Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload.

Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in normal diet (ND) and high fat diet (HFD) mice with cardiac pressure overload. Five-week-old male C57BL/6J mice were randomized to receive a HFD (60% of calories from fat) or remain on ND for 12 weeks. One week later, transverse aortic constriction (TAC) was employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in left ventricular hypertrophic remodeling and cardiac fibrosis, albeit preserved ejection fraction. At 4 weeks post-TAC, mice were treated for 7 weeks by oral gavage once daily with sotagliflozin (10 mg/kg body weight) or vehicle (0.1% tween 80). In ND mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilization, increased circulating ketones, nor increased cardiac ketolysis. In HFD mice, sotagliflozin reduced the mildly elevated glucose and insulin levels but did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound sotagliflozin-induced diuresis and glucosuria, which suggests dampened drug action. We demonstrate the utility of dual SGLT1/2 inhibition in treating cardiac injury induced by pressure overload in normoglycemic mice. Its efficacy in high fat-fed mice with mild hyperglycemia and compromised renal morphology requires further study.

Characterisation of a Novel A-Superfamily Conotoxin.

Conopeptides belonging to the A-superfamily from the venomous molluscs, Conus, are typically α-conotoxins. The α-conotoxins are of interest as therapeutic leads and pharmacological tools due to their selectivity and potency at nicotinic acetylcholine receptor (nAChR) subtypes. Structurally, the α-conotoxins have a consensus fold containing two conserved disulfide bonds that define the two-loop framework and brace a helical region. Here we report on a novel α-conotoxin Pl168, identified from the transcriptome of Conus planorbis, which has an unusual 4/8 loop framework. Unexpectedly, NMR determination of its three-dimensional structure reveals a new structural type of A-superfamily conotoxins with a different disulfide-stabilized fold, despite containing the conserved cysteine framework and disulfide connectivity of classical α-conotoxins. The peptide did not demonstrate activity on a range of nAChRs, or Ca2+ and Na+ channels suggesting that it might represent a new pharmacological class of conotoxins.

Inflammatory and Neuropathic Gene Expression Signatures of Chemotherapy-Induced Neuropathy Induced by Vincristine, Cisplatin, and Oxaliplatin in C57BL/6J Mice.

Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of many tumors. However, a main side effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to changes in chemotherapeutic treatment. Although symptoms associated with CIPN are recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia following vincristine, oxaliplatin, and cisplatin treatment with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq revealed 368, 295, and 256 differential expressed genes induced by treatment with vincristine, oxaliplatin, and cisplatin, respectively, and only 5 shared genes were dysregulated in all 3 groups. Cell type enrichment analysis and gene set enrichment analysis showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed gene expression signature. PERSPECTIVE: These results provide insight into the recruitment of immune responses to dorsal root ganglia and indicate enhanced neuroinflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.

Late Spontaneous Migration of a Dorsal Column Stimulator Paddle Lead.

The most frequently encountered complication of dorsal column stimulators is lead migration. The vast majority of these events are seen in the first few weeks to months. Late paddle lead migration is a very uncommon occurrence in this setting. We describe a case of a 51-year-old male with a history of reflex sympathetic dystrophy having undergone dorsal column stimulator insertion at the level of C1-C2. A good clinical benefit was appreciated in the postoperative period once the stimulator was turned on. Approximately six months postoperatively, the patient suddenly lost coverage. Radiographic imaging revealed that the lead had migrated caudally to the C3-C4 level. Subsequent revision surgery took place. This description highlights a common complication, but occurring outside the expected time frame after surgery.

Treatment of Penetrating Nonmissile Traumatic Brain Injury. Case Series and Review of the Literature.

INTRODUCTION: Penetrating traumatic brain injuries (TBIs), with the exception of gunshot wounds, are relatively rare occurrences and affect all ages. Clinical presentation varies depending on the mechanism of the injury. Prompt surgical treatment is often indicated and is influenced by patient clinical examination, anatomic trajectory, and the penetrating object's size, shape, and velocity. METHODS: We present 3 cases of penetrating TBI. Their similarities and differences affecting operative and medical management are compared. We relate our experience with management of penetrating intracranial foreign bodies in general and discuss the relevant literature. RESULTS: Our first case was a 12-year-old male who presented with a self-inflicted transfacial transcranial injury by a crossbow. The arrow passed through the left sphenoid and cavernous sinus and exited through the parietal calvarium. Our second case was a 37-year-old man with a transoral intracranial stab wound by a knife. In our third case, we present a 46-year-old male who accidentally fired a nail gun into his right ear. The nail traversed the posterior wall of the external auditory canal into the posterior fossa, ending in the cerebellar vermis. Each case was treated with craniotomy and foreign body removal. All resulted in good outcomes after surgical treatment. CONCLUSION: Surgery in penetrating TBI is the treatment of choice. Our cases demonstrate how certain principles applied to individual patient scenarios may optimize clinical results. Severity of the injury and operative approach are among the most important considerations to achieve the best patient outcomes.

