Rotational stability and clinical outcomes after implantation of a new monofocal toric intraocular lens with double C-loop design.

PURPOSE: To investigate rotational stability and visual outcomes of patients unilaterally or bilaterally implanted with a new monofocal toric intraocular lens (IOL). SETTING: Ophthalmology service, clinique Beausoleil, avenue de Lodève, Montpellier. DESIGN: Single-center retrospective study. METHODS: This study included patients who underwent routine cataract surgery with the PODEYE toric (BVI/PhysIOL SA, Liège, Belgium) IOL using the ZEISS CALLISTO eye®. Biometry and keratometry data, refractive outcomes, rotational stability, and astigmatism correction were recorded. IOL rotation was evaluated using an image analysis technique. Postoperative assessments were performed at 1 week, 1 month, and 4 to 6 months after surgery. RESULTS: Clinical outcomes of 102 patients (136 eyes) were analyzed. Patients had a mean age of 74 years. Of the included eyes, 25% had an axial length greater than 24.5mm. Median postoperative IOL rotation from baseline (surgery) was 2̊. With the exception of one outlier (15̊ rotation), IOL rotation was ≤ 6̊ (1 month) and ≤ 10̊ (4-6 months) in 100% of the eyes. No surgical IOL re-positioning was required. Median postoperative corrected distance visual acuity was -0.08 logMAR, and median postoperative subjective cylinder was between 0.25 and 0.50 D. CONCLUSION: The PODEYE toric IOL showed high rotational stability, allowing for correction of corneal astigmatism during cataract surgery.

Gonadotropin stimulation in mice leads to ovarian accumulation of immature myeloid cells and altered expression of proangiogenic genes.

OBJECTIVE: Ovarian hyperstimulation syndrome is associated with increased angiogenesis and vascular leakage. Immature myeloid cells (IMCs) and dendritic cells have been shown to be actively involved in angiogenesis in several disease models in mice and humans. Nevertheless, little is known about the role of these cells in the ovary. As such, this study sought to determine whether alterations in these ovarian myeloid cell populations are associated with gonadotropin stimulation in a mouse model. STUDY DESIGN: Four-week-old pre-pubertal C57Bl/6 female mice were allocated into three groups: high-dose stimulation (n=4; pregnant mare serum gonadotropins (PMSG) 20U for 2 days), low-dose stimulation (n=5; PMSG 5U for 1 day) and sham-treated controls (n=4). Human chorionic gonadotropin 5U was injected on Day 3, and the mice were killed on Day 5. Ovaries were analysed by flow cytometry, confocal microscopy and quantitative polymerase chain reaction. RESULTS: Gonadotropin stimulation increased the proportion of CD11b(+)Gr1(+) IMCs among the ovarian myeloid cells: 22.6±8.1% (high dose), 7.2±1.6% (low dose) and 4.1±0.3% (control) (p=0.02). Conversely, gonadotropin stimulation decreased the proportion of ovarian CD11c(+)MHCII(+) dendritic cells: 15.1±1.9% (high dose), 20.7±4.8% (low dose) and 27.3±8.2% (control) (p=0.02). IMCs, unlike dendritic cells, were localized adjacent to PECAM1(+) endothelial cells. Finally, gonadotropin stimulation was associated with increased expression of S100A8, S100A9, Vcan and Dmbt1, and decreased expression of MMP12. CONCLUSIONS: Gonadotropin stimulation is associated with proangiogenic myeloid cell alterations, reflected by a dose-dependent increase in ovarian IMCs and a parallel decrease in dendritic cells. Recruited IMCs localize strategically at sites of angiogenesis. These changes are associated with differential expression of key proangiogenic genes.

Unique expression patterns associated with preferential recruitment of immature myeloid cells into angiogenic versus dormant tumors.

