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Objective: To evaluate a regimen of inhaled Technosphere insulin (TI) plus insulin degludec in adults with type 1 diabetes, who prestudy were predominately using either an automated insulin delivery (AID) system or multiple daily insulin injections (MDI) with continuous glucose monitoring., Research Design and Methods: At 19 sites, adults with type 1 diabetes were randomly assigned to TI plus insulin degludec (N = 62) or usual care (UC) with continuation of prestudy insulin delivery method (N = 61) for 17 weeks., Results: Prestudy, AID was used by 48% and MDI by 45%. Mean ± SD HbA1c was 7.57% ± 0.97% at baseline and 7.62% ± 1.06% at 17 weeks in the TI group and 7.59% ± 0.80% and 7.54% ± 0.77%, respectively, in the UC group (adjusted difference 0.11%, 95% CI -0.10 to 0.33, P value for noninferiority = 0.01). HbA1c improved from baseline to 17 weeks by >0.5% (5.5 mmol/mol) in 12 (21%) in the TI group and in 3 (5%) in the UC group and worsened by >0.5% (5.5 mmol/mol) in 15 (26%) in the TI group and in 2 (3%) in the UC group. The most common TI side effect was a brief cough; eight participants discontinued TI due to side effects., Conclusions: In adults with type 1 diabetes, HbA1c after 17 weeks with a regimen of TI and degludec was noninferior to UC, which consisted predominately of either AID or MDI. TI should be considered an option for people with type 1 diabetes, particularly those who are motivated to further reduce postprandial hyperglycemia., (© 2024 by the American Diabetes Association.)

Objective: To compare postprandial glucose excursions following a bolus with inhaled technosphere insulin (TI) or subcutaneous rapid-acting analog (RAA) insulin., Research Design and Methods: A meal challenge was completed by 122 adults with type 1 diabetes who were using multiple daily injections (MDI), a nonautomated pump, or automated insulin delivery (AID) and who were randomized to bolus with their usual RAA insulin (n = 61) or TI (n = 61)., Results: The primary outcome, the treatment group difference in area under the curve for glucose >180 mg/dL over 2 h, was less with TI versus RAA (adjusted difference -12 mg/dL, 95% CI -22 to -2, P = 0.02). With TI, the glucose excursion was smaller (P = 0.01), peak glucose lower (P = 0.01), and time to peak glucose shorter (P = 0.006). Blood glucose <70 mg/dL occurred in one participant in each group., Conclusions: Postmeal glucose excursion was smaller with TI than with RAA insulin in a cohort that included both AID and MDI users., (© 2024 by the American Diabetes Association.)

Therapeutic oligonucleotides (ONs) commonly incorporate phosphorothioate (PS) modifications. These introduce chiral centers and generate ON diastereomers. The increasing number of ONs undergoing clinical trials and reaching the market has led to a growing interest to better characterize the ON diastereomer composition, especially for small interfering ribonucleic acids (siRNAs). In this study, and for the first time, we identify higher-order structures as the major cause of ON diastereomer separation in hydrophilic interaction chromatography (HILIC). We have used conformational predictions and melting profiles of several representative full-length ONs to first analyze ON folding and then run mass spectrometry and HILIC to underpin the link between their folding and diastereomer separation. On top, we show how one can either enhance or suppress diastereomer separation depending on chromatographic settings, such as column temperature, pore size, stationary phase, mobile-phase ionic strength, and organic modifier. This work will significantly facilitate future HILIC-based characterization of PS-containing ONs; e.g., enabling monitoring of batch-to-batch diastereomer distributions in full-length siRNAs, a complex task that is now for the first time shown as possible on this delicate class of therapeutic double-stranded ONs.

