A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway

2021 ◽  
pp. 1-10
Author(s):  
Varvara Kanti ◽  
Lia Puder ◽  
Irina Jahnke ◽  
Philipp Maximilian Krabusch ◽  
Jan Kottner ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Skin Pigmentation ◽  
Gene Mutations ◽  
Continuous Treatment ◽  
Whole Body ◽  
Hair Color ◽  
Phase 2 ◽  
Loss Of Function ◽  
The Impact ◽  
Over Time

<b><i>Background and Objectives:</i></b> Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist <i>setmelanotide</i> in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with <i>setmelanotide,</i> changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. <b><i>Methods:</i></b> In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist <i>setmelanotide</i>. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. <b><i>Results:</i></b> We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of <i>setmelanotide</i> treatment. <b><i>Discussion:</i></b> <i>Setmelanotide</i> treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

scholarly journals PKCδ deficiency inhibits fetal development and is associated with heart elastic fiber hyperplasia and lung inflammation in adult PKCδ knockout mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0253912
Author(s):  
Yuko S. Niino ◽  
Ikuo Kawashima ◽  
Yoshinobu Iguchi ◽  
Hiroaki Kanda ◽  
Kiyoshi Ogura ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Fetal Development ◽  
Elastic Fiber ◽  
Gene Mutations ◽  
Whole Body ◽  
Loss Of Function ◽  
Recognition Sequence ◽  
Knockout Mouse Model ◽  
Multiple Protein ◽  
B Cell Homeostasis

Protein kinase C-delta (PKCδ) has a caspase-3 recognition sequence in its structure, suggesting its involvement in apoptosis. In addition, PKCδ was recently reported to function as an anti-cancer factor. The generation of a PKCδ knockout mouse model indicated that PKCδ plays a role in B cell homeostasis. However, the Pkcrd gene, which is regulated through complex transcription, produces multiple proteins via alternative splicing. Since gene mutations can result in the loss of function of molecular species required for each tissue, in the present study, conditional PKCδ knockout mice lacking PKCδI, II, IV, V, VI, and VII were generated to enable tissue-specific deletion of PKCδ using a suitable Cre mouse. We generated PKCδ-null mice that lacked whole-body expression of PKCδ. PKCδ+/- parental mice gave birth to only 3.4% PKCδ-/- offsprings that deviated significantly from the expected Mendelian ratio (χ2(2) = 101.7, P < 0.001). Examination of mice on embryonic day 11.5 (E11.5) showed the proportion of PKCδ-/- mice implanted in the uterus in accordance with Mendelian rules; however, approximately 70% of the fetuses did not survive at E11.5. PKCδ-/- mice that survived until adulthood showed enlarged spleens, with some having cardiac and pulmonary abnormalities. Our findings suggest that the lack of PKCδ may have harmful effects on fetal development, and heart and lung functions after birth. Furthermore, our study provides a reference for future studies on PKCδ deficient mice that would elucidate the effects of the multiple protein variants in mice and decipher the roles of PKCδ in various diseases.

368 Durability of Tx Response to Zolpidem using a Partial Reinforcement Regimen: Does this strategy require contingent reinforcement?

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A146-A147
Author(s):  
Michael Perlis ◽  
Knashawn Morales ◽  
Ivan Vargas ◽  
Alexandria Muench ◽  
Mark Seewald ◽  
...  
Keyword(s):  
Treatment Response ◽  
Phase 1 ◽  
Partial Reinforcement ◽  
Continuous Treatment ◽  
Phase 2 ◽  
Sleep Continuity ◽  
Average Improvement ◽  
Average Change ◽  
Treatment Responses ◽  
Over Time

Abstract Introduction In 2015, partial reinforcement (PR) was assessed as an alternative approach to maintenance therapy with zolpidem. The method being: once a treatment response is obtained over the course of 1-month’s Tx with QHS dosing (Phase-1), Tx response can maintained over time with a PR regimen (Phase-2 [nightly pill/capsule use with 50% of capsules having medication and 50% having only inert filler]). In that study, it was assumed that Phase1 QHS dosing was required 1) to maximize treatment responding and 2) for the conditioning of pharmacologic responses to the medication vehicle (capsule). In the present study, these assumptions were tested by including both QHS and PR arms into Phase-1. Methods In Phase-1 (1 month), subjects were randomized to the QHS or PRS conditions (2QHS:1PRS). In Phase-2 (3 months), the PRS group continued forward without a change in the treatment regimen (variable dose [VD-VD]) and the QHS group was re-randomized to either continued QHS Tx (full dose [FD-FD]) or to PRS Tx [FD-VD]). Both study phases were evaluated for treatment responses rates and for average change in TWT (SL+WASO+EMA). Results 55 subjects (age 61.2+/-8.1, 64% female, & 73% white) were enrolled into Phase-1; 39 were randomized to the QHS condition and 16 to the PRS condition. In Phase-1, 77% (QHS) and 50% (PRS) exhibited treatment responses (p=0.09) where the average change in TWT was similar by group (QHS was -43min [CI -76,-9] and PRS was -76min [CI -138,-14];p=0.35). In Phase-2, 73% (FD-FD), 57% (FD-VD), and 88% (VD-VD) exhibited continued treatment responses (p=0.22) where the average improvement of TWT continued with FD-FD and remained stable for FD-VD and VD-VD (p&lt;0.01). Conclusion These data, while preliminary, suggest that QHS (vs. PRS) dosing produces more treatment responders and similar initial effects on sleep continuity during Phase-1, comparable maintenance of treatment response over time, and continued improvement on sleep continuity during Phase-2. These results suggest that partial reinforcement can maintain effects but cannot allow for the additional clinical gains afforded by continuous treatment. Given this, it may be the case that the partial reinforcement technique could be improved upon by extending phase from 1 to 2–4 months. Support (if any):

