Propranolol reduces IFN-γ driven PD-L1 immunosuppression and improves anti-tumour immunity in ovarian cancer.

The immune system plays an important role in controlling epithelial ovarian cancer (EOC). EOC is considered to be a "cold tumour," a tumour that has not triggered a strong response by the immune system. However, tumour infiltrating lymphocytes (TILs) and the expression of programmed cell death ligand (PD-L1) are used as prognostic indicators in EOC. Immunotherapy such as PD-(L)1 inhibitors have shown limited benefit in EOC. Since the immune system is affected by behavioural stress and the beta-adrenergic signalling pathway, this study aimed to explore the impact of propranolol (PRO), a beta-blocker, on anti-tumour immunity in both in vitro and in vivo EOC models. Noradrenaline (NA), an adrenergic agonist, did not directly regulate PD-L1 expression but PD-L1 was significantly upregulated by IFN-γ in EOC cell lines. IFN-γ also increased PD-L1 on extracellular vesicles (EVs) released by ID8 cells. PRO significantly decreased IFN-γ levels in primary immune cells activated ex vivo and showed increased viability of the CD8+ cell population in an EV-immune cell co-incubation. In addition, PRO reverted PD-L1 upregulation and significantly decreased IL-10 levels in an immune-cancer cell co-culture. Chronic behavioural stress increased metastasis in mice while PRO monotherapy and the combo of PRO and PD-(L)1 inhibitor significantly decreased stress-induced metastasis. The combined therapy also reduced tumour weight compared to the cancer control group and induced anti-tumour T-cell responses with significant CD8 expression in tumour tissues. In conclusion, PRO showed a modulation of the cancer immune response by decreasing IFN-γ production and, in turn, IFN-γ-mediated PD-L1 overexpression. The combined therapy of PRO and PD-(L)1 inhibitor decreased metastasis and improved anti-tumour immunity offering a promising new therapy.

[A man with pink urine]. / Een man met roze urine.

A 44-year-old male was submitted to the Intensive Care Unit after a drug intoxication with respiratory depression. Pink urine was observed after 20 hours of use of propofol for sedation. This phenomena is named 'pink urine syndrome' and is occasionally seen after sedation with propofol caused by an upregulated urate excretion in the urine.

Is hypnotherapy an acceptable treatment option for children with habit cough?

Habit cough is a chronic, persistent dry cough which occurs in children only when awake. It is considered functional (non-organic) and can have a significant impact on the quality of life of the child and their family. One possible treatment option for habit cough is hypnotherapy. At our centre we offered hypnotherapy sessions to patients diagnosed with habit cough, and conducted telephone interviews with patients' parents to determine the acceptability of this therapy. Nine patients' parents were interviewed, and despite being unsure of what to expect with hypnotherapy, all nine found it an acceptable treatment option. Parents reported that hypnotherapy appeared to result in cough reduction or cessation in 6 out of 9 cases.

The South African universal preschool year: a case study of policy development and implementation.

BACKGROUND: South Africa is the first sub-Saharan African country to legislate, fund and implement free preschool education. Human rights and restitution were at the forefront of the political struggle for democracy in South Africa. Levelling the playing fields by improving the school readiness of children disadvantaged by the racist policies of Apartheid is essential to the transformation of South African society. METHODS: A review of published and unpublished documents on Grade R was undertaken, and access and enrolment data come from the National Department of Basic Education's Education Management Information System (EMIS). RESULTS: A decade after initiation in 2005, 79% of 5-year-olds was enrolled in a preschool class; the vast majority of them in free public schools. Grade R is near universal and on track to becoming compulsory. It is part of the Foundation Phase (Grades 1-3) of schooling, falling under the Department of Basic Education, but also part of a broader national strategy to improve early child development under the direction of an Inter-Departmental Steering. Evaluations demonstrate wide access to Grade R and high uptake, especially in the poorest areas. However, the quality of Grade R provision in these areas is not up to standard because of low levels of funding; inadequate training, supervision, remuneration and retention of Grade R teachers; insufficient learner support materials; and inadequate monitoring and quality assurance. CONCLUSIONS: Lack of quality, amongst other factors, contributes to a widening school performance gap between children from more and less privileged areas. Quality of Grade R as well as earlier learning and subsequent years of schooling must be improved to achieve South Africa's aim to reduce poverty and inequality through, amongst others, parent and family involvement, learning in the home and preschool preparation.

