Rejected

We present a 15-year-old Japanese girl with no previous medical history who presented with a gradually worsening series of orthostatic headaches. We diagnosed spontaneous intracranial hypotension, worsened by playing the saxophone and its Valsalva maneuver effect. She was treated with Japanese herbal medicine  7.5 g/day in three divided doses, and her symptoms gradually improved. Her headache has never recurred for a year when she played the saxophone. Our case's headache may have been further exacerbated by cerebrospinal fluid (CSF) leakage due to CSF pressure increase by Valsalva maneuvers while playing the saxophone. Our case suggested that the Japanese herbal medicine can facilitate the glymphatic system and adjust the CSF pressure appropriately.

Background and objective The field of kidney transplantation in sub-Saharan Africa is still in the rudimentary stages. The majority of patients with chronic kidney disease have no access to renal replacement therapy, leading to very high mortality rates. Donor nephrectomy (DN) is an important aspect of kidney transplantation. Over the last two decades, open DN (ODN) has given way to minimally invasive techniques like laparoscopic DN (LDN) and robotic-assisted DN. In this study, we aimed to describe our experience with mini-flank incision donor nephrectomy (MIDN) at a Nigerian renal transplant center. Materials and methods We conducted a retrospective review of all DN cases performed at a single Nigerian kidney transplantation center over a three-year period. Information obtained from these patients was classified into pre-, intra-, and postoperative. The data included sociodemographic characteristics, preoperative preparation, details of intraoperative techniques, and postoperative findings. These were entered into a proforma and analyzed using SPSS Statistics version 21 (IBM Corp., Armonk, NY). Results A total of 230 patients underwent ODN during the study period. The majority of the donors were males (92.8%) with a mean age of 30.83 ±8.43 years. The body mass index (BMI) of most (76.1%) of the donors was within the normal range (18.5-24.9 kg/m). The duration of DNs ranged from 72 to 154 minutes with a mean duration of 130 ±28 minutes. The length of flank incisions ranged from 7.8 to 12 cm with a mean incision length of 10.8 ±1.0 cm. Donors who had MIDN attained satisfactory postoperative pain control with about 90% of them having a BMI of <30 kg/m. Oral intake and ambulation were commenced on the first postoperative day, and the cosmetic outcomes were deemed acceptable in over 90% of kidney donors. Conclusion Mini-incision for DN through the flank approach is a suitable alternative to LDN in the developing world where facilities and skills for LDN or robotic nephrectomies are largely unavailable. It offers a short recovery time, early ambulation, and excellent allograft outcomes.

Optimal analgesia following knee surgery is essential for early mobilization and rehabilitation and minimizing morbidity.

Whether pancreatic extracorporeal shock wave lithotripsy (ESWL) is safe for patients with autosomal dominant polycystic kidney disease (ADPKD) is unclear. A woman in her early 30s was admitted to our hospital because of intermittent upper abdominal pain and recurrent pancreatitis. The imaging results confirmed the diagnosis of pancreatic stones and ADPKD. We performed pancreatic ESWL using a third-generation lithotripter to pulverize the pancreatic stones. A maximum of 5000 shock waves was delivered per therapeutic session. A second session of ESWL was performed the next day. The patient developed no adverse events or complications related to pancreatic ESWL. Three years after treatment, the patient had developed no relapse of pancreatitis or abdominal pain. Shock waves do not lead to complications such as hematuria, cyst rupture, or deterioration of the inner bleeding of renal cysts. Multiple kidney cysts are not a contraindication for pancreatic ESWL.

To assess the outcomes of patients after rib nonunion reconstruction.

Few studies have compared conventional and self-assisted shoulder reduction maneuvers. The goal of this study was to evaluate the results of self-assisted Davos vs. traction/countertraction (T/Ct) techniques in the treatment of acute anterior shoulder dislocations.

