Gonadotropin-releasing hormone-I (GnRH-I) is thought to be expressed by a single, highly spatially restricted group of neurons, which originate in the olfactory placode and migrate through the nose into the medial septum and hypothalamus from where they control fertility. Transgenic mice bearing a 13.5 kb GnRH-I-lacZ reporter construct were derived and found to express high levels of ␤-galactosidase mRNA and protein within the septohypothalamic GnRH neurons in a correct temporal and spatial manner. Unexpectedly, low levels of ␤-galactosidase were also present in three further populations of cells within the lateral septum, bed nucleus of the stria terminalis, and tectum. Analysis of wild-type mice with three different GnRH-I antibodies revealed distinct and transient patterns of GnRH-I peptide expression during development in all three of these populations revealed by transgenics. The synthesis of GnRH by cells of the lateral septum was the most persistent and remained until the third postnatal week. Embryonic "small eye" Pax-6 null mice, which fail to develop an olfactory placode, were also examined and shown to have equivalent populations of GnRH-I-immunoreactive cells in the lateral septum, tectum, and bed nucleus of the stria terminalis but none of the migrating cells that form the septohypothalamic GnRH population. These results prove that so-called "ectopic" expression in promoter transgenic lines can reflect authentic developmental patterns of gene expression. They further provide the first demonstration in mammalian brain that multiple neuronal populations of different embryological origin express GnRH-I peptide during embryonic and postnatal development.

Objective The “Bow-tie” optimal pathway discovery analysis uses large clinical event datasets to map clinical pathways and to visualize risks (improvement opportunities) before, and outcomes after, a specific clinical event. This proof-of-concept study assesses the use of NHS Hospital Episode Statistics (HES) in England as a potential clinical event dataset for this pathway discovery analysis approach. Materials and Methods A metaheuristic optimization algorithm was used to perform the “bow-tie” analysis on HES event log data for sepsis (ICD-10 A40/A41) in 2016. Analysis of hospital episodes across inpatient and outpatient departments was performed for the period 730 days before and 365 days after the index sepsis hospitalization event. Results HES data captured a sepsis event for 76 523 individuals (>13 years), relating to 580 000 coded events (across 220 sepsis and non-sepsis event classes). The “bow-tie” analysis identified several diagnoses that most frequently preceded hospitalization for sepsis, in line with the expectation that sepsis most frequently occurs in vulnerable populations. A diagnosis of pneumonia (5 290 patients) and urinary tract infections (UTIs; 2 057 patients) most often preceded the sepsis event, with recurrent UTIs acting as a potential indicative risk factor for sepsis. Discussion This proof-of-concept study demonstrates that a “bow-tie” pathway discovery analysis of the HES database can be undertaken and provides clinical insights that, with further study, could help improve the identification and management of sepsis. The algorithm can now be more widely applied to HES data to undertake targeted clinical pathway analysis across multiple healthcare conditions.

The mechanisms through which gonadal steroids exert feedback actions on the activity of the GnRH neurons are not understood. Using a series of GnRH-LacZ transgenic mice we have examined the manner in which gonadal steroids suppress GnRH mRNA expression in male and female mice. The long-term gonadectomy of 5.5-GNZ-3.5 transgenic mice resulted in significant increases in cellular GnRH mRNA expression (P < 0.05) and plasma LH concentrations (P < 0.01) in both sexes. However, cellular levels of LacZ mRNA and beta-galactosidase, which provide an index of GnRH gene transcription, were only elevated in males after gonadectomy. This sexually differentiated response was also observed in mice gonadectomized for 2 wk. Estrogen replacement in gonadectomized males returned transgene expression to intact levels. Experiments in transgenic mice with 3' and 5' deleted GnRH-LacZ constructs revealed that the suppressive influence of estrogen on LacZ transcription in the male required a critical element located between -5.2 and -1.7 kb of the GnRH promoter. These studies show that the suppression of GnRH mRNA expression by estrogen in the male involves a decrease in GnRH gene transcription that is dependent on a distal GnRH promoter element. The same mechanism does not exist in females, indicating that gonadal steroids suppress GnRH mRNA levels in a sexually dimorphic manner.

ObjectiveTo assess temporal clinical and budget impacts of changes in atrial fibrillation (AF)-related prescribing in England.MethodsData on AF prevalence, AF-related stroke incidence and prescribing for all National Health Service general practices, hospitals and registered patients with hospitalised AF-related stroke in England were obtained from national databases. Stroke care costs were based on published data. We compared changes in oral anticoagulation prescribing (warfarin or direct oral anticoagulants (DOACs)), incidence of hospitalised AF-related stroke, and associated overall and per-patient costs in the periods January 2011–June 2014 and July 2014–December 2017.ResultsBetween 2011–2014 and 2014–2017, recipients of oral anticoagulation for AF increased by 86.5% from 1 381 170 to 2 575 669. The number of patients prescribed warfarin grew by 16.1% from 1 313 544 to 1 525 674 and those taking DOACs by 1452.7% from 67 626 to 1 049 995. Prescribed items increased by 5.9% for warfarin (95% CI 2.9% to 8.9%) but by 2004.8% for DOACs (95% CI 1848.8% to 2160.7%). Oral anticoagulation prescription cost rose overall by 781.2%, from £87 313 310 to £769 444 028, (£733,466,204 with warfarin monitoring) and per patient by 50.7%, from £293 to £442, giving an incremental cost of £149. Nevertheless, as AF-related stroke incidence fell by 11.3% (95% CI −11.5% to −11.1%) from 86 467 in 2011–2014 to 76 730 in 2014–2017 with adjustment for AF prevalence, the overall per-patient cost reduced from £1129 to £840, giving an incremental per-patient saving of £289.ConclusionsDespite nearly one million additional DOAC prescriptions and substantial associated spending in the latter part of this study, the decline in AF-related stroke led to incremental savings at the national level.

SUMMARYRoutine blood pressure measurements are performed on all non-ambulatory patients attending the Accident and Emergency Department, Leicester Royal Infirmary, England. However, the patient's general practitioner is not always informed of the reading, even if it is found to be raised. One of the chief reasons for this omission is the fact that single, elevated blood pressure readings taken in an accident and emergency department are considered to be of doubtful significance.Sixty patients with a single, elevated blood pressure measurement were studied. Fifteen of these patients were found to continue to have an elevated blood pressure measurement when reviewed in a quiet, relaxed environment. Fourteen of these 15 patients are currently being treated for hypertension after independent assessment by their family practitioners.It was concluded that single, elevated blood pressure readings are useful indicators of hypertension in non-ambulatory patients attending accident and emergency departments. It is, therefore, important to inform general practitioners of incidentally raised blood pressure readings.