Treatment of Cushing Disease With Pituitary-Targeting Seliciclib.

CONTEXT: Preclinical studies show seliciclib (R-roscovitine) suppresses neoplastic corticotroph proliferation and pituitary adrenocorticotrophic hormone (ACTH) production. OBJECTIVE: To evaluate seliciclib as an effective pituitary-targeting treatment for patients with Cushing disease (CD). METHODS: Two prospective, open-label, phase 2 trials, conducted at a tertiary referral pituitary center, included adult patients with de novo, persistent, or recurrent CD who received oral seliciclib 400 mg twice daily for 4 consecutive days each week for 4 weeks. The primary endpoint in the proof-of-concept single-center study was normalization of 24-hour urinary free cortisol (UFC; ≤ 50 µg/24 hours) at study end; in the pilot multicenter study, primary endpoint was UFC normalization or ≥ 50% reduction in UFC from baseline to study end. RESULTS: Sixteen patients were consented and 9 were treated. Mean UFC decreased by 42%, from 226.4 ± 140.3 µg/24 hours at baseline to 131.3 ± 114.3 µg/24 hours by study end. Longitudinal model showed significant UFC reductions from baseline to each treatment week. Three patients achieved ≥ 50% UFC reduction (range, 55%-75%), and 2 patients exhibited 48% reduction; none achieved UFC normalization. Plasma ACTH decreased by 19% (P = 0.01) in patients who achieved ≥ 48% UFC reduction. Three patients developed grade ≤ 2 elevated liver enzymes, anemia, and/or elevated creatinine, which resolved with dose interruption/reduction. Two patients developed grade 4 liver-related serious adverse events that resolved within 4 weeks of seliciclib discontinuation. CONCLUSION: Seliciclib may directly target pituitary corticotrophs in CD and reverse hypercortisolism. Potential liver toxicity of seliciclib resolves with treatment withdrawal. The lowest effective dose requires further determination.

Challenge or opportunity: Rehabilitation outcomes in patients with metastatic spinal cord compression - a UK single center experience.

CONTEXT /OBJECTIVE: Metastatic Spinal Cord Compression (MSCC) is a devastating complication of cancer, affecting approximately 3000 patients per annum in England. However, access to rehabilitation services for MSCC patients is limited. The London Spinal Cord Injury Centre has set up a bespoke MSCC rehabilitation pathway from May 2013. This article aims to describe the clinical features and functional outcomes of patients with MSCC admitted to a Specialist Spinal Cord Injury Rehabilitation Centre between May 2013 and December 2021. DESIGN: Retrospective analysis of medical records from a single specialist rehabilitation centre database. SETTING: London Spinal Cord Injury Centre (LSCIC), Stanmore, United Kingdom. PARTICIPANTS: Adult patients diagnosed with MSCC who were admitted to and discharged from LSCIC from May 2013 to December 2021. INTERVENTIONS: Specialist Inpatient Spinal Cord Injury Rehabilitation Program. OUTCOME MEASURES: Spinal Cord Independence Measure 19 (SCIM version III), Discharge Destination. RESULTS: A total of 40 patients with MSCC were admitted - 32 male and 8 female patients. The average length of stay was 6 weeks. 17(42.5%) patients had primary prostate cancer. Most patients (34(85%)) had thoracic MSCC. There was an improvement in the Spinal Cord Independence Measure in all patients with an average significant improvement from 43.8 to 64.5 (P < 0.001). There was no significant difference in SCIM scores between patients under 65 and over 65. 28 (70%) patients required psychological input. 33(82.5%) patients were discharged home. CONCLUSION: Patients with MSCC show improvement in SCIM outcome measures after a six-week inpatient Specialist Spinal Rehabilitation program.

Superior mesenteric artery syndrome - A rare presentation and challenge in spinal cord injury rehabilitation: A case report and literature review.

BACKGROUND: Obstruction of the third part of the duodenum (D3) is a very rare cause of gastric outflow obstruction. Rapid weight loss is the biggest risk factor. Patients seen in acute rehabilitation settings, not uncommonly, have a period of rapid weight loss. We report two cases of superior mesenteric artery (SMA) syndrome and review the literature. CLINICAL DETAILS: The patients presented differently, one with repeated, refractory autonomic dysreflexia and severe spasticity and one with nausea, abdominal discomfort, and vomiting. CT abdomen with contrast identified dynamic duodenal (D3) obstruction against the posterior structures by narrow angled SMA, gastric distension and, in one case, dilation of the left renal vein. Both patients responded well to optimizing nutrition in different ways. Surgery was successfully avoided. DISCUSSION: SMA syndrome is an atypical cause of high intestinal obstruction, frequently occurring in patients who have had rapid weight loss during spinal cord injury (SCI) rehabilitation. It may co-exist with left renal vein dilation "nutcracker phenomena". The associated neurogenic bowel dysfunction due to the nature of SCI could possibly contribute to delay in diagnosis. CONCLUSION: Clinicians should consider the risk of SMA syndrome in patients with SCI with rapid weight loss. Early diagnosis is possible by doing a CT abdomen with contrast and angiography if there is a high index of suspicion. SMA syndrome can be successfully treated by aggressive nutritional management. This may include total parenteral nutrition or feeding by a nasojejunal tube. Duodenojejunostomy could be required in refractory cases.

Joint CO2 and CH4 accountability for global warming.

