Sotagliflozin: a dual sodium-glucose co-transporter-1 and -2 inhibitor for the management of Type 1 and Type 2 diabetes mellitus.

AIMS: To evaluate the evidence for the novel dual sodium-glucose co-transporter-1 (SGLT1) and -2 (SGLT2) inhibitor, sotagliflozin, which may enhance the efficacy of SGLT2 inhibitors by additionally reducing intestinal glucose absorption. METHODS: The search terms 'sotagliflozin', 'LX4211', 'SGLT' and 'diabetes' were entered into PubMed. Evidence for the pharmacokinetics, pharmacodynamics, safety and efficacy of sotagliflozin in Type 1 and 2 diabetes was extracted from the retrieved literature, critically evaluated, and contextualized in relation to data on existing SGLT2 inhibitors. RESULTS: There is convincing evidence from a range of phase II and III clinical trials that sotagliflozin significantly improves glycaemic control in both Type 1 and Type 2 diabetes. Additional benefits, such as smaller postprandial plasma glucose excursions, lower insulin requirements, appetite suppression and weight loss have been documented. While this is encouraging, several safety concerns remain; a dose-dependent increase in the rate of diabetic ketoacidosis, diarrhoea and genital mycotic infection is apparent, although statistical exploration of the data regarding such events is currently lacking. Speculatively, use of a 200-mg rather than a 400-mg dose may help to limit unwanted effects. CONCLUSIONS: The current evidence for sotagliflozin in diabetes appears promising. Further studies sufficiently powered to assess present and emerging safety concerns, as well as to identify individuals for whom sotagliflozin may be of particular benefit/harm would now be informative for regulatory decision-making. Direct comparisons with existing SGLT2 inhibitors are also needed to determine relative safety/efficacy profiles for the different indications.

Fabrication of hierarchical micro-nanotopographies for cell attachment studies.

We report on the development of micro/nanofabrication processes to create hierarchical surface topographies that expand from 50 nm to microns in size on different materials. Three different approaches (named FIB1, FIB2, and EBL) that combine a variety of techniques such as photolithography, reactive ion etching, focused ion beam lithography, electron beam lithography, and soft lithography were developed, each one providing different advantages and disadvantages. The EBL approach was employed to fabricate substrates comprising channels with features between 200 nm and 10 µm in size on polymethylmethacrylate (PMMA), which were then used to investigate the independent or competitive effects of micro- and nanotopographies on cell adhesion and morphology. Rat mesenchymal stem cells (rMSCs) were cultured on four different substrates including 10 µm wide and 500 nm deep channels separated by 10 µm distances (MICRO), 200 nm wide and 100 nm deep nanochannels separated by 200 nm distances (NANO), their combination in parallel (PARAL), and in a perpendicular direction (PERP). Rat MSCs behaved differently on all tested substrates with a high degree of alignment (as measured by both number of aligned cells and average angle) on both NANO and MICRO. Furthermore, cells exhibited the highest level of alignment on PARAL, suggesting a synergetic effect of the two scales of topographies. On the other hand, cells on PERP exhibited the lowest alignment and a consistent change in morphology over time that seemed to be the result of interactions with both micro- and nanochannels positioned in the perpendicular direction, also suggesting a competitive effect of the topographies.

The study to investigate the potential benefits of probiotics in yogurt, a patient-oriented, double-blind, cluster-randomised, placebo-controlled, clinical trial.