The Therapist’s Reaction to a Patient’s Suicide

Crisis ◽  
2011 ◽  
Vol 32 (2) ◽  
pp. 99-105 ◽  
Author(s):  
Friedrich Martin Wurst ◽  
Isabella Kunz ◽  
Gregory Skipper ◽  
Manfred Wolfersdorf ◽  
Karl H. Beine ◽  
...  
Keyword(s):  
Emotional Responses ◽  
Well Being ◽  
Emotional Reaction ◽  
Emotional Reactions ◽  
Analog Scale ◽  
General Hospitals ◽  
Item Questionnaire ◽  
Retrospective Nature ◽  
The Impact ◽  
Over Time

Background: A substantial proportion of therapists experience the loss of a patient to suicide at some point during their professional life. Aims: To assess (1) the impact of a patient’s suicide on therapists distress and well-being over time, (2) which factors contribute to the reaction, and (3) which subgroup might need special interventions in the aftermath of suicide. Methods: A 63-item questionnaire was sent to all 185 Psychiatric Clinics at General Hospitals in Germany. The emotional reaction of therapists to patient’s suicide was measured immediately, after 2 weeks, and after 6 months. Results: Three out of ten therapists suffer from severe distress after a patients’ suicide. The item “overall distress” immediately after the suicide predicts emotional reactions and changes in behavior. The emotional responses immediately after the suicide explained 43.5% of the variance of total distress in a regression analysis. Limitations: The retrospective nature of the study is its primary limitation. Conclusions: Our data suggest that identifying the severely distressed subgroup could be done using a visual analog scale for overall distress. As a consequence, more specific and intensified help could be provided to these professionals.

Has Aid Helped in Pakistan?

1997 ◽  
Vol 36 (4II) ◽  
pp. 947-957 ◽  
Author(s):  
Shahrukh Rafi Khan
Keyword(s):  
Economic Growth ◽  
Negative Impact ◽  
Negative Association ◽  
Causal Impact ◽  
The Impact ◽  
Over Time

This paper has a two-fold objective: first, to examine the terms on which Pakistan receives aid and whether its debt situation is sustainable, and second, to examine the impact of aid and debt on economic growth. It is found that there is little encouraging that can be said about how the terms on which Pakistan has received aid over time have changed, and its current debt situation is not sustainable. Also reported is the analysis done elsewhere which shows that aid has a negative (Granger) causal impact on GDP, and aid has a robust negative impact on economic growth after controlling for supplyside shocks. We provide various reasons for this negative association.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

Conclusion

2018 ◽  
Author(s):  
Manuel Fröhlich ◽  
Abiodun Williams
Keyword(s):  
Security Council ◽  
International Context ◽  
Peace And Security ◽  
Executive Action ◽  
Trends Over Time ◽  
The Impact ◽  
Over Time ◽  
The Way ◽  
Guiding Questions

The Conclusion returns to the guiding questions introduced in the Introduction, looking at the way in which the book’s chapters answered them. As such, it identifies recurring themes, experiences, structures, motives, and trends over time. By summarizing the result of the chapters’ research into the interaction between the Secretaries-General and the Security Council, some lessons are identified on the changing calculus of appointments, the conditions and relevance of the international context, the impact of different personalities in that interaction, the changes in agenda and composition of the Council as well as different formats of interaction and different challenges to be met in the realm of peace and security, administration, and reform, as well as concepts and norms. Taken together, they also illustrate the potential and limitations of UN executive action.

Understanding Rising Income Inequality and Stagnating Ordinary Living Standards in Germany

2018 ◽  
Author(s):  
Gerhard Bosch ◽  
Thorsten Kalina
Keyword(s):  
Income Inequality ◽  
Labour Market ◽  
Economic Crisis ◽  
Household Income ◽  
Wage Bargaining ◽  
Living Standards ◽  
Social Model ◽  
Real Wages ◽  
The Impact ◽  
Over Time

This chapter describes how inequality and real incomes have evolved in Germany through the period from the 1980s, through reunification, up to the economic Crisis and its aftermath. It brings out how reunification was associated with a prolonged stagnation in real wages. It emphasizes how the distinctive German structures for wage bargaining were eroded over time, and the labour market and tax/transfer reforms of the late 1990s-early/mid-2000s led to increasing dualization in the labour market. The consequence was a marked increase in household income inequality, which went together with wage stagnation for much of the 1990s and subsequently. Coordination between government, employers, and unions still sufficed to avoid the impact the economic Crisis had on unemployment elsewhere, but the German social model has been altered fundamentally over the period

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