Treatment challenges in the management of moderate-to-severe plaque psoriasis - role of secukinumab.

Psoriasis is a chronic inflammatory skin disease that has a negative impact on psychosocial well-being and cardiometabolic health. Treatment options for moderate-to-severe psoriasis have expanded with the development of interleukin-17 (IL-17) inhibitors, the first of which is now available - secukinumab. Secukinumab is a fully human monoclonal immunoglobulin G1 κ antibody that selectively inhibits the ligand IL-17A. In head-to-head studies, it is more effective than etanercept and ustekinumab, particularly in achieving Psoriasis Area and Severity Index (PASI) 90/100 and achieving PASI 50/75 as early as week 4. No head-to-head trials are available for comparison of adalimumab to secukinumab. Significant improvement in health care-related quality of life was also observed using the dermatology quality index in clinical studies. Safety data for secukinumab is comparable to available biologics. Specific safety concerns for the use of secukinumab include its use in patients with inflammatory bowel disease, reversible transient neutropenia, in those with a latex allergy, and the occurrence of mild to moderate oral or genital candidiasis. Secukinumab is an effective and safe treatment option that achieves high clearance rates up to PASI 90 and 100 as monotherapy in cases of moderate-to-severe psoriasis. It may be particularly helpful in patients with psoriasis who have formed antidrug antibodies or failed other biologic agents and in patients with psoriatic arthritis or ankylosing spondylitis.

Chronic ethanol and withdrawal differentially modulate lateral/basolateral amygdala paracapsular and local GABAergic synapses.

Withdrawal-related anxiety is cited as a major contributor to relapse in recovering alcoholics. Changes in lateral/basolateral amygdala (BLA) neurotransmission could directly influence anxiety-like behaviors after chronic ethanol exposure and withdrawal. We have shown that these treatments enhance BLA glutamatergic function and neurotransmission. However, the BLA GABAergic system tightly controls the expression of anxiety-like behavior, and additional neuroadaptations in this system are potentially important as well. The intrinsic BLA GABAergic system consists of at least two populations of interneurons: local feed-back interneurons scattered throughout the region and feed-forward interneurons concentrated within groups found in the lateral/paracapsular region of the BLA. In the present study, we found that withdrawal from chronic ethanol robustly decreased presynaptic function at feed-forward GABA synapses but did not alter neurotransmitter release from local interneurons. Differential presynaptic changes at these synapses were complemented by decreased zolpidem sensitivity at feed-forward synapses and decreased midazolam sensitivity at local synapses. Consistent with this, chronic ethanol/withdrawal decreased expression of GABA α1-subunit total protein and increased surface expression of α4-subunit protein. We also found transient increases in GABA-receptor-associated protein levels and persistent increases in γ2-subunit and gephyrin proteins that would suggest alterations in GABA(A) receptor trafficking that might help regulate changes in α4-subunit localization. These data together suggest that chronic ethanol and withdrawal differentially modulate local and lateral paracapsular cell GABAergic synapses via distinct presynaptic and postsynaptic mechanisms. These findings extend our understanding of the neurobiological mechanisms governing changes in anxiety-like behavior after chronic ethanol exposure and withdrawal.

Dopamine D3-like receptors modulate anxiety-like behavior and regulate GABAergic transmission in the rat lateral/basolateral amygdala.

Central among the brain regions that regulate fear/anxiety behaviors is the lateral/basolateral amygdala (BLA). BLA output is tightly controlled by the relative activity of two populations of inhibitory GABAergic interneurons, local feedback cells distributed throughout the nucleus, and feedforward cells found along the lateral paracapsular border of this subdivision. Recent studies suggest that dopamine (DA) can modulate the BLA GABAergic system, thus linking fear/anxiety states with mesolimbic reward/attentional processes. However, the precise dopaminergic mechanisms regulating the activity of the two BLA GABAergic neuron populations have not been fully explored. We therefore examined the effects of DA D3-like receptors on BLA-dependent anxiety-like behavior and neurophysiology. After confirming the presence of D3-like receptors within the BLA, we found that microinjection of a D3-selective antagonist into the BLA decreased anxiety-like behavior expressed in both the light/dark transition test and the elevated plus maze. Consistent with this, we found that in vitro D3-like receptor activation selectively inhibits synaptic transmission at both BLA feedback and feedforward GABAergic interneuron populations, with no effect on glutamatergic transmission. This inhibition of GABAergic transmission is a result of a D3-like receptor-mediated, dynamin-dependent process that presumably reflects endocytosis of postsynaptic GABA(A) receptors found on principal BLA neurons. Because environmental cues alter both DA release and relative activity states of the BLA, our data strongly suggest that DA, potentially acting through D3-like receptors, may suppress the relative contribution by inhibitory processes in the BLA and modify the expression of BLA-related behaviors.

