Prenatal aripiprazole induces alterations of rat placenta: a histological, immunohistochemical and ultrastructural study.

Antipsychotic drugs (APDs) are used to treat many psychiatric illnesses as schizophrenia. Typical antipsychotic drugs (TAPDs) are being used; however, they have many side effects. Atypical antipsychotic drugs (AAPDs) are newer medications with known fewer side effects. Aripiprazole (ARI) is an AAPD, recommended by healthcare providers, even during pregnancy. It can cross the placental barrier and enter fetal circulation, so it might be possible that ARI can adversely impair normal placental development and growth, if it is given prenatally. ARI was applied orally to pregnant female rats in two doses (3& 6 mg/kg body weight). On gestation day 20, the mothers were sacrificed, and the placentas were removed and processed for general histological and electron microscopic evaluations. Immunohistochemistry was done using anti-PCNA (proliferating cell nuclear antigen), anti-Bax (for apoptosis) and anti-vascular endothelial growth factor alpha (VEGFA). Morphological evaluation revealed degenerative changes in the placenta as dark nuclei, vacuolization, and cyst formation. Ultra-structurally, there was degeneration of cellular components including organelles and nuclei. These changes were found in different cells of the basal and labyrinth zones and were dose dependent. Immunohistochemistry revealed upregulation of Bax and VEGFA and downregulation of PCNA. Prenatal administration of the AAPD, ARI to pregnant female rats resulted in histological changes in the placenta. Additionally, there was a decrease in cellular proliferation and increase in apoptosis, and vascular impairment. This indicates placental atrophy and dysgenesis and might suggest possible teratogenic effects to ARI, which needs further evaluation.

Data-Driven Surveillance Protocol for Patients at Risk for Peritoneal Recurrence of Primary Colon Cancer: Surveillance for Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is rarely discovered early due to low sensitivity of screening imaging and tumor markers, however, earlier identification may improve outcomes. This study assesses risk factors and time to recurrence of PC and implementation of a surveillance system. Patients with stage II-III colon adenocarcinoma undergoing curative colectomy between 2005-2022 were retrospectively reviewed at a single tertiary care institution. Patients were divided into three cohorts: no recurrence (NR), PC, and other types of recurrence (OTR). Baseline characteristics between cohorts were compared with univariate analysis. Overall survival and PC risk were assessed using multivariate analysis with Cox's proportional-hazard modelling. 412 patients were included; 78.4% had NR, 7.8% had PC, and 13.8% had OTR. Patient demographics, comorbidities, tumor side, and histologic features were similar between cohorts. Patients with PC were more likely to have microscopic tumor perforation (25% vs. 8.8% vs. 6.8%, p = 0.002), margin involvement (25% vs. 8.8% vs. 4.6%, p < 0.001), lymphovascular invasion (56.2% vs. 33.3%, vs. 24.5%, p < 0.001), perineural invasion (28.1% vs. 15.8% vs. 11.5%, p = 0.026) compared to OTR or NR. Median time to PC after colectomy was 11 months. Tumor characteristics of stage II-III colon cancer define a high-risk profile for PC. An early surveillance program sensitive for peritoneal disease should be adopted for these patients.

In Vitro and Biological Evaluation of Oral Fast-Disintegrating Films Containing Ranitidine HCl and Syloid® 244FP-Based Ternary Solid Dispersion of Flurbiprofen.

Flurbiprofen (FBP), a nonsteroidal anti-inflammatory drug (NSAID), is commonly used to treat the pain of rheumatoid arthritis, but in prolonged use it causes gastric irritation and ulcer. To avoid these adverse events of NSAIDs, the simultaneous administration of H2 receptor antagonists such as ranitidine hydrochloride (RHCl) is obligatory. Here, we developed composite oral fast-disintegrating films (ODFs) containing FBP along with RHCl to provide a gastroprotective effect as well as to enhance the solubility and bioavailability of FBP. The ternary solid dispersion (TSD) of FBP was fabricated with Syloid® 244FP and poloxamer® 188 using the solvent evaporation technique. The synthesized FBP-TSD (coded as TSD) was loaded alone (S1) and in combination with plain RHCl (S2) in the composite ODFs based on hydroxypropyl methyl cellulose E5 (HPMC E5). The synthesized composite ODFs were evaluated by in vitro (thickness, folding endurance, tensile strength, disintegration, SEM, FTIR, XRD and release study) and in vivo (analgesic, anti-inflammatory activity, pro-inflammatory cytokines and gastroprotective assay) studies. The in vitro characterization revealed that TSD preserved its integrity and was effectively loaded in S1 and S2 with optimal compatibility. The films were durable and flexible with a disintegration time ≈15 s. The release profile at pH 6.8 showed that the solid dispersion of FBP improved the drug solubility and release when compared with pure FBP. After in vitro studies, it was observed that the analgesic and anti-inflammatory activity of S2 was higher than that of pure FBP and other synthesized formulations (TSD and S1). Similarly, the level of cytokines (TNF-α and IL-6) was also markedly reduced by S2. Furthermore, a gastroprotective assay confirmed that S2 has a higher safety profile in comparison to pure FBP and other synthesized formulations (TSD and S1). Thus, composite ODF (S2) can effectively enhance the FBP solubility and its therapeutic efficacy, along with its gastroprotective effect.