Subdural evacuating port system (SEPS)--minimally invasive approach to the management of chronic/subacute subdural hematomas.

OBJECTIVE: The population suffering from chronic/subacute subdural hematomas (SDHs) generally includes elderly patients with co-morbidities; therefore the success of less invasive surgical techniques has been of long standing interest. The optimum treatment option for chronic/subacute SDH has not been well established. We report our retrospective outcomes of SDH drainage through a subdural evacuating port system (SEPS). PATIENTS AND METHODS: Fifty-two consecutive adult patients with chronic/subacute SDH treated with SEPS (total 64 procedures), over a period of 3 years (June 2006-June 2009), were included. 9/52 patients had SEPS performed for bilateral SDHs. Three patients had SEPS placed for recurrent SDH. This retrospective study was approved by the Institutional Review Board of SUNY Upstate Medical University and Crouse Hospital. RESULTS: Overall 38/52 patients (73%) showed clinical improvement, 10/52 patients (19%) did not show any clinical improvement and 4/52 (8%) patients became clinically worse after the SEPS placement during initial hospitalization. 41/52 patients, treated initially with SEPS were followed as outpatients. 32/41 patients improved, returning to baseline neurological status, 5/41 patients improved, but still had some residual symptoms. The remaining 4/41 patients, presented with recurrent symptoms and had recurrent SDH on CT scans. During the in-hospital post-SEPS period, 8 SDH had >75% decrease, 17 SDH had between 50 and 75% decrease, 23 SDH had between 25 and 50% decrease and 14 procedures had <25% decrease in maximal width of the SDH on postoperative scans. Outpatient follow up CT scans after SEPS placement were available for 46/64 procedures. At final outpatient follow up, 33/46 SDHs showed >75% decrease in maximal thickness, 4/46 SDH showed between 50 and 75% and 2/46 SDH showed between 25 and 50% decreases in maximal width of chronic SDH. However, in 7/46 patients, SDH re-accumulated (i.e. increased in thickness) as outpatients, after initial response to treatment on post-operative in-hospital CT scans. CONCLUSION: SEPS is an effective, relatively safe and convenient treatment strategy with low invasiveness; among management options of chronic/subacute SDH.

Intractable nausea in a patient with synchronous pancreatic cancer and a fourth-ventricular ependymoma.

Symptoms of nausea and vomiting can present a diagnostic challenge for physicians. In this article, we report a patient who was found to have synchronous presentation of an ependymoma and pancreatic cancer. This case illustrates some of the diagnostic challenges in patients with constitutional symptoms. Furthermore, it illustrates the importance of surgical intervention as both a diagnostic as well as a therapeutic measure when managing patients with presumed metastatic disease to the brain.

Night/day changes in pineal expression of >600 genes: central role of adrenergic/cAMP signaling.

The pineal gland plays an essential role in vertebrate chronobiology by converting time into a hormonal signal, melatonin, which is always elevated at night. Here we have analyzed the rodent pineal transcriptome using Affymetrix GeneChip(R) technology to obtain a more complete description of pineal cell biology. The effort revealed that 604 genes (1,268 probe sets) with Entrez Gene identifiers are differentially expressed greater than 2-fold between midnight and mid-day (false discovery rate <0.20). Expression is greater at night in approximately 70%. These findings were supported by the results of radiochemical in situ hybridization histology and quantitative real time-PCR studies. We also found that the regulatory mechanism controlling the night/day changes in the expression of most genes involves norepinephrine-cyclic AMP signaling. Comparison of the pineal gene expression profile with that in other tissues identified 334 genes (496 probe sets) that are expressed greater than 8-fold higher in the pineal gland relative to other tissues. Of these genes, 17% are expressed at similar levels in the retina, consistent with a common evolutionary origin of these tissues. Functional categorization of the highly expressed and/or night/day differentially expressed genes identified clusters that are markers of specialized functions, including the immune/inflammation response, melatonin synthesis, photodetection, thyroid hormone signaling, and diverse aspects of cellular signaling and cell biology. These studies produce a paradigm shift in our understanding of the 24-h dynamics of the pineal gland from one focused on melatonin synthesis to one including many cellular processes.