Cancer progression from microscopic dormant tumors into disseminated disease involves tumor angiogenesis, and is commonly referred to as the 'angiogenic switch'. CD11b(+)Gr1(+) immature myeloid cells (IMCs) were reported to promote angiogenesis and tumor progression. Here, we studied a model of tumor dormancy, in which Lewis Lung Carcinoma tumor cells were inoculated intra-abdominally into C57Bl/6J mice. Dormancy versus expansive growth was determined by the site of tumor implantation (lower vs upper abdomen). Global gene expression of IMCs was evaluated in different stages of recruitment, starting in the bone marrow, followed by the peripheral blood and finally in the vascular versus dormant tumors. We first demonstrated a ∼3 fold enrichment of IMCs within vascular tumors as compared with dormant tumors, correlating with tumor-infiltrating CD31(+) endothelial cells. Although their migration from the PB into dormant tumors led to differential expression of a relatively small number of genes, recruitment of IMCs into the upper tumors was associated with a profound transcriptional response. Importantly, a large set of proangiogenic genes were significantly upregulated in IMCs derived from vascular tumors compared with those derived from dormant tumors. We therefore, suggest that proangiogenic versus nonangiogenic transcriptional patterns is associated with the ability of IMCs to promote tumor angiogenesis.

Distribution of effervescent inhalable nanoparticles after pulmonary delivery: an in vivo study.

BACKGROUND: Effervescent inhalable nanoparticles (NPs) have previously been shown to be a promising alternative to conventional lung cancer treatment in animals. This study investigates the biodistribution of effervescent inhalable NPs after a single dose administration via pulmonary route in lung cancer-bearing mice. METHODS & RESULTS: Whole-body autoradiography and confocal laser-scanning microscopy (CLSM) were used to investigate the distribution of inhalable NPs loaded in an effervescent microcarrier. Inhalable doxorubicin-loaded NPs were tagged with 14C for whole-body autoradiography, or with fluorescein isothiocyanate for CLSM imaging. After pulmonary delivery, NPs were widely disseminated in the lungs with a long retention time (24 h). The heart was radioactivity free at all time points of the study. CLSM images showed that inhalable NPs were taken up by cells and that doxorubicin was released to the cell nuclei. CONCLUSION: This is the first study to investigate the distribution of inhalable NPs in a lung cancer-bearing animal model. Inhalable NPs achieved deep lung deposition, were actively released from microcarrier particles, spread to different parts of the lung and released doxorubicin in vivo. These NP characteristics contribute to the efficacy of effervescent inhalable NPs as a lung cancer treatment.

First trimester diagnosis of forked cord in monoamniotic twin pregnancy.

A 29-year-old healthy woman at 10 weeks gestation was suspected for monoamniotic twin pregnancy, thus referred for evaluation and treatment. Ultrasound examination confirmed intrauterine monoamniotic twin gestation with central insertion of both umbilical cords by brief conjoined part (9 mm) - comprising a forked umbilical cord. Early diagnosis, planned prenatal care and close surveillance allowed preventing perinatal mortality.

Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model.

Doxorubicin-loaded nanoparticles (NPs) were incorporated into inhalable effervescent and non-effervescent carrier particles using a spray-freeze drying technique. The prepared inhalable powders were tested in a tumor bearing Balb/c mouse model. Control mice were treated with blank inhalable NPs, inhalable lactose powder containing free doxorubicin, and intravenous injections of a suspension of doxorubicin NPs, doxorubicin solution, or saline solution. The survival of treatment groups was plotted with Kaplan-Meier curves. Animals treated with inhalable effervescent nanoparticle powder containing 30µg doxorubicin showed a highly significant improvement in survival compared to all other treatment groups. Mice in control groups treated with doxorubicin solution or doxorubicin NPs as intravenous injection, died in less than 50 days. Inhalable free doxorubicin showed high cardiac toxicity. Pathological samples showed large tumor masses in the lungs of animals not treated or treated with i.v. injections of doxorubicin NPs or doxorubicin solution. The lungs of animals treated with inhalable effervescent doxorubicin NPs showed fewer and much smaller tumors compared to the control groups, as visualized by MRI imaging which confirmed the observed pathology results. The present study demonstrates that inhalable effervescent doxorubicin NPs are an effective way to treat lung cancer. This non-invasive route of administration might change the way lung cancer is treated in the future.

Pulmonary delivery of inhalable nanoparticles: dry powder inhalers.