Fatigue in women receiving intraperitoneal chemotherapy for ovarian cancer: a review of contributing factors.

Women diagnosed with stage III or IV ovarian cancer typically are treated with surgery followed by chemotherapy. Intraperitoneal (IP) chemotherapy, the direct administration of chemotherapy into the IP cavity, has been explored as a viable treatment option for some women with advanced ovarian cancer. Fatigue may occur as a result of the disease process, treatment, or a wide variety of physical, psychological, or situational factors. Fatigue is one of the most common and distressing side effects associated with chemotherapy and it may be intensified in women receiving IP chemotherapy. The purpose of this article is to examine fatigue in women receiving IP chemotherapy for advanced ovarian cancer and to examine what aspects of IP chemotherapy may contribute to fatigue development. Factors reviewed include surgery for debulking the tumor and placement of the IP catheter, administration of IV chemotherapy in addition to IP chemotherapy, pain, anemia, sleep disturbances, gastrointestinal disturbances, and emotional distress. Oncology nurses who are knowledgeable about the factors that contribute to fatigue in women receiving IP chemotherapy will be better prepared to conduct a comprehensive assessment and develop effective treatment strategies.

Long-term ethanol self-administration by the nonhuman primate, Macaca fascicularis, decreases the benzodiazepine sensitivity of amygdala GABA(A) receptors.

BACKGROUND: Rodent models of chronic alcohol exposure are typically constrained to relatively short periods of forced ethanol due to the lifespan of these animals. Nonhuman primate models, particularly those employing long-term self-administration, are conceptually more similar to human alcoholic individuals. METHODS: We performed whole-cell patch clamp recordings on acutely dissociated amygdala neurons isolated from cynomolgus macaque coronal temporal lobe slices. Slices were prepared from control monkeys or monkeys allowed to self-administer oral ethanol for 18 months. Flunitrazepam and acute ethanol modulation of currents gated by exogenous gamma-aminobutyric acid (GABA) application was assessed in these isolated neurons. Complementary experiments were performed on amygdala total RNA using quantitative real-time reverse transcription/polymerase chain reaction to understand potential ethanol-dependent adaptations to subunit composition. RESULTS: Gamma-aminobutyric acid-gated currents from ethanol-exposed macaque amygdala neurons exhibited reduced modulation by flunitrazepam compared with control neurons. However, this was specific for benzodiazepines as the modest inhibition of GABA-gated currents by acute ethanol was not affected by the chronic ethanol consumption. We also measured mRNA expression levels for the beta, gamma, and delta subunits in total amygdala RNA isolated from control and ethanol-drinking animals. beta1 and gamma2 expression was significantly reduced in samples from ethanol-exposed amygdala. CONCLUSIONS: Our findings demonstrate that chronic ethanol self-administration reduces the benzodiazepine sensitivity of amygdala GABA(A) receptors. This reduced sensitivity may be the result of decreased expression of an amygdala gamma subunit. These findings suggest that, while rodent and nonhuman primate models of chronic ethanol exposure share many characteristics, the specific molecular adaptations associated with the amygdala GABAergic system may not be identical.

Aphthous ulcers associated with imiquimod and the treatment of actinic cheilitis.

Our case series report is the first documented depiction of the appearance of aphthous ulcers secondary to imiquimod application. This case series presentation discusses the underlying pathophysiology of aphthous ulcer development and imiquimod therapy in terms of the stimulation of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha). The literature review suggests more than just a mere coincidence for the development of aphthous ulcers subsequent to the treatment of actinic cheilitis with imiquimod application.