A novel pineal-specific product of the oligopeptide transporter PepT1 gene: circadian expression mediated by cAMP activation of an intronic promoter.

The oligopeptide transporter 1, PepT1, is a member of the Slc15 family of 12 membrane-spanning domain transporters; PepT1 has proton/peptide cotransport activity and is selectively expressed in intestinal epithelial cells, where it is responsible for the nutritional absorption of di- and tri-peptides. Here, a novel PepT1 gene product has been identified in the rat pineal gland, termed pgPepT1. It encodes a 150-amino acid protein encompassing the C-terminal 3 membrane-spanning domains of intestinal PepT1 protein, with 3 additional N-terminal residues. Expression of pgPepT1 appears to be restricted to the pineal gland and follows a marked circadian pattern with >100-fold higher levels of mRNA occurring at night; this is accompanied by an accumulation of membrane-associated pgPepT1 protein ( approximately 16 kDa). The daily rhythm in pgPepT1 mRNA is regulated by the well described neural pathway that controls pineal melatonin production. This includes the retina, the circadian clock in the suprachiasmatic nucleus, central structures, and projections from the superior cervical ganglia; activation of this pathway results in the release of norepinephrine. Here it was found that pgPepT1 expression is mediated by a norepinephrine-->cyclic AMP mechanism that activates an alternative promoter located in intron 20 of the gene. pgPepT1 protein was found to have transporter-modulator activity; it could contribute to circadian changes in pineal function through this mechanism.

NGFI-B (Nurr77/Nr4a1) orphan nuclear receptor in rat pinealocytes: circadian expression involves an adrenergic-cyclic AMP mechanism.

NGFI-B (Nur77/Nr4a1) is a member of a nuclear steroid receptor subgroup that includes the related factors Nurr1 (Nr4a2) and NOR-1 (Nr4a3). These proteins do not have recognized ligands and in fact function independently as orphan receptors with transcriptional regulatory activity. In the present study, expression of the NGFI-B gene in the rat pineal gland was found to exhibit a robust circadian rhythm, with elevated levels of NGFI-B mRNA occurring at night. The rhythm of NGFI-B mRNA is translated into a circadian rhythm of NGFI-B protein, which accumulates in the nucleus of pinealocytes. In addition, there is a parallel marked nocturnal increase in pineal DNA binding activity to a NGFI-B response element (NBRE, AAAGGTCA). Pharmacological studies indicate that NGFI-B mRNA and protein levels are elevated via activation of adrenergic receptors. NGFI-B protein levels are also elevated by dibutyryl cyclic AMP, as in other systems. In the pineal gland, regulation of NGFI-B expression also involves the AP-1 protein Fra-2, based on studies with a transgenic Fra-2 knockdown rat, in which pineal NGFI-B expression increases. This set of observations extends the number of pineal genes that are known to be regulated by Fra-2, and also provides the first indication that a member of the NGFI-B group of nuclear receptors is involved in controlling gene expression in the pineal gland.

Primary central nervous system cytotoxic/suppressor T-cell lymphoma: report of a unique case and review of the literature.

Peripheral T-cell lymphoma primary to the central nervous system is a rare occurrence. The authors report a case of an 89-year-old woman who presented with a 3-month history of worsening confusion and recent onset of headache, nausea and vomiting, and upper limb tremors. Computed tomography and magnetic resonance imaging examinations demonstrated a 4.5-cm solitary brain mass in the right basal ganglia with compression along the ventricular system. No other lesion was found in the patient. Histologic and immunohistochemical studies of a stereotactic biopsy of the mass showed a T-cell lymphoproliferative lesion positive for CD3, CD8, CD57, and T-cell intracellular antigen 1 and negative for CD4, CD56, CD30, anaplastic lymphoma kinase, and CD20. A monoclonal T-cell receptor-gamma gene rearrangement was detected by polymerase chain reaction analysis of genomic DNA isolated from paraffin-embedded tumor tissue sections. These findings were consistent with peripheral T-cell lymphoma of cytotoxic/suppressor phenotype, resembling the phenotype of T-cell large granular cell leukemia. To the authors' best knowledge, this represents the first reported case of primary brain T-cell lymphoma with a cytotoxic/suppressor immunophenotype. A brief review of the literature of primary brain T-cell lymphoma is also presented.