Pulmonary administration of inhalable nanoparticles (NPs) is an emerging area of interest. Dry powder inhalers may offer particular advantages for pulmonary administration of NPs. This article reviews research performed on the formulation of inhalable NPs as dry powder to achieve deep-lung deposition and enhance NP redispersibility. Moreover, the article summarizes up-to-date in vivo applications of inhalable NPs as dry powder inhalers.

Microcalorimetric method to assess phagocytosis: macrophage-nanoparticle interactions.

This study evaluated the use of isothermal microcalorimetry (ITMC) to detect macrophage-nanoparticle interactions. Four different nanoparticle (NP) formulations were prepared: uncoated poly(isobutyl cyanoacrylate) (PIBCA), polysorbate-80-coated PIBCA, gelatin, and mannosylated gelatin NPs. Changes in NP formulations were aimed to either enhance or decrease macrophage-NP interactions via phagocytosis. Alveolar macrophages were cultured on glass slabs and inserted in the ITMC instrument. Thermal activities of the macrophages alone and after titration of 100 µL of NP suspensions were compared. The relative interactive coefficients of macrophage-NP interactions were calculated using the heat exchange observed after NP titration. Control experiments were performed using cytochalasin B (Cyto B), a known phagocytosis inhibitor. The results of NP titration showed that the total thermal activity produced by macrophages changed according to the NP formulation. Mannosylated gelatin NPs were associated with the highest heat exchange, 75.4 ± 7.5 J, and thus the highest relative interactive coefficient, 9,269 ± 630 M-1. Polysorbate-80-coated NPs were associated with the lowest heat exchange, 15.2 ± 3.4 J, and the lowest interactive coefficient, 890 ± 120 M-1. Cyto B inhibited macrophage response to NPs, indicating a connection between the thermal activity recorded and NP phagocytosis. These results are in agreement with flow cytometry results. ITMC is a valuable tool to monitor the biological responses to nano-sized dosage forms such as NPs. Since the thermal activity of macrophage-NP interactions differed according to the type of NPs used, ITMC may provide a method to better understand phagocytosis and further the development of colloidal dosage forms.

Primary Submucosal Squamous Cell Carcinoma of the Rectum Diagnosed by Endoscopic Ultrasound: Case Report and Literature Review.

Primary colorectal squamous cell carcinoma (SCC) is one of the very rare malignancies of the gastrointestinal tract. The diagnosis cannot be made before ruling out other common primary sites. Using the endoscopic ultrasound (EUS) technique to get a tissue biopsy for submucosal tumors has not been demonstrated as the best diagnostic approach in the literature. Surgery is the gold standard treatment with arising evidence of good efficacy following conventional chemoradiation therapy. A 49-year-old male presented with rectal discomfort. Sigmoidoscopy revealed multiple submucosal masses in the rectosigmoid colon. Mucosal biopsies showed nonspecific inflammation. Subsequently, an EUS with fine needle biopsy was done and established the diagnosis of rectal SCC. There were no other primary sites noticed in the extensive evaluation. The patient chose to be treated only with chemoradiation without surgery. At the time of writing this report he had no evidence of recurrence achieving 2.5 years of survival. EUS is an emerging excellent approach to diagnose submucosal colorectal SCC. This case will add supportive evidence of having a complete response following combining treatment with squamous cell directed chemotherapy and external beam radiotherapy without preceded surgery.

Isothermal microcalorimetry as a quality by design tool to determine optimal blending sequences.

This study was designed to assess the value of isothermal microcalorimetry (ITMC) as a quality by design (QbD) tool to optimize blending conditions during tablet preparation. Powder mixtures that contain microcrystalline cellulose (MCC), dibasic calcium phosphate dihydrate (DCPD), and prednisone were prepared as 1:1:1 ratios using different blending sequences. ITMC was used to monitor the thermal activity of the powder mixtures before and after each blending process. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) were performed on all final powder mixtures. Final powder mixtures were used to prepare tablets with 10 mg prednisone content, and dissolution tests were performed on all tablet formulations. Using ITMC, it was observed that the powder mixtures had different thermal activity depending on the blending sequences of the ingredients. All mixtures prepared by mixing prednisone with DCPD in the first stage were associated with relatively fast and significant heat exchange. In contrast, mixing prednisone with MCC in the first step resulted in slower heat exchange. Powder mixture with high thermal activity showed extra DSC peaks, and their dissolution was generally slower compared to the other tablets. Blending is considered as a critical parameter in tablet preparation. This study showed that ITMC is a simple and efficient tool to monitor solid-state reactions between excipients and prednisone depending on blending sequences. ITMC has the potential to be used in QbD approaches to optimize blending parameters for prednisone tablets.