Prioritisation of native legume species for further evaluation as potential forage crops in water-limited agricultural systems in South Africa.

In the face of climate change, identification of forage species suitable for dryland farming under low rainfall conditions in South Africa is needed. Currently, there are only a limited number of forage species suitable for dryland farming under such conditions. The objective of this study was to identify and prioritise native legume species that could potentially be used in dryland farming systems in water-limited agro-ecosystems in South Africa. Using a combination of ecological niche modelling techniques, plant functional traits, and indigenous knowledge, 18 perennial herbaceous or stem-woody legume species were prioritised for further evaluation as potential fodder species within water-limited agricultural areas. These species will be evaluated further for their forage quality and their ability to survive and produce enough biomass under water limitation and poor edaphic conditions.

Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

Loss of pons-to-hypothalamic white matter tracks in brainstem obesity.

Hyperphagia and obesity have been reported following damage to the hypothalamus in humans. Other brain sites are also postulated to be involved in the control of food intake and body weight regulation, such as the amygdala and brainstem. The brainstem, however, is thought to primarily integrate short-term meal-related signals but not affect long-term alterations in body weight, which is controlled by higher centers. The objective of this study was to identify structural pathways damaged in a patient with a brainstem cavernoma who experienced sudden onset of hyperphagia and >50 kg weight gain in <1 year following surgical drainage via a midline suboccipital craniotomy. Diffusion tensor imaging revealed loss of nerve fiber connections between her brainstem, hypothalamus and higher brain centers with preservation of motor tracks. Imaging and endocrine testing confirmed normal hypothalamic structure and function. Gastric bypass surgery restored normal appetite and body weight to baseline. This is the first report of 'brainstem obesity' and adds to the brain regions that can determine the long-term body weight set point in humans.

Bisphosphonate therapy for painless fracture: change of HSAN 1 clinical course with biphosphonate and Vitamin D therapy.

Hereditary Sensory and Autonomic Neuropathies comprise a set of 5 rare neurologic conditions, little known to radiologists as the neurologic and skin abnormalities precede the radiographic changes by months or even years. We report a Caucasian patient with a clinical history of HSAN, most consistent with subtype 1, whose progressive, destructive bone changes of the foot were not only controlled but to a degree reversed by the administration of bisphosphonates (Alendronate ) and vitamin D (Colecalciferol). The authors believe that combined bisphosphonate and vitamin D therapy is the treatment of choice for progressive bony changes in HSAN1. This therapy may be beneficial in other neuropathic osteoarthropathies and possibly osteolytic bone disorders.

46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism.

Familial recurrence risks are poorly understood in cases of de novo mutations. In the event of parental germ line mosaicism, recurrence risks can be higher than generally appreciated, with implications for genetic counseling and clinical practice. In the course of treating a female with pubertal delay and hypergonadotropic hypogonadism, we identified a new missense mutation in the SRY gene, leading to somatic feminization of this karyotypically normal XY individual. We tested a younger sister despite a normal onset of puberty, who also possessed an XY karyotype and the same SRY mutation. Imaging studies in the sister revealed an ovarian tumor, which was removed. DNA from the father's blood possessed the wild type SRY sequence, and paternity testing was consistent with the given family structure. A brother was 46, XY with a wild type SRY sequence strongly suggesting paternal Y-chromosome germline mosaicism for the mutation. In disorders of sexual development (DSDs), early diagnosis is critical for optimal psychological development of the affected patients. In this case, preventive karyotypic screening allowed early diagnosis of a gonadal tumor in the sibling prior to the age of normal puberty. Our results suggest that cytological or molecular diagnosis should be applied for siblings of an affected DSD individual.

Novel mutations in the sacsin gene in ataxia patients from Maritime Canada.

We ascertained two families in Eastern Canada segregating a form of ataxia consistent with a recessive mode of inheritance. We performed a whole genome scan using dense SNP genotyping, and despite an absence of shared homozygosity in the families we defined linkage to a small region on chromosome 13. Direct DNA resequencing was employed to screen biologically relevant candidate genes in the interval, and two presumptive pathogenic mutations were found in the gene encoding sacsin. One variant is an obligate truncating mutation, the second is a missense variant in a highly conserved residue. Unexpectedly, one family was homozygous for the missense mutation, the other compound heterozygous for the two mutations. Our results expand the genotype phenotype correlation of mutations in the sacsin gene, and highlight the challenge of diagnosing genetically heterogeneous disorders on primarily clinical grounds. We demonstrate that whole genome genotyping on a modest scale can be productive in research, and potentially in a clinical context.

