Minocycline-Induced Black Bone Disease in Foot and Ankle Surgery: A Case Report.

BACKGROUND: Bone and periarticular tissue discoloration can be an unexpected finding that is often disconcerting for surgeons and may alter surgical plans and overall patient management. Common causes of bone discoloration include infection, avascular necrosis, and bone inflammation. Minocycline-induced black bone disease is a rare and relatively benign abnormality encountered in foot and ankle surgery that can cause significant black, blue, and gray discoloration of bone. METHODS: Unanticipated intraoperative findings of diffuse black, blue, and gray bone discoloration during an elective forefoot operation raised concern for a metabolically malignant process and prompted the conversion of plans for a first metatarsophalangeal joint implant arthroplasty to a Keller arthroplasty. The plan for proximal interphalangeal joint arthroplasties of the lesser digits were continued as planned. Bone specimens were sent for pathologic analysis. RESULTS: Postoperative analysis identified chronic use of a minocycline for acne vulgaris. Pathologic analysis of the specimens ruled out malignant processes. Altogether, the data available led to the diagnosis of minocycline-induced black bone disease. Since the last follow-up, the patient has healed well without complications. CONCLUSIONS: Our case report underscores the importance of including the chronic use of tetracyclines in medical history intake during preoperative visits to assist the surgeon in intraoperative decision-making.

Impaired Endogenous Neurosteroid Signaling Contributes to Behavioral Deficits Associated With Chronic Stress.

BACKGROUND: Chronic stress is a major risk factor for psychiatric illnesses, including depression. However, the pathophysiological mechanisms whereby stress leads to mood disorders remain unclear. Allopregnanolone acts as a positive allosteric modulator preferentially on δ subunit-containing GABAA (gamma-aminobutyric acid A) receptors. Accumulating clinical and preclinical evidence supports the antidepressant effects of exogenous administration of allopregnanolone analogs; yet, the role of endogenous allopregnanolone in the pathophysiology of depression remains unknown. METHODS: We utilized a chronic unpredictable stress (CUS) mouse model, followed by behavioral and biochemical assays, to examine whether altered neurosteroid signaling contributes to behavioral outcomes following CUS. We subsequently performed in vivo CRISPR (clustered regularly interspaced short palindromic repeats) knockdown of rate-limiting enzymes involved in allopregnanolone synthesis, 5α-reductase type 1 and 2 (5α1/2), in addition to lentiviral overexpression of 5α1/2 in the basolateral amygdala (BLA) of mice that underwent CUS to assess the impact of 5α1/2 on behavioral outcomes. RESULTS: The expression of δ subunit-containing GABAA receptors and endogenous levels of allopregnanolone were reduced in the BLA following CUS. Treatment with an exogenous allopregnanolone analog, SGE-516, was sufficient to increase allopregnanolone levels in the BLA following CUS. Knockdown of 5α1/2 in the BLA mimicked the behavioral outcomes associated with CUS. Conversely, overexpression of 5α1/2 in the BLA improved behavioral outcomes following CUS. CONCLUSIONS: Our findings demonstrate that chronic stress impairs endogenous neurosteroid signaling in the BLA, which is sufficient to induce behavioral deficits. Further, these studies suggest that allopregnanolone-based treatments may directly target the underlying pathophysiology of mood disorders suggesting that targeting endogenous neurosteroidogenesis may offer a novel therapeutic strategy.

Efficacy and tolerability of nortriptyline in the management of neuropathic corneal pain.

PURPOSE: Neuropathic corneal pain (NCP) is a recently acknowledged disease entity. However, there is no consensus in potential treatment strategies, particularly in patients with a centralized component of pain. This study aims to assess the efficacy and tolerability of the tricyclic antidepressant, nortriptyline, among NCP patients. METHODS: Patients with clinically diagnosed NCP and a centralized component of pain, treated with oral nortriptyline, who had recorded pain scores as assessed by the ocular pain assessment survey at the first and last visit were included. Patients were excluded if they had any other ocular pathology that might result in pain or had less than 4 weeks of nortriptyline use. Demographics, time between visits, concomitant medications, systemic and ocular co-morbidities, duration of NCP, side effects, ocular pain scores, and quality of life (QoL) assessment were recorded. RESULTS: Thirty patients with a mean age of 53.1 ± 18.5 were included. Male to female ratio was 8:22. Mean ocular pain in the past 24 h improved from 5.7 ± 2.1 to 3.6 ± 2.1 after 10.5 ± 9.1 months (p < 0.0001). Twelve patients (40.0%) had equal to or more than 50% improvement, 6 patients (20.0%) had 30-49% improvement, 6 patients (20.0%) had 1-29% improvement, 4 patients (13.3%) did not improve, while 2 patients (6.7%) reported increase in pain levels. Mean QoL improved from 6.0 ± 2.5 to 4.3 ± 2.4 (p = 0.019). Eight patients (26.6%) discontinued treatment due to persistent side effects, despite improvement by 22.4%. CONCLUSION: Nortriptyline was effective in relieving NCP symptoms in patients with centralized component and insufficient response to other systemic and topical therapies who tolerated the drug for at least 4 weeks. Nortriptyline may be used in the management of patients with NCP.

Seizure-induced activation of the HPA axis increases seizure frequency and comorbid depression-like behaviors.

Our laboratory recently demonstrated that seizures activate the hypothalamic-pituitary-adrenal (HPA) axis, increasing circulating levels of corticosterone (O'Toole et al., 2013). Given the well-established proconvulsant actions of corticosterone, we hypothesized that seizure-induced activation of the HPA axis may contribute to future seizure susceptibility. Further, since hypercortisolism is associated with depression, we propose that seizure-induced activation of the HPA axis may contribute to comorbid depression and epilepsy. To test this hypothesis, we generated mice lacking the GABAA receptor (GABAAR) δ subunit specifically in corticotropin-releasing hormone (CRH) neurons (Gabrd/Crh mice), which exhibit hyporeactivity of the HPA axis (Lee et al., 2014). Gabrd/Crh mice exhibit blunted seizure-induced elevations in corticosterone, establishing a useful tool to investigate the contribution of HPA axis dysfunction on epilepsy and associated comorbidities. Interestingly, Gabrd/Crh mice exhibit decreased acute seizure susceptibility following kainic acid (KA) administration. Furthermore, chronically epileptic Gabrd/Crh mice exhibit a decrease in both spontaneous seizure frequency and depression-like behaviors compared with chronically epileptic Cre-/- littermates. Seizure susceptibility and associated depression-like behaviors can be restored to wild type levels by treating Gabrd/Crh mice with exogenous corticosterone. Similarly, chemogenetic activation of CRH neurons in the paraventricular nucleus (PVN) is sufficient to increase seizure susceptibility; whereas, chemogenetic inhibition of CRH neurons in the PVN of the hypothalamus is sufficient to decrease seizure susceptibility and depression-like behaviors in chronically epileptic mice. These data suggest that seizure-induced activation of the HPA axis promotes seizure susceptibility and comorbid depression-like behaviors, suggesting that the HPA axis may be a novel target for seizure control.