Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPAR gamma ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR gamma in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPAR gamma activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPAR gamma agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPAR gamma-mediated increases in glucose utilization in muscle. In liver, PPAR gamma activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPAR gamma agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.     

Vascular graft infection: the role of indium scanning

Infection of a prosthetic graft is one of the most feared complications of vascular surgery. The difficulties of accurate, objective diagnosis are well recognised. We have used III Indium labelled white blood cell scans (InWBC) in two groups: 9 control patients who underwent uncomplicated aortic aneurysm surgery, and 23 patients with suspected graft sepsis. In the control group there was one positive scan in a patient with an inflammatory aneurysm. In the suspected sepsis group, 11 patients subsequently has proven graft sepsis. Nine were correctly predicted by Indium scanning. Ten of 12 patients who did not have proven graft sepsis had negative scans. There was a total of 5 inflammatory aneurysms in the control and suspected sepsis groups, of whom two had positive scans. False positive scans were not present in the early postoperative period i patients without inflammatory aneurysms. In our experience Indium labelled WBC scanning for suspected graft sepsis has a accuracy of 83% a negative predictive value of 83% and a positive predictive value of 82%. These results suggest that Indium white cell labelling techniques which do not involve substantial cross-labelling of platelets are the best objective methods of establishing the presence or absence of graft sepsis.     

Spinal radiation before surgical decompression adversely affects outcomes of surgery for symptomatic metastatic spinal cord compression

STUDY DESIGN: A retrospective chart review was performed. OBJECTIVE: To determine whether preoperative spinal radiation increases the number of major wound complications in patients with cancer who have symptomatic spinal cord compression. SUMMARY OF BACKGROUND DATA: Many factors have increased the number of patients hospitalized with symptomatic spinal cord compression after spinal irradiation. The surgical management of metastatic spinal cord compression may be complicated by preoperative radiation. METHODS: A retrospective review of 123 patients admitted with symptomatic metastatic spinal cord compression from 1970 through 1996 was conducted. The final study population of 85 patients was separated into three treatment groups: 1) radiation only, 2) radiation followed by surgery, and 3) de novo surgery followed by radiation. RESULTS: The major wound complication rate for patients who had radiation before surgical decompression and stabilization was 32%, or threefold, higher than the 12% observed in patients who had de novo surgery (P < 0.05). No other clinical factor or condition predicted the development of a major wound complication. Patients treated initially with surgery had superior functional outcomes in an analysis stratified by Frankel grade (P < 0.05). Of the ambulatory patients who underwent de novo surgery, 75% remained ambulatory and continent 30 days after treatment, whereas only 50% of those treated with radiation before surgery had similar outcomes. CONCLUSIONS: Spinal radiation before surgical decompression for metastatic spinal cord compression is associated with a significantly higher major wound complication rate. In addition, preoperative spinal irradiation might adversely affect the surgical outcome.     

COVID-19 Vaccination Coverage,Behaviors, and Intentions among Adults with Previous Diagnosis,United States

To determine the extent of gaps in coronavirus disease (COVID-19) vaccine coverage among those in the United States with and without previous COVID-19 diagnoses, we used July 21–August 2, 2021, data from a large, nationally representative survey (Household Pulse Survey). We analyzed vaccine receipt (≥1 dose and full vaccination) and intention to be vaccinated for 63,266 persons. Vaccination receipt was lower among those who had a prior diagnosis of COVID-19 compared to those without: >1 dose: 73% and 85%, respectively, p<0.001; full vaccination: 69% and 82%, respectively, p<0.001). Reluctance to be vaccinated was higher among those with a previous COVID-19 diagnosis (14%) than among those without (9%). These findings suggest the need to focus educational and confidence-building interventions on adults when they receive a COVID-19 diagnosis, during clinic visits, or at the time of discharge if hospitalized and to better educate the public about the value of being vaccinated, regardless of previous COVID-19 status.     

Drugs and Afghanistan

Within a highly volatile socio-economic, political and legal environment, opium poppy has become an integral part of livelihood strategies in many rural communities in Afghanistan. Over the past decade Afghanistan has become the world's leading producer of opium. The easy availability of both opium and heroin, as well as a wide range of pharmaceutical drugs, coupled with an impoverished population traumatized by 20 years of war and conflict, has led to an increase in drug problems both in Afghanistan and refugee communities in neighbouring countries. This overview of the supply of, and demand for, drugs in Afghanistan provides insights into the complexities of drug production and consumption within the broader context of development issues and objectives.     

