Short tail with skin lesion phenotype occurs in transgenic mice with keratin-14 promoter-directed expression of mutant CXCR2

CXCR2 plays an important role during cutaneous wound healing. Transgenic mice were generated using the keratin-14 promoter/enhancer to direct expression of wild-type human CXCR2 (K14hCXCR2 WT) or mutant CXCR2, in which the carboxyl-terminal domain (CTD) was truncated at Ser 331 and the dileucine AP-2 binding motif was mutated to alanine (K14hCXCR2 331T/LL/AA/IL/AA). Our results indicate that K14hCXCR2WT transgenic mice exhibited a normal phenotype, while K14hCXCR2 331T/LL/AA/IL/AA transgenic mice were born with tails of normal length, but three to eight days after birth their tails degenerated, leaving only a short tail stub. The tissue degeneration in the tail started between caudal somites with degeneration of bone and connective tissue distal to the constriction, which was replaced with stromal tissue heavily infiltrated with inflammatory cells. The tail lesion site revealed coagulation in enlarged vessels and marked edema that eventually led to loss of the distal tail. Moreover, 66% of the mice exhibited focal skin blemishes and inflammation that exhibited an increase in the number of sebaceous glands and blood vessels, enlargement of the hair follicles due to increased number of keratinocytes, reduction in the connective tissue content, and a thickening of the epidermis. Furthermore, immunohistochemical staining of the epidermis from tail tissue in the transgenic mice indicated a loss of the cell adhesion markers E-cadherin and desmoplakin. These data suggest that keratinocyte expression of a CTD mutant of CXCR2 has effects on homeostasis of the connective tissue in the tail, as well as the maintenance of the epidermis and its appendages.     

Receptor-directed therapy of T-cell leukemias and lymphomas

T-Cell leukemias and lymphomas represent a less common and heterogeneous group of lymphoid neoplasms. Overall, they respond less well to chemotherapy and have a poorer prognosis than their B-cell counterparts. T-Cell tumors express a number of potential targets for receptor-directed antibody therapy; however, there is no available therapeutic monoclonal antibody for these diseases with comparable activity to that of rituximab in B-cell disorders. Despite this, alemtuzumab, a humanized anti-CD52 monoclonal antibody has demonstrated meaningful anti-tumor activity in a variety of T-cell malignancies. A number of other antibodies, modified antibodies and immunotoxins directed against targets such as CD2, CD4, CD5, CD25, CD30 and CD122 expressed on malignant T-cells are under investigation. The current status of receptor-directed antibody therapy for T-cell leukemia and lymphoma is reviewed.     

Guideline Adherence As An Indicator of the Extent of Antithrombotic Overuse and Underuse: A Systematic Review

Thromboembolic events are a common risk in adults with atrial fibrillation, those with previous cerebrovascular accidents and undergoing emergency or elective surgeries. The widespread availability of antithrombotic agents and differing guidelines contribute to practice variations and increased risk of complications and deaths. The objective of this review was to investigate the extent of overuse and underuse of antithrombotics for primary or secondary prevention as measured by deviation from prescribing guideline recommendations. We conducted a systematic review of Medline and EMBASE for quantitative articles published between 2000 and 2021 and used a modified version of the Hoy’s risk of bias assessment tool. Here we report evidence from the past decade about wide practice variations in hospitals and primary care, and discuss clinician and patient-driven determinants of non-adherence to guidelines. Finally, we summarise implications for practice, identify enhanced ways of measuring overuse and underuse, and propose potential solutions to the measurement challenges.     

Effect of Immunosuppressive Therapy on the Serum Fatty Acids of Phospholipids Fraction in Patients After Heart Transplantation

Background

The effects of tacrolimus (Tac) and cyclosporine (CsA) on lipid profile is well known; however, little is known about the changes in fatty acids (FA) of phosholipids fraction (PL) in heart transplant patients after treatment with these immunosuppressants. This study aimed to investigate the effect of Tac and CsA on serum FA of PL in heart transplant patients.

Methods

The study included 23 patients after heart transplantation on Tac (n = 14; group II) or CsA (n = 9; group I). Eleven healthy persons served as a control group. Serum FA of PL were extracted, separated on Sep-Pak NH₂, methylated, and measured with the use of gas chromatography. Chemstation software was used to analyze the data.