Thermal treating of acrylic matrices as a tool for controlling drug release.

The purpose of the present study was to investigate the effect of thermal-treating on the release of ibuprofen from the granules prepared using aqueous dispersions of Eudragit. To accomplish this goal, different formulations were prepared using wet granulation method containing two different types of Eudragit aqueous dispersions, RS30D, RL30D and Avicel as filler. Tablets were prepared using direct compression method. The prepared tablets were thermally treated at 50 and 70 degrees C for 24 h. The drug release from tablets was assessed before and after thermal-treating. The results of release study showed that, thermally-treating the tablets at the temperatures higher than glass transition temperature (Tg) of the polymer can decrease the drug release from matrices. For mechanistic evaluation of the effect of thermal-treating, powder X-ray diffraction (XPD), scanning electron microscopy (SEM), differential scanning calorimeter (DSC), Fourier transform infrared (FT-IR) and helium pycnometer have been employed. The SEM graphs showed that the tablets have smoother surface with less porosity after thermal-treating. FT-IR spectra showed no change in the spectrum of thermally-treated tablet compared to control. In DSC graphs, no crystalline change was seen in the heat-treated samples of ibuprofen tablets, but decreased and widened peak size were related to the probable formation of solid solution of ibuprofen in Eudragit matrix. The results of helium pycnometer showed a significant decrease in the total porosity of some heat-treated samples. This study revealed the importance of thermal treating on the drug release from sustained release tablets containing Eudragit polymer.

Extramammary Perianal Paget's Disease.

Perianal Paget's disease is a rare malignancy. It is rarely isolated and often associated with an underlying adenocarcinoma. It usually presents with anal itchiness and discomfort and can be misdiagnosed as hemorrhoids. Once the diagnosis of perianal Paget's disease is granted, extensive work-up to find an underlying primary malignancy is crucial. Surgery is the standard modality of treatment of extramammary Paget's disease (EMPD) with recurrence rates of 44-60%. Other different treatment modalities including radiotherapy, laser therapy, topical and systemic chemotherapy and the new emerging, promising photodynamic therapy are in the field of study. A 76-year-old man was referred to our hospital with a one-year history of anal itchiness and intermittent rectal bleeding. Skin shave and punch biopsies from the perianal area were reported back as perianal Paget's disease with no underlying adenocarcinoma. The immunohistochemical stains were positive for cytokeratin 7 but also positive for cytokeratin 20 and CEA which indicated the essentiality of extensive investigations to find a primary malignancy. Skin exam showed no primary source. The investigations were unable to find the primary malignancy. Given the results of immunohistochemical stains we recommended local perianal Paget's disease resection. The intraoperative frozen section showed adenocarcinoma around the anal sphincter. Ten days later the patient underwent an abdominoperineal resection and the final pathology report showed extensive adenocarcinoma in three quadrants of the perianal area with focal involvement of the rectal mucosa. We recommended an adjuvant chemotherapy with FOLFOX following surgery given the bulkiness of the disease. We conclude that once perianal Paget's disease is diagnosed, an extensive work-up should be done to find the underlying primary malignancy. Immunohistochemical stains are helpful in raising the suspicion of underlying primary malignancy. Finding an underlying primary malignancy in patients with EMPD is prompt to choose the treatment modality and estimate the prognosis.

Cervical and Vulvar Intraepithelial Neoplasia after Treatment with Oral Isotretinoin for Severe Acne Vulgaris.

