Rejected

The fruit of Tetradium ruticarpum (FTR) known as Tetradii fructus or Evodiae fructus (Wu-Zhu-Yu in Chinese) is a versatile herbal medicine which has been prescribed in Chinese herbal formulas and recognized in Japanese Kampo. FTR has been clinically used to treat various diseases such as headache, vomit, diarrhea, abdominal pain, dysmenorrhea and pelvic inflammation for thousands of years.

The release and extracellular action of ATP are a widespread mechanism for cell-to-cell communication in living organisms through activation of P2X and P2Y receptors expressed at the cell surface of most tissues, including the nervous system. Among ionototropic receptors, P2X4 receptors have emerged in the last decade as a potential target for CNS disorders such as epilepsy, ischemia, chronic pain, anxiety, multiple sclerosis and neurodegenerative diseases. However, the role of P2X4 receptor in each pathology ranges from beneficial to detrimental, although the mechanisms are still mostly unknown. P2X4 is expressed at low levels in CNS cells including neurons and glial cells. In normal conditions, P2X4 activation contributes to synaptic transmission and synaptic plasticity. Importantly, one of the genes present in the transcriptional program of myeloid cell activation is P2X4. Microglial P2X4 upregulation, the P2X4 state of microglia, seems to be common in most acute and chronic neurodegenerative diseases associated with inflammation. In this review, we summarize knowledge about the role of P2X4 receptors in the CNS physiology and discuss potential pitfalls and open questions about the therapeutic potential of blocking or potentiation of P2X4 for different pathologies.

Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors. One of the most frequent localizations of PEComas is the female genitourinary tract, and the uterus is the most involved site after the kidney. Correct preoperative diagnosis is rarely achieved due to the presence of nonspecific imaging features. We report a case of a uterine PEComa with particular reference to ultrasound's role in characterizing this rare occurrence.

Metformin is the first-line therapy for patients with type 2 diabetes, and its most common adverse effects are gastrointestinal. Lactic acidosis associated with metformin use is rare. Here, we report the case of a 77-year-old man with a medical history of diabetes (treated with metformin), hypertension, chronic alcohol abuse, and prostate and bladder cancer, who presented with abdominal pain, nausea, vomiting, and diarrhea for five days. He was admitted with severe metabolic acidosis due to metformin toxicity (metformin-associated lactic acidosis) with metformin level 23 mcg/mL (therapeutic range approximately 1-2 mcg/mL) in the setting of acute kidney failure due to acute pancreatitis and sepsis secondary to aspiration pneumonia. He was intubated, required pressor support, and received daily hemodialysis. Despite aggressive management, his hospital course became complicated with acute respiratory distress syndrome, myocardial infarction, acute hepatic failure, and ischemic and metabolic encephalopathy. In the end, the family decided to withdraw care and the patient was terminally extubated.

We evaluated the effects of menstrual types inclusive of PMS on reports of chronic pain intensity and psychopathology in twenty-eight women (mean age 38.93 ± 13.51) with Sickle Cell disease (SCD).

Opioid use disorder and overdose have reached unprecedented levels in many countries across the globe, including the United States, and pain is one of the most common reasons American adults seek healthcare. To address the interrelated public health crises of opioid use disorder and chronic pain, it is vital that clinicians practicing in diverse roles and settings possess the ability and knowledge to effectively manage pain, responsibly prescribe and monitor opioid analgesics, educate patients about harm reduction techniques, and treat opioid use disorder. However, future healthcare professionals are not receiving the training needed to competently provide this care. This gap in curriculum may lead to clinicians being unwilling and unprepared to address the current opioid and overdose crises, which requires a clinical understanding of pain and substance use disorders as well as knowledge about public health and policy interventions. To address this gap, we designed and are teaching an innovative transdisciplinary elective course titled "Opioids: From Receptors to Epidemic" for undergraduate nursing and premedical students.