Health status, mood, and cognition in experimentally induced subclinical thyrotoxicosis.

OBJECTIVE: Our objective was to determine whether subclinical thyrotoxicosis alters health status, mood, and/or cognitive function. DESIGN: This was a double-blinded, randomized, cross-over study of usual dose l-T(4) (euthyroid arm) vs. higher dose l-T(4) (subclinical thyrotoxicosis arm) in hypothyroid subjects. PATIENTS: A total of 33 hypothyroid subjects receiving l-T(4) were included in the study. MEASUREMENTS: Subjects underwent measurements of health status, mood, and cognition: Short Form 36 (SF-36); Profile of Mood States (POMS); and tests of declarative memory (Paragraph Recall, Complex Figure), working memory (N-Back, Subject Ordered Pointing, and Digit Span Backwards), and motor learning (Pursuit Rotor). These were repeated after 12 wk on each of the study arms. RESULTS: Mean TSH levels decreased from 2.15 to 0.17 mU/liter on the subclinical thyrotoxicosis arm (P < 0.0001), with normal mean free T(4) and free T(3) levels. The SF-36 physical component summary and general health subscale were slightly worse during the subclinical thyrotoxicosis arm, whereas the mental health subscale was marginally improved. The POMS confusion, depression, and tension subscales were improved during the subclinical thyrotoxicosis arm. Motor learning was better during the subclinical thyrotoxicosis arm, whereas declarative and working memory measures did not change. This improvement was related to changes in the SF-36 physical component summary and POMS tension subscales and free T(3) levels. CONCLUSIONS: We found slightly impaired physical health status but improvements in measures of mental health and mood in l-T(4) treated hypothyroid subjects when subclinical thyrotoxicosis was induced in a blinded, randomized fashion. Motor learning was also improved. These findings suggest that thyroid hormone directly affects brain areas responsible for affect and motor function.

Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.

Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

Health status, mood, and cognition in experimentally induced subclinical hypothyroidism.

OBJECTIVE: The objective of the study was to determine whether subclinical hypothyroidism causes decrements in health status, mood, and/or cognitive function. DESIGN: This was a double-blinded, randomized, crossover study of usual dose l-thyroxine (L-T4) (euthyroid arm) vs. lower dose L-T4 (subclinical hypothyroid arm) in hypothyroid subjects. PATIENTS: Nineteen subjects on L-T4 therapy for primary hypothyroidism participated in the study. MEASUREMENTS: Subjects underwent measurements of health status, mood, and cognition using validated instruments: Short Form 36, Profile of Mood States, and tests of declarative memory (paragraph recall, complex figure), working memory (N-back, subject ordered pointing, digit span backward), and motor learning (pursuit rotor). The same measures were repeated after 12 wk on each of the study arms. RESULTS: Mean TSH levels increased to 17 mU/liter on the subclinical hypothyroid arm (P < 0.0001). Mean free T4 and free T3 levels remained within the normal range. The Profile of Mood States fatigue subscale and Short Form 36 general health subscale were slightly worse during the subclinical hypothyroid arm. Measures of working memory (N-back, subject ordered pointing) were worse during the subclinical hypothyroid arm. These differences did not depend on mood or health status but were related to changes in free T4 or free T3 levels. There were no decrements in declarative memory or motor learning. CONCLUSIONS: We found mild decrements in health status and mood in L-T4-treated hypothyroid subjects when subclinical hypothyroidism was induced in a blinded, randomized fashion. More importantly, there were independent decrements in working memory, which suggests that subclinical hypothyroidism specifically impacts brain areas responsible for working memory.

Microscopic intrarenal particles after pulsatile machine preservation do not adversely affect outcomes after renal transplantation.