Oral isotretinoin is the drug of choice for severe acne vulgaris, but its use is still controversial in preventing, treating or stopping the progression of the cervical intraepithelial neoplasia [6, 7, 8]. It induces cell differentiation, inhibits cell proliferation, stimulates host immune reaction, inhibits the oncogene expression, augments cell-mediated cytotoxicity, and induces apoptosis [5]. The isotretinoin has many side effects including teratogenicity. There is no previous report of developing cervical intraepithelial neoplasia (CIN) or vulvar intraepithelial neoplasia (VIN) after introducing oral isotretinoin to a patient. We are reporting a 37-year-old female with no risk factors for cervical cancer who had developed CIN-I and VIN-I during a 6-month treatment period of oral isotretinoin for her severe acne vulgaris. Interestingly, the patient had complete spontaneous pathologic-proven remission after stopping the isotretinoin. Further case reports are warranted to support this incidence.

Suspected macrosomia? Better not tell.

OBJECTIVE: To evaluate the management policy of delivery in a suspected macrosomic fetus and to describe the outcome of this policy. STUDY DESIGN: For this prospective observational study we followed the management by reviewing the medical records of 145 women and their infants. The study population included women at term admitted to the obstetrics department with suspected macrosomic infants, as was diagnosed by an obstetrician and/or by fetal sonographic weight estimation of > or =4,000 g. The comparison group (n = 5,943) consisted of all women who gave birth during the data collection period. RESULTS: Induction of labor and cesarean delivery rates in the macrosomic pregnancies (actual birth weight >4,000 g) of the study group were significantly higher when compared with the macrosomic pregnancies of the comparison group. When comparing the non-macrosomic to the macrosomic pregnancies (actual birth weight 4,000 g) of the study group no significant difference was demonstrated regarding maternal or infant complications. The sensitivity, specificity and positive predictive value of the methods used for detecting macrosomia were 21.6, 98.6 and 43.5%, respectively. CONCLUSION: Our ability to predict macrosomia is poor. Our management policy of suspected macrosomic pregnancies raises induction of labor and cesarean delivery rates without improving maternal or fetal outcome.

Myelin basic protein functions as a microtubule stabilizing protein in differentiated oligodendrocytes.

Myelin basic protein (MBP) is an oligodendrocyte-specific protein essential for oligodendrocyte morphogenesis at late stages of cell differentiation. There is evidence that the morphogenetic function of MBP is mediated by MBP interaction with the cytoskeleton. Thus, an MBP/cytoplasmic microtubule association has been reported, and MBP has Ca(2+)/calmodulin-regulated microtubule cold-stabilizing activity in vitro. However, the unambiguous demonstration of a microtubule-stabilizing activity for MBP in cells has been difficult because oligodendrocytes contain variants of STOP (stable tubule only polypeptide) proteins, which are responsible for microtubule cold stability in different cell types. Herein, we have used genetic mouse models and RNA interference to assay independently the microtubule cold-stabilizing activities of MBP and of STOP in developing oligodendrocytes. In wild-type oligodendrocytes, microtubules were cold stable throughout maturation, which is consistent with the presence of STOP proteins from early stages of differentiation. In contrast, in oligodendrocytes from STOP-deficient mice, microtubules were cold labile in the absence of MBP expression or when MBP expression was restricted to the cell body and became stable in fully differentiated oligodendrocytes, where MBP is expressed in cell extensions. The suppression of MBP by RNA interference in STOP-deficient oligodendrocytes suppressed microtubule cold stability. Additionally, STOP suppression in oligodendrocytes derived from shiverer mice that lack MBP led to the complete suppression of microtubule cold stability at all stages of cell differentiation. These results demonstrate that both STOP and MBP function as microtubule-stabilizing proteins in differentiating oligodendrocytes and could be important for the morphogenetic function of MBP.

Remodeling of hippocampal GABAergic system in adult offspring after maternal hypoxia and magnesium sulfate load: immunohistochemical study.