Circulating neutrophil-derived microvesicles (NMVs) are markedly elevated during sepsis and therefore could have a role in the development of indirect acute lung injury (ALI). We recently found that NMV-enriched CD11b MVs, immunoaffinity isolated from lipopolysaccharide (LPS)-stimulated healthy volunteer blood, have potent pro-inflammatory activity in a human peripheral blood mononuclear cell (PBMC) and lung microvascular endothelial cell (HLMEC) coculture model of pulmonary vascular inflammation (1). By contrast, immunoaffinity isolated platelet-MVs (CD61 ) produced negligible responses in these assays, suggesting specificity of the NMV-enriched CD11b MV, activity. Here, we investigated the signaling mechanisms responsible for NMV-mediated activation of monocytes and HLMECs in this model.

Kappa opioid receptor (KOR) agonists produce a variety of beneficial effects such as nonaddictive analgesia and diuresis, but their translation into the clinic has been hindered by central adverse effects (dysphoria). In clinical studies, difelikefalin, a KOR agonist recently FDA approved for treatment of pruritus in hemodialysis patients, was shown to be devoid of producing adverse CNS effects suggesting that this compound is peripherally restricted. This is of interest from a renal excretory perspective, since it would be predicted that difelikefalin would not produce diuresis, which is a classical centrally mediated response produced by KOR agonists. However, in preliminary studies in rats we have shown that IV administration of difelikefalin markedly increased urine output and decreased urinary sodium and potassium excretion similar to that produced by other KOR agonists. Therefore, we hypothesized that difelikefalin activates a central KOR pathway to cause diuresis. To test this hypothesis, Sprague-Dawley rats were implanted with bladder, femoral artery, and femoral vein catheters and administered an isotonic saline infusion. To delineate the central and/or peripheral site of action of difelikefalin, renal excretory function was measured in rats pretreated centrally or peripherally with norBNI (KOR antagonist) or vehicle via an intracerebroventricular (ICV) cannula or IV catheter. Following stabilization, conscious rats were administered an IV bolus of difelikefalin (10 µg/kg) and urine output, mean arterial pressure (MAP), and heart rate (HR) were recorded for 90 minutes. The results demonstrated that ICV norBNI pretreatment significantly decreased the diuretic response to IV difelikefalin but had no effect on urinary sodium or potassium concentration (Table 1). In contrast, IV norBNI pretreatment prevented the diuresis to IV difelikefalin and increased urinary sodium/potassium concentration (Table 1). Notably, ICV and IV norBNI pretreatment abolished the difelikefalin-induced decrease in MAP that was also seen in the vehicle pretreated groups. Together, these findings suggest that difelikefalin produces its diuretic and blood pressure effects through a central KOR pathway, while the sodium/potassium retaining effects of difelikefalin are mediated through peripheral KORs.