Results

No differences between the studied groups and control were noted for saturated FA, monounsaturated FA, polyunsaturated FA (PUFA), total FA, and PUFA n-6. The mean value of PUFA n-3 was significantly higher in the CsA group compared with the Tac group (P < .015) and control (P < .002) as well as in the Tac group compared with control (P < .001). For individual FA, higher mean concentration, compared with control, was found for C24, C20:2, C20:4, and C22:6 (P < .001 in all cases) and lower for C18:2cis (P < .001 in both groups) and for C18:3 in the Tac group. The mean values of PUFA n-6 to PUFA n-3 ratios were lower than in control (both P < .001).

Conclusions

Different pattern of FA of PL may indicate the different FA metabolism in heart transplant patients treated by different immunosuppressants. This should be taken into account when FA supplementation in these patients is considered.     

Childhood tic disorders: diagnosis and management

Tics are considered to be benign but often cause great distress to the child and family, especially when there is a lack of understanding about their nature and the related conditions. This article is a clinical guide to assessment, diagnosis and management; with focus on practical aspects, caveats and catches and most importantly recognising and managing developmental and psychiatric co-morbidities in Tourette Syndrome and other Tic conditions.     

Motivation Precedes Goal Setting in Prediction of Cannabis Treatment Outcomes in Adolescents

Studies have shown that motivation to change is related to better substance use outcomes among treatment-seeking adolescents. Goal setting, which may be related to motivation, also has been shown to be associated with positive treatment outcomes. However, relationships between motivation and goal setting as mediators of change in cannabis use over time among treated youths have not been investigated. This study tested direct and indirect associations of motivation and goal setting with cannabis use frequency over 12-month follow-up among treated adolescents. A longitudinal study of 163 adolescents enrolled in intensive outpatient substance use treatment (mean age = 16.69, 34% female, 87% Caucasian) provided repeated assessment of motivation, goal setting, and cannabis use. Path analysis tested direct and indirect effects of motivation and goal setting on cannabis use. A comparison of two path models that tested motivation and goal setting independently showed that goal setting had better model fit and accounted for more of the variance in six-month (R² = .35) and 12-month (R² = .46) cannabis use frequency than motivation (R² = .28, .44, respectively). When both mediators were included in the same model, better model fit was found for motivation preceding goal setting in the context of double mediation. Overall, results suggest that goal setting, or the combination of motivation preceding goal setting in a double mediation model, predicted lower cannabis use in treated adolescents.     

Using hip measures to avoid misdiagnosing early rapid onset osteoarthritis for osteonecrosis

In the early phases, subchondral insufficiency fractures and rapidly destructive osteoarthritis of the hip are often mistaken for osteonecrosis of the hip. Three hip measures were used comparing combined subchondral insufficiency fractures and rapidly destructive 18 osteoarthritis patients to 18 osteonecrosis patients. Due to the rarity of these conditions there was no statistical power. Initial diagnoses for the osteoarthritis patients were recorded. The osteoarthritis group had significantly higher means for Tönnis angle (P < 0.001), lateral center edge angle (P = 0.006), and acetabular extrusion index (P = 0.014). Only 7 of the 18 patients were initially diagnosed without reservation as subchondral insufficiency fracture or rapidly destructive osteoarthritis. Using hip measures will reduce the misdiagnosis of rapid onset osteoarthritis of the hip for osteonecrosis.     

Racial/ethnic differences in life-course heavy drinking from adolescence to midlife

Information on heavy drinking over the life course might help to explain racial/ethnic disparities in alcohol-related problems, morbidity, and mortality. Using data from the 2009–2010 U.S. National Alcohol Survey (n?=?3,026), we analyzed retrospective decades-based measures of heavy drinking during respondents’ teens, 20s, 30s, and 40s. Results indicate that Latino men and African American women have greater risk for persistent-high (vs. declining) heavy-drinking trajectories than Caucasian men and women, and that socioeconomic disadvantage partly accounts for this disparity in women. Prospective longitudinal studies are needed to confirm these results and to elucidate the relationship of life-course heavy-drinking patterns with health-related outcomes, and disparities in these.