INTRODUCTION: Our center has recently observed foreign carbohydrate-appearing particles (FP) on transplant postreperfusion biopsy specimens: (PRBx). METHODS: To further characterize FPs, we reviewed all renal transplant RBx (30-45 minutes) performed between September 1, 2004 and December 3, 2005. Donor, preservation, and outcome variables were collected among patients with FP. RESULTS: A total of 135 PRBx were performed (45 deceased donors [DD] and 90 live donors [LD]). Fifteen PRBx demonstrated FP. All 15 cases were DD kidneys that underwent machine perfusion (MP) on the Waters RM3 (Waters Medical Systems, Rochester, Minn, United States) with Belzer MP solution (Trans Med, Elk River, Minn, United States). Donor age was 39.8 +/- 15.7 years. Terminal creatinine level was 1.45 +/- 0.8 mg/dL. Two of 15 were flushed in situ with HTK solution (no starch). Cold ischemia time was 28.8 +/- 9.1 hours with 14.3 +/- 5.1 hours of MP. In 13 of 15 patients, perfusion parameters were excellent (flow > 100 mL; resistance < .35). CHARACTERISTICS OF FP: Particles were 10-30 mu and globular in shape. FP were not visible on hematoxylin and eosin stain, but stained strongly periodic acid-Schiff-(PAS) positive and were refractile under polarized light. FP were seen segmentally within glomerular capillaries in all cases and in peritubular capillaries in 3. In 11 of the 15 cases with FP, focal glomerular fibrin thrombi or intracapillary neutrophil margination was seen. Ten of 15 patients with FP had a biopsy within the first week with no identifiable FP. OUTCOMES: Recipient age was 45.3 +/- 11.6 years. Eight patients (53.3%) had delayed graft function. Biopsy-proven rejection occurred in 3 patients (20%). Three-month creatinine level was 1.59 +/- 0.35 mg/dL. One graft was lost to early thrombosis in a patient with a hypercoagulable state and 1 patient died of sepsis at 2 months. All remaining 13 patients are alive with excellent graft function at a median follow-up of 6.7 months (range, 3-17 months). CONCLUSIONS: Microscopic intrarenal particles may be seen on DD kidney PRBx after MP. These FPs likely originate from surgical gloves. FPs are too small to be captured by standard filters but clear spontaneously and do not have deleterious effects on renal function or outcomes.

Central nervous system vasculitis caused by propylthiouracil therapy: a case report and literature review.

Antineutrophil cytoplasmic antibodies (ANCA) are associated with vasculitis, including vasculitis induced by drugs such as the thionamides. The affected organ systems in thionamide-induced vasculitis have been primarily renal, musculoskeletal, and dermatologic. We describe the first case of thionamide-induced central nervous system vasculitis presenting as confusion, with complete resolution after discontinuation of propylthiouracil. We review the literature and summarize 42 additional cases of thionamide-induced ANCA-positive vasculitis since 1992. Propylthiouracil was responsible in 93% of cases and the predominant ANCA pattern on immunofluorescent staining was perinuclear (p-ANCA). Clinical improvement occurred after drug discontinuation in 93%, steroid therapy was used in some cases. The mean duration of treatment with thionamides was 35 months prior to presentation. Long-term medical treatment with thionamides for hyperthyroidism may increase the risk of this severe side effect.

Review of treatment of bronchiolitis related apnoea in two centres.

AIMS: To determine whether the use of negative pressure ventilation (NPV) was associated with a lower rate of endotracheal intubation in infants with recurrent apnoea secondary to acute bronchiolitis. METHODS: Retrospective review of two paediatric intensive care units (PICU) databases and case notes; one PICU offered NPV. RESULTS: Fifty two infants with bronchiolitis related apnoea were admitted to the two PICUs (31 to the NPV centre). There were no significant differences between infants in the two centres in age and weight on admission, gestational age at birth, birth weight, history of apnoea of prematurity or chronic lung disease, days ill before referral, respiratory syncytial virus status, oxygen requirement before support, and numbers retrieved from secondary care centres. Respiratory support was provided to all 31 infants in the NPV centre (23 NPV, 8 PPV), and 19/21 in the non-NPV centre (18 PPV, 1 CPAP); the NPV centre had lower rates of endotracheal intubation rates (8/31 v 18/21), shorter durations of stay (median 2 v 7 days), and less use of sedation (16/31 v 18/21). In the two years after the NPV centre discontinued use of NPV, 14/17 (82%) referred cases were intubated, with a median PICU stay of 7.5 days. CONCLUSIONS: The use of NPV was associated with a reduced rate of endotracheal intubation, and shorter PICU stay. A prospective randomised controlled trial of the use of NPV in the treatment of bronchiolitis related apnoea is warranted.