cancer patients receiving palliative care : subjective and objective assessment

Objective : Prevalence rates of sleep difficulties in advanced cancer patients have varied widely across studies (12 to 96%), and none of these employed a diagnostic interview to distinguish different types of sleep–wake disorders. Moreover, very limited information is available on subjective and objective sleep parameters in this population. Our study was conducted in palliative cancer patients and aimed to assess rates of sleep–wake disorders and subsyndromal symptoms and to document subjective and objective sleep–wake parameters across various types of sleep–wake difficulties. Method : The sample was composed of 51 community-dwelling cancer patients receiving palliative care and having an Eastern Cooperative Oncology Group score of 2 or 3. Relevant sections of the Duke Interview for Sleep Disorders were administered over the phone. An actigraphic recording and a daily sleep diary were completed for 7 consecutive days. Results : Overall, 68.6% of the sample had at least one type of sleep–wake difficulty (disorder or symptoms): 31.4% had insomnia and 29.4% had hypersomnolence as their main sleep–wake problem. Participants with insomnia as their main sleep difficulty had greater disruptions of subjective sleep parameters, while objectively-assessed sleep was more disrupted in patients with hypersomnolence comorbid with another sleep–wake difficulty. Significance of the Results : The high rates of sleep–wake difficulties found in this study indicate a need to screen more systematically for sleep–wake disorders, including insomnia and hypersomnolence, in both palliative care research and clinical practice, and to develop effective nonpharmacological interventions specifically adapted to this population