BACKGROUND: Probiotic functional foods are widely advertised to consumers primarily based on probiotic supplements. OBJECTIVE: Determine if consumption of yogurt containing a high dose of probiotics improves health in children ages 1-3 years attending daycare/school centers. SUBJECTS/METHODS: Double-blinded, randomized, placebo-controlled, allocation concealment clinical trial. SETTING: Outpatient participants in the Washington, DC area. PARTICIPANTS: 182 healthy children between the age of 1 and 3 years attending daycare/school at least 3 days a week. INTERVENTION: Active was a strawberry yogurt-based drink supplemented with Bifidobacterium animalis ssp. lactis (B. lactis) BB-12. The placebo was indistinguishable from the active drink, differing only in absence of the probiotic BB-12. Primary objective was to determine if consumption of a probiotic-containing yogurt-based drink decreases absences due to illnesses from daycare for children ages 1-3 years. Secondary was to determine if probiotic-containing yogurt-based drink improves overall parental satisfaction due to decreased absences from work and an overall healthier child. RESULTS: There were no significant differences in the days of missed school per group, with 51.9% in the active group and 47.1% in the placebo group missing at least 1 day of school throughout the study. Additionally, there were no differences in any secondary outcomes among the groups. CONCLUSIONS: Consumption of a yogurt-based drink delivering 10(10) CFU of Bifidobacterium animalis ssp. lactis (B. lactis) BB-12 per day did not decrease the number of days missed of school due to an illness. Additional independent research on the potential of BB-12 to reduce illness in children needs to be conducted.

Predicting acute ischemic stroke by measuring the degree of ocular gaze deviation (Prevost's sign) on CT.

BACKGROUND AND AIM: Ocular gaze deviation (OGD) is a well known clinical observation (Prevost's sign) in patients with acute cerebral ischemic stroke. Although OGD has been observed on CT in acute stroke, no investigation has quantified the degree of OGD in acute stroke. MATERIAL AND METHODS: A blinded prospective comparison was performed of two groups of adult patients who underwent CT of the brain. Group 1 comprised patients with acute hemiplegia or hemiparesis due to middle cerebral artery ischemic stroke. Group 2 included ambulatory outpatients with a history of headache but no clinical neurologic signs or cerebral pathology on CT. The CT images were cropped to only show the orbital contents. A neuroradiologist, who was blinded to the clinical data, then measured the OGD for both groups. The OGD was quantified using the axial planes of the lenses relative to the nasal midline structures, and the bilateral OGD average was calculated. Both groups were also evaluated for conjugate or disconjugate gaze. RESULTS: were analyzed using Fisher's exact test. RESULTS: 10 of 70 patients in group 1 and 15 of 46 patients in group 2 were eligible for analysis. The frequency of conjugate and disconjugate gaze was similar in the two groups (p = 0.596). An averaged OGD of >14° and an OGD >18° in either globe was predictive of the presence of acute stroke (p = 0.0166). CONCLUSION: Measurement of OGD is useful in predicting the presence of acute ischemic stroke.

Bronchiolitis obliterans syndrome and survival following lung transplantation for patients with sarcoidosis.

BACKGROUND: End-stage sarcoidosis is characterized by severe pulmonary fibrosis and is often poorly responsive to medical therapy. Lung transplantation, therefore, may be the only treatment option. Currently, there are few studies evaluating long-term outcomes following transplantation for these patients. Our aim was to evaluate post-transplant morbidity and survival of patients with sarcoid compared to recipients transplanted for idiopathic pulmonary fibrosis (IPF). METHODS: We retrospectively examined 300 lung transplant recipients using a dedicated database. Over a 10-year period, 15 (5.0%) patients with sarcoidosis and 48 (16%) patients with IPF were identified. Primary outcome measures included rate and time to onset of bronchiolitis obliterans syndrome (BOS) and survival. RESULTS: Recipients in the sarcoid group were younger and predominantly female compared to recipients in the IPF group. Five of 15 (33%) sarcoid patients developed BOS versus 15 of 48 (31%) IPF patients (p=1.0). There was no significant difference in the time to BOS onset. Median survival was 1,365 days for the sarcoid group and 1,593 days for the IPF group (Hazard Ratio 0.94 by Kaplan-Meier analysis; [95% CI] 0.33-2.67; p = 0.90). CONCLUSIONS: We observe similar long term outcomes following lung transplantation for sarcoid and IPF recipients. Transplantation remains a treatment option for end-stage sarcoidosis, as BOS and survival rates are comparable to IPF.

Growth of human stem cell-derived neurons on solid three-dimensional polymers.