We describe a case of superficial acral fibromyxoma arising within the germinal matrix of the index finger. This is an uncommon localisation of this relatively newly described benign soft tissue tumour. Herein, we discuss the varied clinical presentation, distinguishing histopathological features and important differential diagnoses for this condition., Competing Interests: The authors have no conflict of interest to declare., (© 2022 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The low detection rate of conventional imaging and unspecific fluctuations in prostate-specific antigen can hamper early diagnosis of castration-resistant prostate cancer (CRPC). We thus assessed the value of prostate-specific membrane antigen (PSMA) PET/CT in the detection of early CRPC (prostate-specific antigen ≤ 3 ng/mL). Methods: We identified 55 patients with early CRPC from our institutional database. PSMA PET/CT and its CT component were interpreted independently by 3 masked readers. The primary endpoint was the per-patient detection rate; secondary endpoints were interobserver agreement and predictors of PET positivity. Results: PSMA PET/CT was positive in 41 of 55 (75%) patients. Sixteen of 55 (29%) patients had local disease only, and 25 of 55 (45%) had M1 disease. Overall, PSMA PET/CT interobserver agreement was substantial by Landis and Koch criteria (Fleiss κ = 0.77). Conclusion: PSMA PET/CT localized prostate cancer lesions in 75% of patients and M1 disease in 45%. Detection of early CRPC facilitates disease-delaying therapies for local or oligometastatic disease. PSMA PET/CT is of value in early CRPC and should be included in the CRPC entry criteria of the European Association of Urology and Prostate Cancer Working Group 3., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Advanced prostate cancer has long been known to respond to androgen deprivation, but disease inevitably progresses to become androgen independent. Lengthening the responsive period is an important, yet underinvestigated, clinical goal. This study aims to determine whether cyclooxygenase-2 (COX-2) inhibitors are potentially useful agents in prolonging androgen sensitivity., Methods: The expression of COX-2 in human prostate surgical specimens, both benign and malignant, androgen dependent and independent, was determined by immunohistochemistry. Nude mice, in which prostate cancer xenografts had been established, were castrated and randomized to receive either COX-2 inhibitor or vehicle for 8 weeks. Time to androgen independence (AIPC), growth rate and rate of PSA rise were compared between groups. COX-2 expression, at the mRNA and protein level, was determined in the native xenograft cell line and in tissues of varying androgen sensitivity derived from the xenografts., Results: In human tissues, COX-2 protein was expressed in prostate epithelium and was upregulated in prostate cancer and remained upregulated after androgen ablation and in the androgen-independent state. Tissue obtained from the LNCaP xenograft model showed variable COX-2 expression, with some evidence of downregulation in AIPC. The addition of a COX-2 inhibitor to castration does not lengthen the time to AIPC (P= 0.53), rate of tumour growth (P= 0.59) or rate of PSA rise (P= 0.34) in the LNCaP xenograft model., Conclusion: This study does not support a role for COX-2 inhibitors in prolonging androgen responsiveness in prostate cancer.

Purpose: Cytosolic phospholipase A2-alpha (cPLA2-alpha) provides intracellular arachidonic acid to supply both cyclooxygenase and lipoxygenase pathways. We aim to determine the expression and activation of cPLA2-alpha in prostate cancer cell lines and tissue and the effect of targeting cPLA2-alpha in vitro and in vivo., Experimental Design: The expression of cPLA2-alpha was determined in prostate cancer cells by reverse transcription-PCR, Western blot, and immunocytochemistry. Growth inhibition, apoptosis, and cPLA2-alpha activity were determined after inhibition with cPLA2-alpha small interfering RNA or inhibitor (Wyeth-1). Cytosolic PLA2-alpha inhibitor or vehicle was also administered to prostate cancer xenograft mouse models. Finally, the expression of phosphorylated cPLA2-alpha was determined by immunohistochemistry in human normal, androgen-sensitive and androgen-insensitive prostate cancer specimens., Results: cPLA2-alpha is present in all prostate cancer cells lines, but increased in androgen-insensitive cells. Inhibition with small interfering RNA or Wyeth-1 results in significant reductions in prostate cancer cell numbers, as a result of reduced proliferation as well as increased apoptosis, and this was also associated with a reduction in cPLA2-alpha activity. Expression of cyclin D1 and phosphorylation of Akt were also observed to decrease. Wyeth-1 inhibited PC3 xenograft growth by approximately 33% and again, also reduced cyclin D1. Immunohistochemistry of human prostate tissue revealed that phosphorylated cPLA2-alpha is increased when hormone refractory is reached., Conclusions: Expression and activation of cPLA2-alpha are increased in the androgen-insensitive cancer cell line and tissue. Inhibition of cPLA2-alpha results in cells and xenograft tumor growth inhibition and serves as a potentially effective therapy for hormone refractory prostate cancer.