Multianalyte profiling of serum antigens and autoimmune and infectious disease molecules to identify biomarkers dysregulated in epithelial ovarian cancer

Ovarian cancer is the deadliest gynecologic cancer in the United States. When detected early, the 5-year survival rate is 92%, although most cases remain undetected until the late stages where 5-year survival rates are 30%. Serum biomarkers may hold promise. Although many markers have been proposed and multivariate diagnostic models were built to fit the data on small, disparate sample sets, there has been no systematic evaluation of these markers on a single, large, well-defined sample set. To address this, we evaluated the dysregulation of 204 molecules in a sample set consisting of serum from 294 patients, collected from multiple collection sites, under a well-defined Gynecologic Oncology Group protocol. The population, weighted with early-stage cancers to assess biomarker value for early detection, contained all stages of ovarian cancer and common benign gynecologic conditions. The panel of serum molecules was assayed using rigorously qualified, high-throughput, multiplexed immunoassays and evaluated for their independent ovarian cancer diagnostic potential. Seventy-seven biomarkers were dysregulated in the ovarian cancer samples, although cancer antigen 125, C-reactive protein, epidermal growth factor receptor, interleukin 10, interleukin 8, connective tissue growth factor, haptoglobin, and tissue inhibitor of metalloproteinase 1 stood out as the most informative. When analyzed by cancer subtype and stage, there were differences in the relative value of biomarkers. In this study, using a large sample cohort, we show that some of the reported ovarian cancer biomarkers are more robust than others, and we identify additional informative candidates. These findings may guide the development of multivariate diagnostic models, which should be tested on additional, prospectively collected samples.     

Assessment of a daily online implanted fiducial marker‐guided prostate radiotherapy process

The aims of this study were to investigate whether intrafraction prostate motion can affect the accuracy of online prostate positioning using implanted fiducial markers and to determine the effect of prostate rotations on the accuracy of the software‐predicted set‐up correction shifts. Eleven patients were treated with implanted prostate fiducial markers and online set‐up corrections. Orthogonal electronic portal images were acquired to determine couch shifts before treatment. Verification images were also acquired during treatment to assess whether intrafraction motion had occurred. A limitation of the online image registration software is that it does not allow for in‐plane prostate rotations (evident on lateral portal images) when aligning marker positions. The accuracy of couch shifts was assessed by repeating the registration measurements with separate software that incorporates full in‐plane prostate rotations. Additional treatment time required for online positioning was also measured. For the patient group, the overall postalignment systematic prostate errors were less than 1.5 mm (1 standard deviation) in all directions (range 0.2–3.9 mm). The random prostate errors ranged from 0.8 to 3.3 mm (1 standard deviation). One patient exhibited intrafraction prostate motion, resulting in a postalignment prostate set‐up error of more than 10 mm for one fraction. In 14 of 35 fractions, the postalignment prostate set‐up error was greater than 5 mm in the anterior–posterior direction for this patient. Maximum prostate rotations measured from the lateral images varied from 2° to 20° for the patients. The differences between set‐up shifts determined by the online software without in‐plane rotations to align markers, and with rotations applied, was less than 1 mm (root mean square), with a maximum difference of 4.1 mm. Intrafraction prostate motion was found to reduce the effectiveness of the online set‐up for one of the patients. A larger study is required to determine the magnitude of this problem for the patient population. The inability in the current software to incorporate in‐plane prostate rotations is a limitation that should not introduce large errors, provided that the treatment isocentre is positioned near the centre of the prostate.     

Study of internal structure of the human fetus in utero by echo-planar magnetic resonance imaging

The ultrafast echo-planar magnetic resonance imaging technology, developed and built in Nottingham, has been used to produce the first snapshot images of the human fetus in utero. The imager, operating at a proton resonance frequency of 22 MHz, produces transaxial views in 64 or 128 milliseconds. These images comprise either 64 x 128 or 128 x 128 pixels with an in-plane resolution of 3 x 3 mm2. The slice thickness is 10 mm. Fetal scans of up to 32 contiguous slices are produced in a few minutes. These have been used to study the internal structure of the uterus and the fetus in a range of cases with gestations ranging from 26 weeks to term. Echo-planar imaging seems particularly suitable as an imaging modality since its high speed obviates image blurring arising from fetal motion.     

An ultrasonographic study of Peyronie's disease

A study was undertaken to determine the usefulness of ultrasonography as an investigative tool, and its role in deciding the management of Peyronie's disease. Fifteen patients with Peyronie's disease were studied by ultrasonography. The plaque could be demonstrated in all patients. The dimensions of the plaque varied from less than 1 cm to more than 7cm in length and 2-4mm in thickness. The disease was active in 26% of the patients, as indicated by the presence of hypoechoic areas around a central region of hyperechoism. Ultrasonogram was more accurate than clinical assessment in delineating the extent of lesions. In one-third of the patients, sonography demonstrated the plaques to be more extensive than had been detected by clinical examination. Calcification and activity of disease (which are clearly defined by ultrasonogram) are determining factors in the management of Peyronie's disease. This information allows the surgeon to select the modality of treatment, the timing of surgery and extent of excision. Thus, ultrasonography plays a vital role in the preliminary investigation and management of Peyronie's disease.     

Thrombolytic therapy for delayed occlusion of knitted Dacron bypass grafts in the axillofemoral, femoropopliteal and femorotibial positions

Selective intra-arterial streptokinase therapy successfully reopened ten axillofemoral and lower extremity Dacron bypass grafts that had undergone delayed closure from two to 47 months after implantation. In four, completion arteriograms revealed no runoff obstruction acquired since implantation; additional runoff obstruction had developed in the remaining six. All of the grafts without obstruction have remained open from two to 11 months. Three of the six grafts with obstruction have remained open from two and one-half to four months after specific surgical correction of the obstructive lesion. We conclude that intra-arterial streptokinase therapy is an effective means to reopen knitted Dacron grafts that have undergone delayed closure in the axillofemoral and above-knee femoropopliteal positions.