Characterized by bone marrow dysplasia and peripheral blood monocytosis, chronic myelomonocytic leukemia (CMML) is one of the most aggressive chronic leukemias and has a propensity for progression to acute myeloid leukemia (AML). Patients with newly diagnosed AML generally present with symptoms related to complications of pancytopenia but can also present with renal insufficiency. We present a 79-year-old male with a past medical history of CMML and chronic kidney disease stage 3 (baseline creatinine 1.8 mg/dL) who presented with one day of inability to urinate and 20-lb unintentional weight loss, fatigue, and bone pain over 3 months. Laboratory evaluation revealed leukocytosis of 88.5 x 10/uL (normal 4.8-10.8 x 10/uL) with 24.0% monocytes on differential, creatinine 2.94 mg/dL (baseline creatinine 1.7-1.9 mg/dL), uric acid 19.8 mg/dL, potassium 4.0 mmol/L, phosphorus 4.0 mg/dL, calcium 9.2 mg/dL, and albumin 3.2 g/dL. Urinalysis was significant for protein 200 mg/dL, 20/LPF granular casts, and 7/LPF hyaline casts. Bone marrow biopsy revealed 20-30% blasts with monocytic features of differentiation consistent with acute myeloid leukemia. Computed tomography (CT) of the abdomen and pelvis appreciated splenomegaly with retroperitoneal, and pelvic lymphadenopathy. Kidney failure can complicate the presentation of AML but can be rapidly reversible with treatment. In patients with CMML who have progressive renal insufficiency and hyperuricemia, there should be a high index of suspicion for progression to AML.

Patients with jaundice and abdominal pain should be assessed immediately for biliary obstruction. The development of cholangitis, or an inflammation of the bile ducts, can lead to infection. A nurse practitioner must complete a thorough health history and physical examination to assist in differentiating potential causes of jaundice.

The avenue of effective migraine therapies blocking calcitonin gene-related peptide (CGRP) transmission is the successful outcome of 35 years of translational research. Developed after short-acting, small antagonists of the CGRP receptor (the "gepants"), the monoclonal antibodies blocking CGRP or its receptor (CGRP/rec mAbs) have changed the paradigm in migraine treatment. Contrary to the classical acute medications like triptans or nonsteroidal anti-inflammatory drugs (NSAIDs) with a transient effect, they act for long durations exclusively in the peripheral portion of the trigeminovascular system and can thus be assimilated to a durable attack treatment, unlike the classical preventives that chiefly act upstream on the central facets of migraine pathophysiology. Randomized controlled trials (RCT) of eptinezumab, erenumab, fremanezumab and galcanezumab have included collectively several thousands of patients, making them the most extensively studied class of preventive migraine treatments. Their results clearly indicate that CGRP/rec mAbs are significantly superior to placebo and have been comprehensively reviewed by Dodick [Cephalalgia 2019;39(3):445-458]. In this review we will briefly summarize the placebo-subtracted outcomes and number-needed-to-treat (NNT) of these pivotal RCTs and analyze new and post-hoc studies published afterwards focusing on effect size, effect onset and sustainability, response in subgroups of patients, safety and tolerability, and cost-effectiveness. We will also summarize our limited real-world experience with one of the CGRP/rec mAbs. Although methodological differences and lack of direct comparative trials preclude any reliable comparison, the overall impression is that there are only minor differences in efficacy and tolerability profiles between the four monoclonals: the average placebo-subtracted 50% responder rates for reduction in migraine headaches are 21.4% in episodic migraine (NNTs: 4-5), 17.4% in chronic migraine (NNTs: 4-8). Patients with an improvement exceeding 50% are rare, chronic migraineurs with continuous headache are unlikely to be responders and migraine auras are not improved. The effect starts within the first week after administration and is quasi maximal at one month. It is sustained for long time periods and may last for several months after treatment termination. CGRP/rec mAbs are effective even after prior preventive treatment failures and in patients with medication overuse, but the effect size might be smaller. They significantly reduce disability and health care resource utilization. The adverse effect profile of CGRP/rec mAbs is close to that of placebo with few minor exceptions and despite concerns related to the safeguarding role of CGRP in ischemia, no treatment-related vascular adverse events have been reported to date. Putting the CGRP/rec mAbs in perspective with available preventive migraine drug treatments, their major advantage seems not to be chiefly their superior efficacy but their unprecedented efficacy over adverse event ratio. Regarding cost-effectiveness, preliminary pharmaco-economic analyses of erenumab suggest that it is cost-effective for chronic migraine compared to no treatment or to onabotulinumtoxinA, but likely not for episodic migraine unless attack frequency is high, indirect costs are considered and its price is lowered.