A strong relationship between hypoxia and fetal brain damage has been described. Specific susceptibility of the GABAergic neurons to these conditions may be crucial to the damage induced. We have previously shown, in a mouse model, that maternal pretreatment with magnesium sulfate (Mg) partially prevented the behavioral consequences of maternal hypoxia in the adult offspring. Here, we tested the effect of maternal hypoxia and maternal Mg load on the GABAergic system of 8-month-old offspring. The immunoreactivity (IR) of several proteins expressed in GABAergic neurons and inhibitory synapses was analyzed in the following regions of the adult offspring brain: hippocampus, cortical M1, caudate putamen, and lateral globus pallidus. Maternal hypoxia reduced the density of parvalbumin (PV)-IR neurons in the hippocampus. The density of PV-IR and calbindin (CB)-IR neurons was also reduced in the deep and superficial layers of the M1. Maternal pretreatment with Mg had a prophylactic action in the superficial, but not the deep, layers of M1. Also, in offspring from the maternal hypoxia group, the vesicular GABA transporter (VGAT)-IR was enhanced in the hippocampal CA1 and hilus regions. No effect of maternal hypoxia on VGAT-IR was observed in the M1. However, maternal pretreatment with Mg enhanced VGAT-IR and glutamate decarboxylase-IR in the deep layers of the M1. In the globus pallidus, maternal hypoxia enhanced CB-IR, which was prevented by maternal pretreatment with Mg. In conclusion, maternal hypoxia induced a loss of PV-IR and CB-IR neurons; maternal pretreatment with Mg partially protected these neuron populations. An increase in proteins of inhibitory synapses, observed under hypoxic conditions in several brain regions, may be a result of some compensatory mechanism.

Specific neurodevelopmental damage in mice offspring following maternal inflammation during pregnancy.

Intrauterine inflammation is a major risk for offspring neurodevelopmental brain damage and may result in cognitive limitations and poor cognitive and perceptual outcomes. Pro-inflammatory cytokines, stimulated during inflammatory response, have a pleotrophic effect on neurons and glia cells. They act in a dose-dependent manner, activate cell-death pathways and also act as trophic factors. In the present study, we have examined in mice the effect of short, systemic maternal inflammation on fetal brain development. Maternal inflammation, induced by lipopolysaccharide (LPS) at gestation day 17, did not affect morphogenic parameters and reflex development during the first month of life. However, maternal inflammation specifically increased the number of pyramidal and granular cells in the hippocampus, as well as the shrinkage of pyramidal cells, but not of the granular cells. No additional major morphological differences were observed in the cerebral cortex or cerebellum. In accordance with the morphological effects, maternal inflammation specifically impaired distinct forms of learning and memory, but not motor function or exploration in the adult offspring. The specific deficiency observed, following maternal inflammation, may suggest particular sensitivity of the hippocampus and other associated brain regions to inflammatory factors during late embryonic development.

Maternal hypoxia during pregnancy induces fetal neurodevelopmental brain damage: partial protection by magnesium sulfate.

Fetal low brain oxygenation may be an outcome of maternal complications during pregnancy and is associated with increased risk of cerebral palsy and periventricular leukomalacia in newborns. One treatment used for prevention of fetal brain damage is maternal treatment with MgSO(4). Although this treatment is indicated to reduce the risk of cerebral palsy in newborns, its use remains controversial. We have shown previously that pretreatment with MgSO(4) in a mouse model of maternal hypoxia prevented a delay in the development of motor reflexes induced by hypoxia. We demonstrate here that pretreatment with MgSO(4) reduces hypoxia-induced motor disabilities in adult offspring. This effect is associated with histologic protection of the Purkinje cells in the cerebellum and stabilization of brain-derived neurotrophic factor (BDNF) levels in the cerebellum. MgSO(4) did not prevent the reduction in cerebral cortex cell density and cell size induced by maternal hypoxia, however, nor did it interfere with the modulation of BDNF and nerve growth factor (NGF) expression in the cerebral cortex. MgSO(4) pretreatment also prevented the impairment of short-term memory (30 min, P < 0.05) but not long-term memory (7 days). Nevertheless, maternal pretreatment with MgSO(4) reduced CA1 cell layer width and induced alterations in both NGF and BDNF in the hippocampus. These results support the prophylactic effect of MgSO(4) against motor disabilities; however, they may also indicate possible harmful effects on the cerebral cortex and hippocampus.