Purpose: The arachidonic acid pathway incorporates phospholipase, cyclooxygenase, lipoxygenase and epoxygenase enzymes. This pathway has been shown to have a major role in the development and progression of a number of cancers, including prostate cancer. We discuss the current status of research of this pathway in the area of prostate cancer, ranging from preclinical in vitro studies to human clinical trials., Materials and Methods: We performed an online search of the current and past peer reviewed literature on prostate cancer and arachidonic acid, phospholipase, cyclooxygenase, lipoxygenase, epoxygenase, platelet activating factor, prostaglandin and eicosanoid. We retrieved and evaluated all full-length articles published in English from the 1980s to January 2007., Results: Epidemiological evidence suggested that nonsteroidal anti-inflammatory drugs may decrease the risk of prostate cancer. This effect, presumably through the inhibition of cyclooxygenase-2, has been validated in preclinical studies. Cyclooxygenase-2 inhibition has also decreased the rate of prostate specific antigen increase in men with biochemical recurrence after treatment for prostate cancer. Although lipoxygenase and secretory phospholipase A2 inhibition was also effective for decreasing prostate cancer growth in preclinical studies, to our knowledge these strategies have not yet been used in clinical trials. Cytosolic phospholipase A2, platelet activating factor and epoxygenase need further investigation to determine a role in prostate cancer., Conclusions: Evolving data suggest a significant role for some areas of the arachidonic acid pathway in prostate cancer. Inhibiting 1 or a number of these enzymes in combination may hold promise for future prostate cancer treatment.

Unlabelled: The analgesic properties of alpha(2)-agonists are well known. In experimental models, tumor necrosis factor (TNF)-alpha regulates adrenergic responses in the brain. Constitutive TNF-alpha, in brain regions involved in pain perception, is decreased after the administration of clonidine. We investigated patients undergoing lower-extremity revascularization. Seven patients were treated with clonidine 0.2 mg per os (low), and three patients received 0.4 mg per os clonidine (high) before surgery. Eight patients received placebo and served as controls. Continuous spinal anesthesia was provided by insertion of a pliable catheter into the subarachnoid space. Baseline plasma and cerebrospinal fluid (CSF) samples were obtained before injection of local anesthetic. Samples were analyzed for TNF-alpha using a biologic assay. Systemic and central release of catecholamines were assessed by high-pressure liquid chromatography measurement of norepinephrine in plasma and CSF, vanillylmandelic acid and methoxy hydroxyl phenyl glycol in 24-h urinary excretion, respectively. Clonidine 0.2 mg pretreatment decreased TNF-alpha concentrations both in plasma and CSF. Patients receiving clonidine had lower pain visual analog scale scores and required less morphine compared with the Placebo group (P < 0.01). Preoperative administration of clonidine decreased catecholamine release in the periphery, as well as in the central nervous system. A smaller norepinephrine concentration in plasma and CSF, and less secretion of vanillylmandelic acid (P < 0.01) and methoxy hydroxyl phenyl glycol in the urine, were observed. Larger dose clonidine (0.4 mg) resulted in no detectable TNF-alpha in CSF. These results suggest that an interaction between TNF-alpha and the function of adrenergic neurons in the central nervous system may contribute to the sedative and analgesic effects of adrenergic agonists., Implications: Preoperative administration of clonidine decreases both plasma and cerebrospinal fluid concentrations of inflammatory cytokines, resulting in perioperative analgesia and decreased sympathetic tone.

Previously we have demonstrated that prolonged exposure to 100% ambient oxygen leads to a marked loss in functional lung volume and lung compliance, hypoxemia, and surfactant system abnormalities similar to acute respiratory distress syndrome (ARDS). However, 50% oxygen administration is believed to be safe in most clinical settings. In the present study, we have evaluated the effects of a 24-h exposure to 50% oxygen in rabbits immediately following experimental gastric acid aspiration. Mild hypoxemia, but no changes in mortality, lung volume, lung compliance, surfactant metabolism, or edema formation occurred after 24 h of normoxia postacid aspiration. Conversely, a relatively short (24-h) exposure to 50% oxygen after acid aspiration results in increased pulmonary edema, physical signs of respiratory distress, and mortality, as well as decreased arterial oxygenation, lung volume, lung compliance, and type II alveolar cell surfactant synthesis. These results suggest that acid aspiration alters the "set point" for oxygen toxicity, possibly by "priming" cells through activation of inflammatory pathways. This pathogenic mechanism may contribute to the progression of aspiration pneumonia to ARDS.

Objective: To analyze the costs and discharge status for patients with prolonged mechanical ventilation undergoing tracheostomy., Design: Retrospective analysis of a statewide database., Patients: All patients (n = 37,573) >18 yrs of age who had prolonged mechanical ventilation (procedure code 96.72) and were discharged from the hospital between 1992 and 1996 with a final DRG code of 483., Interventions: None., Measurements and Main Results: Rates of change in discharges and hospital reimbursements and the cost per survivor were examined by case payment groups and discharge year. A direct relation between volume and reimbursement rate was seen over time, although the patient age distributions remained relatively stable. The greatest increase in volume was from 1995 to 1996. For most years, there was a consistent inverse relation between age and survival, with older survivors being more likely to be discharged to residential healthcare facilities and younger patients more likely to be discharged home. There was a consistent direct relation between age and cost per survivor, mainly the result of improved survival rather than decreased reimbursements in later years., Conclusions: More controlled reimbursements and improved overall survival rates for DRG 483 have contributed to the improved cost per survivor among all age groups over the period. Given the greater proportion of elderly that do not survive or who are placed into residential healthcare facilities, more scrutiny is needed concerning the use of DRG 483 resources so that care is better coordinated for these patients in the inpatient and postacute care settings.