Understanding neural differentiation and the development of complex neurite networks in three-dimensional matrices is critical for neural tissue engineering in vitro. In this study we describe for the first time the growth of human stem cell-derived neurons on solid polystyrene matrices coated with bioactive molecules. Highly porous foams were prepared from poly(styrene/divinylbenzene) using a high internal phase emulsion (HIPE) as a template to create the porous structure. The resulting polyHIPE matrices were readily coated with aqueous-based solutions including poly-d-lysine and laminin. Human neurons adhered well to poly-d-lysine coated surfaces and extended neural processes, however, neurite outgrowth was particularly enhanced when polymers also received a coating of laminin. These data clearly demonstrate the potential use of solid polystyrene scaffolds to create three-dimensional environments for cell growth and differentiation. We propose that these robust and stable matrices can be conveniently and routinely used in the tissue culture laboratory to study the behaviour of cells grown in three-dimensions.

Enhanced neurite outgrowth by human neurons grown on solid three-dimensional scaffolds.

Growing and differentiating human stem cells in vitro can provide access to study the molecular mechanisms that control cellular development in a manner pertinent to human embryogenesis. To fully understand such processes, however, it is important to recreate culture conditions that most closely relate to those in living tissues. As step in this direction, we have developed a robust three-dimensional cell culture system using inert highly porous solid matrices manufactured from polystyrene that can be routinely used to study the differentiation of human pluripotent stem cell-derived neurons in vitro. Neurite outgrowth was significantly enhanced when neurons were grown in a three-dimensional environment compared to traditional flat surfaces and resulted in the formation of extensive neural networks. These data suggest that the topography within the culture environment can significantly alter cell development and will therefore be an important feature when investigating the potential of human stem cells.

Anterior ischemic optic neuropathy associated with viagra.

A 42-year-old male presented with acute onset of an inferior visual field defect OD after sildenafil citrate use. Examination revealed a right relative afferent pupillary defect and a swollen disc with a 0.1 cup-to-disc ratio and a prominent disc hemorrhage. Anterior ischemic optic neuropathy (AION) is associated with acute episodes of hypotension in patients with structurally crowded discs. Sildenafil citrate may cause episodes of hypotension and was temporally related to the onset of symptoms in this patient. Because patients are often reluctant to volunteer their history of sildenafil citrate use, the physician may need to ask specifically about use of this medication. Physicians should counsel patients with crowded optic discs and a history of nonarteritic anterior ischemic optic neuropathy in one eye that use of sildenafil citrate might increase their risk of ischemic optic neuropathy in the fellow eye.

Health InfoNet of Jefferson County: collaboration in consumer health information service.

Health InfoNet of Jefferson County is a new collaborative consumer health information service of the Jefferson County public libraries and the UAB Lister Hill Library of the Health Sciences. Working with the input and cooperation of local voluntary health agencies, health care professionals and other health information providers, the intent is to improve the efficiency with which consumers might access such information while avoiding duplication of effort on the part of the information providers. Various considerations in InfoNet's mission include providing service not only to established library and Internet users, but also those on the other side of the "digital divide" as well as those with low literacy skills or English as a second language. The role of health care professionals in guiding their patients to the best consumer health information resources is emphasized.

A case-control study of tobacco and alcohol consumption in Leber hereditary optic neuropathy.