We propose a transparent climate debt index incorporating both methane (CH4) and carbon dioxide (CO2) emissions. We develop national historic emissions databases for both greenhouse gases to 2005, justifying 1950 as the starting point for global perspectives. We include CO2 emissions from fossil sources [CO2(f)], as well as, in a separate analysis, land use change and forestry. We calculate the CO2(f) and CH4 remaining in the atmosphere in 2005 from 205 countries using the Intergovernmental Panel on Climate Change's Fourth Assessment Report impulse response functions. We use these calculations to estimate the fraction of remaining global emissions due to each country, which is applied to total radiative forcing in 2005 to determine the combined climate debt from both greenhouse gases in units of milliwatts per square meter per country or microwatts per square meter per person, a metric we term international natural debt (IND). Australia becomes the most indebted large country per capita because of high CH4 emissions, overtaking the United States, which is highest for CO2(f). The differences between the INDs of developing and developed countries decline but remain large. We use IND to assess the relative reduction in IND from choosing between CO2(f) and CH4`control measures and to contrast the imposed versus experienced health impacts from climate change. Based on 2005 emissions, the same hypothetical impact on world 2050 IND could be achieved by decreasing CH4 emissions by 46% as stopping CO2 emissions entirely, but with substantial differences among countries, implying differential optimal strategies. Adding CH4 shifts the basic narrative about differential international accountability for climate change.

Comparison of tibial intraosseous, sternal intraosseous, and intravenous routes of administration on pharmacokinetics of epinephrine during cardiac arrest: a pilot study.

The purpose of this study was to determine and compare the maximum concentration (C(max)) and time to maximum concentration (T(max)) of epinephrine administered via tibial intraosseous (IO), sternal IO, and intravenous (i.v.) routes in a porcine model of cardiac arrest during cardiopulmonary resuscitation. Five pigs each were randomly assigned to 3 groups: tibial IO, sternal IO, and i.v. Cardiac arrest was induced with i.v. potassium chloride. After 2 minutes, cardiopulmonary resuscitation was initiated. Epinephrine was administered to each animal, and serial blood samples were collected over the next 3 minutes. Enzyme-linked immunosorbent assay was used to determine the epinephrine concentration. Multivariate analysis of variance helped determine if there were statistically significant differences between groups. There were significant differences in Cmax between the sternal IO and i.v. (P = .009) and tibial IO and i.v. (P = .03) groups but no significant difference between tibial and sternal IO groups (P = .75). Significant differences existed in Tmax between the tibial IO and i.v. (P = .04) and between tibial IO and sternal IO (P = .02) groups but no difference between the sternal IO and i.v. groups (P = .56). Intravenous administration of 1 mg of epinephrine resulted in a serum concentration 5.87 and 2.86 times greater than for the tibial and sternal routes, respectively.

Habitual dislocation of patella in knee disarticulation stump in a patient of congenital type I deficiency of tibia: a case report.

The objective of this case report was to describe a patient who developed habitual dislocation of patella after knee disarticulation. Congenital deficiency of the tibia (tibial hemimelia, aplasia or dysplasia) is very rare, with an incidence of approximately 1 per 1 million live births. Knee disarticulation is preferred over transfemoral amputation for type I tibial deficiency. Most of the surgical techniques describe preservation of the patella and suturing of patellar tendon with cruciate ligaments. We present a case of a 14-year-old girl, who underwent disarticulation through the right knee as a primary procedure at age of 5 months for congenital type I tibia deficiency. At 13 years after the primary procedure, the patient developed painful flicking of the patella, which was diagnosed clinically as habitual (spontaneous) dislocation of the patella. In conclusion, type I tibia deficiency is associated with marked hypoplasia of the distal femur along with retardation of ossification of distal femoral epiphysis. This can later result in patellar dislocation. This could delay the rehabilitation of young amputees with knee disarticulation. It would be debatable and would need further evidence as to whether excision of the patella at the initial amputation may be more appropriate to prevent later incidence of dislocation.

Environmental determinants of infectious disease: a framework for tracking causal links and guiding public health research.

BACKGROUND: Discoveries that emerging and re-emerging pathogens have their origin in environmental change has created an urgent need to understand how these environmental changes impact disease burden. In this article we present a framework that provides a context from which to examine the relationship between environmental changes and disease transmission and a structure from which to unite disparate pieces of information from a variety of disciplines. METHODS: The framework integrates three interrelated characteristics of environment-disease relationships: a) Environmental change manifests in a complex web of ecologic and social factors that may ultimately impact disease; these factors are represented as those more distally related and those more proximally related to disease. b) Transmission dynamics of infectious pathogens mediate the effects that environmental changes have on disease. c) Disease burden is the outcome of the interplay between environmental change and the transmission cycle of a pathogen. RESULTS: To put this framework into operation, we present a matrix formulation as a means to define important elements of this system and to summarize what is known and unknown about the these elements and their relationships. The framework explicitly expresses the problem at a systems level that goes beyond the traditional risk factor analysis used in public health, and the matrix provides a means to explicitly express the coupling of different system components. CONCLUSION: This coupling of environmental and disease transmission processes provides a much-needed construct for furthering our understanding of both specific and general relationships between environmental change and infectious disease.

Lessons learned from "the skeptical environmentalist": an environmental health perspective.

Few books about the environment have generated as much heated debate as Bjørn Lomborg's 'The Skeptical Environmentalist: Measuring the Real State of the World', published by Cambridge University Press in 2001. A flavor of the controversy can be gleaned from a series of reviews and rebuttals published in 'Scientific American' (Rennie 2002). In general, most positive reviews appeared in the popular press (e.g., 'The Economist', 'Washington Post Book Review', 'The Wall Street Journal') and most negative reviews appeared in the scientific press (e.g., 'Science', 'Nature', 'Bioscience'). Although 'The Skeptical Environmentalist' (TSE) addresses a number of environmental health issues, voices from the environmental health community have not been prominent among the participants in this debate. Now that the dust from the initial stampede to praise and condemn the book has settled, we will explore lessons to be learned from TSE and the associated debate from an environmental health perspective.