Study Objectives: To examine and describe the relationship between age and disposition in patients undergoing mechanical ventilation., Design: Retrospective analysis of a statewide database., Setting: All acute-care hospitals in New York State., Patients: All patients (n=10,473) aged > or = 18 years discharged from hospital during 1993 with a final diagnosis related group (DRG) coding of 475., Interventions: None., Measurements and Results: The final disposition, according to six codes (other acute-care facility, residential health-care facility, other health-care facility, home, home health-care services, and death) were examined for the whole population. Cost per case was assumed to equal the average statewide Medicaid rate. An inverse relationship between survival rate and age was observed and this resulted in an age-related increased cost per survivor. Also, survivors in older age groups have an increasing rate of hospital discharge to residential health-care facilities., Conclusion: Patients who undergo mechanical ventilation are expensive to care for. The older they are, the less satisfactory is the outcome both from clinical and economic perspectives.

Objective: To examine and describe the relation between age and disposition in patients undergoing tracheostomy., Design: Retrospective analysis of a statewide database., Setting: All acute care hospitals in New York state., Patients: All patients (n = 6,353) > or = 18 yrs of age who were discharged from the hospital during 1993 with a final diagnosis-related groups code of 483., Interventions: None., Measurements and Main Results: The final disposition, according to six disposition codes (other acute care facility, residential healthcare facility, other healthcare facility, home, home healthcare services, and death) was examined for the entire population. Cost per case was assumed to equal the average statewide Medicaid rate. An inverse relation between survival rate and age was observed, which resulted in an age-related increased cost per survivor. Also, survivors in older age groups had an increased rate of discharge to residential healthcare facilities. There was a negative, albeit less marked, effect of older age on the rates of survivors discharged to home and to other healthcare facilities., Conclusions: Care of patients who undergo tracheostomy for prolonged mechanical ventilation is expensive. The older the patient, the less satisfactory the outcome from an economic, clinical, and possibly social perspective.

Effect of six antibiotics on the hemolysin formation by 320 strains of Staphylococcus (including 112 S. aureus) and 100 strains of S. agalactiae isolated from cow udders, have been determined. Tests were performed on plates containing 5% horse red cells, but the hemolytic strains were tested on blood agar plates supplemented with 5% sheep, rabbit and calf cells in addition. One strain of S. aureus produced the rings of hemolysis around the zones of growth inhibition on the media containing the discs of penicillin, erythromycin, oxyterramycin and chloramphenicol. Another strain of S. agalactiae produced similar rings, but only on the medium supplemented with penicillin. On the calf blood agar plate, S. aureus produced the hemolytic rings only in association with streptomycin and neomycin. After five times of propagation on the nutrient agar, the hemolytic phenomenon was not reproducible. It may be suggested that in cow milk there are some inhibitors for hemolysin formation by Staphylococcus and S. agalactiae.

Altogether 111 strains of C. uberis isolated from cow udders of a dairy herd were studied. Only 27 strains gave positive fermentation without gas formation from glucose, 6 strains from maltose, lactose and galactose, 9 strains from maltose, 4 strains from sucrose, and 5 strains from sucrose and lactose. No fermentation was found in 48 strains; 12 strains decomposed various carbohydrates except glucose. Statistically significant differences in the slide haemagglutination test (OH), type A, were obtained only with human blood cells, group O, in connection with acid-producing strains (X20=12.64 greater than 9.21), as well as with those biochemically inactive (X20=9.12 greater than 7.82). The results of OH obtained with sheep, rabbit, horse, cow and calf blood cells were not characteristic, remaining on the levels of X2alpha=0.01 and X2alpha=0.02. Inoculation of C. uberis 22 (2-10(9) organisms in 10 ml inoculum) into 4 udder quarters free from bacteria, and into 8 quarters naturally infected with non-pathogenic coryneform organisms provoked a short-lived positive CMT reaction without clinical symptoms, and elimination of the bacteria. It seems to result from the author's current investigations that C. uberis is able to protect the cow udder against mastitis caused by bacteria.