PURPOSE: To determine if tobacco or alcohol consumption is associated with vision loss among sibships harboring pathogenic mitochondrial mutations associated with Leber hereditary optic neuropathy. METHODS: Retrospective case-control study with questionnaires obtained from both affected and unaffected siblings from 80 sibships with Leber hereditary optic neuropathy. Sibships harbored molecularly confirmed mitochondrial DNA mutations at nucleotide positions 11778 (63), 14484 (10), and 3460 (7). Exposure in affected individuals was calculated based on reported consumption before vision loss. RESULTS: For male probands (67 sibships), the recurrence risk within a sibship was 10.3% (eight of 78) for males and 3.1% (three of 98) for females. For female probands (13 sibships), the recurrence risk within a sibship was 17.6% (three of 17) for males and 0% (zero of 22) for females. Greater risk of vision loss was associated with male sex (odds ratio [OR] = 6.63; 95% confidence interval [CI] = 2.96 to 14.84; P =.00001) and harboring a 3460 or 14484 in comparison with the 11778 mutation (OR = 2.071; 95% CI = 1.19 to 3.58; P =.0095). No significant association of maximal intensity of smoking or cumulative smoking, whether light or heavy, with vision loss was observed. Light (OR = 0. 31; 95% CI = 0.17 to 0.56; P =.0001) and heavy alcohol consumers (OR = 0.25; 95% CI = 0.11 to 0.58; P =.0011) were less likely to be affected than individuals who did not consume alcohol after adjusting for age, sex, and mutation. In a categorical analysis of sibships with the 3460 or 14484 mutation, no relationship of vision loss with tobacco or alcohol consumption was observed. CONCLUSION: Unlike previous studies, the present study calculated exposure based on self-reported consumption of tobacco or alcohol before vision loss. No significant deleterious association between tobacco or alcohol consumption and vision loss among individuals harboring Leber hereditary optic neuropathy mutations was observed. Tobacco and alcohol do not appear to promote vision loss in Leber hereditary optic neuropathy.

Continuous infusion of relaxin on periparturient progesterone, oxytocin and relaxin plasma concentrations and time of parturition in beef heifers.

These studies were designed to determine whether continuous i.v. infusion of increasing dosages of porcine relaxin during late pregnancy in beef heifers would influence circulating blood concentrations of relaxin, progesterone and oxytocin, and time of onset of parturition. Beef heifers were bred by artificial insemination and, on Day 277, fitted with indwelling jugular cannulas for hormone infusion and blood sampling from Day 277 to Day 286. Intravenous infusion of purified porcine relaxin (pRLX, 3000 U mg-1) was started in heifers (n = 8) at increasing dosages (200 U h-1 on Days 277 and 278, 300 U h-1 on Days 279 and 280, 500 U h-1 on Day 281, 600 U h-1 on Day 282, and 700 U h-1 on Days 283-286). Phosphate-buffered saline (PBS, 10 ml h-1) was infused during these same times to control animals (n = 6). Relaxin treatment steadily increased the circulating plasma concentration of immunoreactive relaxin to more than 120 ng ml-1 compared with less than 0.5 ng ml-1 in PBS-treated controls. Relaxin infusion in increasing dosages over the treatment time was associated with a significant decrease (P < 0.01) in plasma progesterone concentration compared with the PBS controls. The rate of change in progesterone levels between pRLX and PBS groups differed (P < 0.05) at 300 U h-1, 600 U h-1 and 700 Uh-1 dosage intervals, respectively. Plasma levels of oxytocin at 4 h intervals remained similar (P > 0.05) during the pretreatment period and throughout continuous infusion of pRLX and PBS. Mean concentrations of oxytocin in PBS control heifers peaked at 0.95 pgml-1 during the corresponding infusion of 700 Uh-1 pRLX, which peaked at 0.77 pgml-1. Although continuous i.v. infusion of relaxin resulted in a decrease in circulating blood levels of progesterone, it did not significantly reduce the interval between the beginning of pRLX treatment and parturition compared with the PBS-infused control heifers. These results indicate that continuous i.v. infusion of high levels of porcine relaxin resulted in a decrease in progesterone secretion in late pregnant beef heifers.

Intrathecal synthesis of anti-sulfatide IgG is associated with peripheral nerve disease in acquired immunodeficiency syndrome.

Peripheral nervous system involvement in the acquired immunodeficiency syndrome (AIDS) can take the form of an acute or chronic inflammatory demyelinating polyneuropathy, polyradiculopathy, mononeuropathy multiplex, or autonomic neuropathy. There is no widely held consensus on the etiology of PNS or other neurological complications associated with HIV infection. We report here that PNS disease in HIV-infected individuals is associated with intrathecal synthesis of an antibody directed against sulfatide, a major component of myelin. The anti-sulfatide antibody is also present nonspecifically in serum. The antibody requires the presence of the 3-O-sulfogalactosyl residue for binding and recognizes preferentially the hydroxy fatty acid-containing form of sulfatide. Anti-sulfatide antibodies are therefore one of the humoral factors responsible for demyelinating diseases in AIDS patients.