Mitragyna speciosa (kratom) is a coffee-like plant containing several biologically active alkaloids, with mitragynine (MG) being the most prevalent. MG has a mixed pharmacological profile, containing both opioid and stimulant-like effects. Chemotherapy-induced peripheral neuropathy (CIPN) is a progressive and dose-limiting chronic pain condition characterized by sensory disturbances such as spontaneous pain, hyperalgesia, and allodynia. Mechanistically, brain-derived neurotrophic factor (BDNF) plays a critical role in CIPN pathophysiology, as its expression contributes to dorsal horn hyperexcitability. Currently, antidepressants (TCA's, SNRI's) are first-line neuropathic pain medications, achieving their therapeutic effect through enhanced adrenergic neurotransmission. Yet, clinical outcomes of CIPN remain poor, proving an unmet need for better pharmacological interventions. Therefore, we wished to test the therapeutic efficacy of MG in a rodent model of CIPN, and to investigate the involvement of adrenergic and BDNF signaling. Given the role of antidepressants in treating CIPN, we also wished to explore antidepressant properties of MG in response to oxaliplatin exposure. Overall, it was hypothesized that MG would reduce oxaliplatin-induced mechanical sensitivity through a mechanism involving α-adrenoceptor activation and BDNF signaling and would produce antidepressant-like effects in mice with CIPN. Baseline mechanical sensitivity was assayed in male adult C57/BL6 mice with von Frey monofilaments, followed by a single injection of the chemotherapeutic oxaliplatin (6 mg/kg, IP). Mice then received MG (1-20 mg/kg, IP) alone or in combination with the α -adrenoceptor antagonist yohimbine (5 mg/kg, IP), or vehicle for 6 days. Mechanical sensitivity was again measured on day 7 post-oxaliplatin treatment. Brains and lumbar dorsal spinal cord were collected immediately following day 7 behavioral assessment and mRNA expression of BDNF, ADRA2A, and ADRA2C was quantified by RT-qPCR. In a separate cohort, mice which received oxaliplatin or MG alone or in combination were subjected to the tail suspension test (TST) to characterize the potential effects of oxaliplatin and MG on depressive-like behaviors. Results indicated that repeated MG exposure produced a significant anti-allodynic effect at doses of 5 and 10 mg/kg compared to controls. Additionally, yohimbine pretreatment completely blocked the anti-allodynic effect produced by MG. Oxaliplatin alone significantly increased mRNA expression of BDNF in the periaqueductal gray (PAG), which was normalized by MG. In the TST, oxaliplatin alone did not affect immobility, nor did MG alone or in combination with oxaliplatin have any effect on immobility times. Overall, these findings suggest oxaliplatin produces neuropathic pain without developing depression-like behaviors. Furthermore, MG achieves its therapeutic efficacy through α -adrenoceptor activation, as well as regulation of supraspinal BDNF expression, without producing any antidepressant-like effects.

A wide variety of plants produce compounds that contain the 4-hydroxy-3-methoxybenzyl or "vanillyl" group. These vanilloid compounds include such well-known food molecules as vanillin, capsaicin, gingerol, and curcumin. Vanilloid compounds have been widely studied for their medicinal properties, and one property that most of them have in common is the ability to induce analgesia. Studies have indicated multiple potential cellular mechanisms for this analgesic activity, including TRPV1 receptors, opioid receptors, and adenosine receptors (ARs). There are only a few studies on the interaction of vanilloid compounds with ARs, and to our knowledge no previous study has measured the binding affinity of any vanilloid compound with either of the two AR subtypes that are linked to the inhibitory G subunit (subtypes A and A ). Our study objective was to assess the binding affinity and receptor activation of a novel curcumin isomer, cis-transcurcumin (CTCUR), at AR subtypes A and A . Since agonism of these subtypes is associated with analgesia, we hypothesized that CTCUR would be an agonist at AR subtypes A and A . Two lines of Chinese hamster ovary cells were used, each transfected to overexpress one of the AR subtypes. Cell survival assays were performed to assess toxicity. Competitive binding assays and confocal microscopy were performed to measure binding affinity. Computer docking was also performed, to assess location of binding. Assays of intracellular cAMP levels were performed to measure receptor activation. Survival results indicate that CTCUR is not toxic to CHO cells at any of the concentrations tested (the highest being 100 μM). Competition assay results indicate that CTCUR binds to subtype A with a K of 306 nM and to subtype A with a K of 400 nM. Microscopy results confirm sub-micromolar affinity for A , but not for A . Docking results confirm sub-micromolar affinity for both subtypes, and furthermore indicate that CTCUR binds to the "toggle switch" domain of α helix 6 that is important for receptor activation. Intracellular cAMP results indicate that CTCUR acts as an agonist of ARs. Thus, we fail to reject our hypothesis. These results are of interest because they provide the first in vitro confirmation of the hypothesis that vanilloid compounds can activate ARs, in accordance with the results of previous studies in vivo. Vanilloid compounds that activate ARs are therefore worthy of further study, as a potential class of analgesic therapeutics.