In Vitro and In Vivo Evaluation of Composite Oral Fast Disintegrating Film: An Innovative Strategy for the Codelivery of Ranitidine HCl and Flurbiprofen.

Here, we evaluate the feasibility of co-loading plain ranitidine hydrochloride (RHCl) and microencapsulated flurbiprofen (FBP) in a Lycoat® RS780-based oral fast disintegrating film (ODF). These films were developed by the solvent casting method to minimize the adverse effects of FBP and reduce the dosage form burden on patients. Optimized FBP microparticles (M3) with an average size of 21.2 ± 9.2 µm were loaded alone (F1) and in combination with plain RHCl (F2) in the composite ODF. All films were evaluated physicomechanically and physicochemically. These films were resilient, flexible, and disintegrated within thirty seconds. SEM images showed intact FBP microparticles in both formulations and, moreover, did not observe an interaction between the drug and film components. Microencapsulated FBP was released in a controlled manner over 48 h from the proposed formulations, while RHCl was released within 5 min from F2. After in vitro evaluation, formulations were also tested for in vivo anti-inflammatory activity, cytokine (TNF-α and IL-6) levels, and gastroprotective effects in rats. The anti-inflammatory activity and gastroprotective effect of F2 were markedly higher than pure FBP and other synthesized formulations (M3 and F1). The average score of gastric lesions was in the order of pure FBP (15.5 ± 1.32) > M3 (8 ± 2) > F1 (1 ± 0.5) > F2 (0.5 ± 0) > control (0). Additionally, F2 showed a sustained anti-inflammatory effect up to 10 h in the rat paw edema model. Furthermore, F2 also markedly reduced TNF-α and IL-6 levels. Conclusively, the Lycoat® RS780-based composite film could be a promising carrier for the co-loading of microencapsulated FBP with RHCl. In the future, an optimized formulation (F2) could be capable of countering the issues related to multiple drug administration in geriatric patients and evading the gastric irritation associated with FBP.

Pomegranate (Punica granatum) peel alleviates lithium-induced alterations in the thyroid gland of rats by modulating apoptosis and oxidative stress.

Lithium carbonate (LC) is known to alter thyroid gland function. Pomegranate (PG) is a fruit with multiple antioxidant and antiapoptotic properties. Here, we studied the effect of PG on LC-induced morphological and functional alterations in the thyroid glands of rats. Rats were divided into four groups: control, lithium, lithium-PG, and PG. After 8 weeks, the rats were sacrificed, the levels of thyroid hormones and oxidative stress markers were estimated, and thyroid tissues were subjected to histological, immunohistochemical, and ultrastructural evaluations. Compared to the control group, the lithium group showed significant changes in thyroid hormone levels, greater expression of the oxidant marker malondialdehyde, and lower expression of the antioxidant marker superoxide dismutase (SOD). Most of these changes improved upon PG treatment. Histological evaluation of the thyroid in the lithium group showed disorganization and follicle involution. Additionally, the periodic acid Schiff staining intensity and SOD immunoreactivity declined significantly, whereas the collagen fiber content and Bax immunoreactivity increased. The follicular ultrastructure showed marked distortion. These changes were mitigated upon PG treatment. In conclusion, PG alleviated the morphological and functional changes in the thyroid glands induced by LC by modulating apoptosis and oxidative stress.

Caffeine protects against hippocampal alterations in type 2 diabetic rats via modulation of gliosis, inflammation and apoptosis.

Type 2 diabetes (T2D) is implicated in the injury of several organs, including the brain resulting in neuronal damage, which may lead to cognitive impairment and dementia. Additionally, it is linked to inflammation, cytokine release, apoptosis and various degenerative conditions. Astrocytes and microglia might have a role in mediating these processes. Caffeine, a psychoactive beverage, has been shown to reduce the risk of cognitive and memory impairment. This study proposes anti-inflammatory and anti-apoptotic role of caffeine, which can be mediated via microglia/astrocyte activation and overexpression of pro-inflammatory molecules. T2D was induced in rats by feeding with high fat high sugar diet and injecting a single low dose streptozotocin (STZ) intraperitoneally. Other diabetic rats were given caffeine orally (in two doses) for 5 weeks, starting 1 week before STZ injection. Measurement of plasma cytokines, TNFα and IL6, was performed using enzyme-linked immunosorbent assay (ELISA) technique. After sacrificing animals, brains were obtained and processed for histological evaluation. Immunohistochemistry was also performed using the following primary antibodies, anti-astrocyte marker GFAP, anti-microglia marker CD11b and apoptotic marker (anti-cleaved caspase-3). There was upregulation of IL6 and TNF-α in diabetic rats. Additionally, histological evaluation of the hippocampus of diabetic rats revealed cellular degeneration. There was increased immunostaining of GFAP, CD11b and cleaved caspase-3 in diabetic rats. Pretreatment with caffeine to diabetic rats, resulted in improvement of structural changes and decrease in cytokine levels and immuno-markers, expression, and this was in a dose-dependent manner. In conclusion, caffeine had an ameliorative role in enhancing hippocampal degenerative changes in T2D.