Heteroplasmy in Leber's hereditary optic neuropathy.

OBJECTIVES: To determine the incidence and clinical significance of peripheral blood heteroplasmy and the presence of normal and mutant mitochondrial DNA in Leber's hereditary optic neuropathy through evaluation of a large series of families with the 11778 mutation and to evaluate the pattern of transmission of heteroplasmy. DESIGN: We studied heteroplasmy in 75 visually symptomatic patients with the 11778 mutation and in 101 asymptomatic family members. We compared the incidence of heteroplasmy in these two groups, collected clinical information for each symptomatic patient, and calculated the incidence of heteroplasmy within each generation of the pedigrees. RESULTS: We detected heteroplasmy in 24 (14%) of the 176 persons tested. Kaplan-Meier life-table analysis suggests that heteroplasmic persons are more likely to remain asymptomatic than those who are homoplasmic mutant (males, P = .17; females, P = .14). However, heteroplasmic persons who become symptomatic do not seem to differ clinically from symptomatic patients who are homoplasmic mutant. Pedigree analysis reveals a strong tendency for progression from heteroplasmy toward homoplasmy in subsequent generations (P = .001). CONCLUSION: Heteroplasmy for the 11778 mutation seems to play a role in the clinical expression of Leber's hereditary optic neuropathy and tends to progress toward homoplasmy in successive generations.

Identical twins who are discordant for Leber's hereditary optic neuropathy.

OBJECTIVE: Leber's hereditary optic neuropathy is a maternally inherited form of visual loss that is associated with several mitochondrial DNA mutations. These mitochondrial DNA mutations are not the sole determinants of visual loss, as epigenetic factors may play a pathogenetic role. To clarify the role of these factors, we studied two visually discordant twins and determined their zygosity and mitochondrial genotype. DESIGN: Case series. SETTING: Referral center. PATIENTS: Identical twin brothers from a family with the 11778 mitochondrial DNA mutation. MAIN OUTCOME MEASURES: Visual acuity, results of testing for visual fields (measured with static and dynamic perimetry) and color vision, and results of funduscopic examination; alcohol and tobacco use, head trauma, co-existent medical illness, and occupational exposure; and results of mitochondrial DNA analysis and determination of zygosity. RESULTS: The monozygous twin brothers have remained discordant for the development of optic neuropathy for 6 1/2 years despite harboring the identical homoplasmic 4216, 13708, and 11778 mitochondrial DNA mutations. CONCLUSIONS: The patients are visually discordant despite being genetically identical at the nuclear and mitochondrial levels. Epigenetic factors are important determinants of visual loss in Leber's hereditary optic neuropathy in these brothers. Among those factors studied in these patients, a substantial difference was noted in regard to occupational exposure to toxic substances. Epigenetic factors that may influence the clinical expression of the mitochondrial DNA mutations associated with Leber's hereditary optic neuropathy should be systematically studied. Risk-factor intervention strategies should be formulated and implemented.

Leber's hereditary optic neuropathy. Clinical manifestations of the 15257 mutation.

BACKGROUND: Leber's hereditary optic neuropathy is associated with four known pathogenetic mutations of mitochondrial DNA (mtDNA) at nucleotide positions (np) 11778, 3460, 15257, and 14484. METHODS: The authors collected clinical data from 12 visually symptomatic patients from seven different pedigrees with the 15257 mutation and compared these data with previously published clinical features of the 11778 and 3460 mutations. RESULTS: The authors' results indicate that these three groups of patients are similar in most clinical characteristics evaluated. However, patients with the 15257 mutation are more likely to experience significant recovery of visual acuity than patients with the 11778 mutation (25% versus 4% of eyes; P < 0.001). Patients with the 15257 mutation who also have an associated mutation at np 15812 are less likely to recover vision than those without this association (P = 0.001). Patients with the 15257 mutation also have a higher incidence of spinal cord and peripheral neurologic symptoms (42%) than patients with the other pathogenetic mutations. CONCLUSIONS: The phenotypic expression of the 15257 mutation differs from the 11778 and 3460 mutations and is affected by the presence of an associated mutation at np 15812. This is the first clinical evidence to support the concept of multiple simultaneous mtDNA mutations producing additive deleterious effects in patients with Leber's hereditary optic neuropathy. The clinical differences between the various genotypes associated with Leber's hereditary optic neuropathy have implications for risk factor management and visual prognosis and, thus, underscore the importance of molecular genetic testing in patients with suspected Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy. Clinical manifestations of the 14484 mutation.

OBJECTIVE: To define the clinical features of Leber's hereditary optic neuropathy associated with the 14484 mitochondrial DNA mutation and to compare these features with those associated with three other pathogenetic mutations. DESIGN AND PATIENTS: Clinical and historical data were collected from 19 visually symptomatic patients from 17 independent pedigrees with the molecularly confirmed 14484 mutation. MAIN OUTCOME MEASURES: Demographic features, age of onset of visual loss, nadir of visual acuity, occurrence and timing of visual recovery, family history of visual loss, and associated medical and environmental conditions. RESULTS: Clinical characteristics associated with the 14484 mutation are similar overall to those of the three other primary mutations. One notable distinguishing feature is the higher incidence of visual recovery among patients with the 14484 mutation. Thirty-seven percent of our patients experienced visual recovery compared with 5% with the 11778 mutation (P < .001), 22% with the 3460 mutation, and 29% with the 15257 mutation. The average age of onset of visual symptoms for the patients with the 14484 mutation who had visual recovery was younger than for those without recovery (19.6 vs 30.6 years). Thirteen of the 19 patients had a history of metabolic disturbance, trauma, or substance abuse. CONCLUSIONS: Leber's hereditary optic neuropathy associated with the 14484 mitochondrial DNA mutation may have a better prognosis for visual recovery. The phenotypic expression of the 14484 mutation may be influenced by concurrent medical and environmental factors. Molecular genetic testing in suspected Leber's hereditary optic neuropathy is useful to confirm the diagnosis and to assess visual prognosis.

Leber's hereditary optic neuropathy. Clinical manifestations of the 3460 mutation.

Leber's hereditary optic neuropathy is associated with three different point mutations of mitochondrial DNA that appear to be pathogenetic for the disease. These mutations affect nucleotide positions 3460, 11,778, and 15,257. We reviewed the clinical characteristics of 12 visually symptomatic patients from nine families with the 3460 mutation and compared them with previously published characteristics of symptomatic patients with the 11,778 mutation. The patients with the 3460 mutation were similar to the patients with the 11,778 mutation in most clinical parameters. However, the patients with the 3460 mutation had a higher incidence of visual recovery (20% vs 4%, P = .001), a higher percentage of pedigrees with more than one affected family member (78% vs 43%, P = .011), and a greater frequency of tobacco and alcohol abuse. The difference in visual prognosis between these two mutations and the need for modification of possible risk factors provide added significance to genetic testing for Leber's hereditary optic neuropathy.

Combined third and sixth nerve paresis following optic nerve sheath fenestration.

The authors report a case of transient third and sixth nerve paresis as a complication of optic nerve sheath fenestration in a patient with pseudotumor cerebri. The motility and pupillary abnormalities that are commonly associated with this procedure are reviewed briefly.

Monocular congenital cataracts: psychological effects of treatment.

Visual success in the treatment of monocular congenital cataracts requires early surgery, and aggressive, long-term amblyopia management and optical correction. These children will have their only normally seeing eye patched for a significant percentage of their early childhood years. We have been concerned about the possibility of an adverse psychological impact of this form of treatment. This study utilized two standardized testing instruments to evaluate the incidence of developmental delay and behavioral problems in children treated for monocular congenital cataracts. A total of 22 children were evaluated with one or both of these instruments and compared to a control group of 18 normal siblings. There was no statistically significant evidence of developmental delay or increased behavioral problems in the treatment group.