Development and evaluation of oral fast disintegrating film of ranitidine HCl by solvent casting method.

Here, we developed oral fast disintegrating film (ODF) of ranitidine hydrochloride (RHCl) by solvent casting method and assessed the impact of various formulation ingredients i.e. polymer concentration, type of plasticizers and superdisintegrants. Optimized film was developed with hydroxypropyl methyl cellulose (HPMC E5, 3% w/v) as film matrix, propylene glycol (PG) (10% w/w of polymer) as plasticizer and Pearlitol flash® (PF) (10% w/w of polymer) as release modifier. This film was chosen based on appearance, transparency, thickness, folding endurance and in vitro disintegration time (DT). Later on, optimized film was loaded with drug (50% w/w of polymer) (A12), which disintegrated within 15 seconds and released 81% of RHCl within two minutes. Furthermore, FTIR studies confirmed the absence of drug film ingredients interaction. SEM showed even distribution of RHCl and all excipients. Thus, A12 will be palatable for geriatric patients and helpful to avoid premature intestinal degradation.

A national survey in United Arab Emirates on practice of passive range of motion by physiotherapists in intensive care unit.

BACKGROUND: Patients admitted to intensive care units (ICU) are at an increased risk of developing immobility related complications. Physiotherapists are challenged to employ preventive and rehabilitative strategies to combat these effects. Passive limb range of motion (PROM) exercises- a part of early mobilization-aid in maintaining joint range of motion and functional muscle strength and forms a part of treatment for patients in ICU. However, there is a lack of evidence on practice of PROM exercises on patients admitted to ICU in the United Arab Emirates (UAE). This study aimed at exploring practices regarding the same in UAE. METHODS: This survey, conducted from January 2021 to February 2021 in College of Physiotherapy, Sharjah University studied practice of physiotherapists in the intensive care units. Physiotherapists currently working in ICU completed an online questionnaire composed of forty-two questions about physiotherapy service provision, assessment and intervention in the intensive care units. RESULTS: 33 physiotherapists completed the survey. 66.6% of respondents routinely assessed PROM for all the patients in ICU referred for physiotherapy. 84.8% of them assessed all the joints. More than half of the respondents (57.8%) reported that they administered PROM regularly to all the patients. According to 63.6% respondents, maintaining joint range of motion was the main reason for performing PROM. Responses pertaining to sets and repetitions of PROM were variable ranging from 1-6 sets and from 3 to 30 repetitions. Personal experience, resources/financial consideration and research findings were found to have influence on the practice. CONCLUSIONS: PROM was found to be one of the frequently used mobilization techniques administered by physiotherapists in the intensive care units and was mostly performed after assessment. Maintaining joint range of motion was the main aim for performing PROM. Variability was found in the sets and repetitions of PROM administered. Various factors influenced the practice of PROM.

Development of an academic disease registry for spinal muscular atrophy.

We report the development of a new disease registry on SMA as the result of a collaboration among three national networks in United States, Italy, and United Kingdom in partnership with a biotechnology company and with the support of advocacy groups. The aim of establishing a large collaborative registry within academic centers was to establish a structured but flexible system for collection of prospective, highly curated data that will deeply phenotype all patients with SMA and follow them longitudinally over several years. This paper describes the process leading to the development of the registry including the identification of the relevant data elements, the design of an electronic CRF with a shared data dictionary, the piloting of the first version and the definition of the final version. The registry will provide a central structure for conducting academic studies based on a much larger cohort of patients than those available in the individual networks. Due to the quality control of the data collected the registry can also be used for postmarketing purposes, allowing to share, in a transparent and controlled way, real-world data with pharmaceutical partners, drug regulatory agencies, and advocacy groups for better understanding of safety and effectiveness of new treatments.

Impact Of Prenatal Administration Of Melamine On Foetal Growth In Rats.

BACKGROUND: Data on the potential effects of maternal exposure to melamine is scarce. We aimed to evaluate the impact of melamine administration on pregnancy outcome and foetal growth in rats. METHODS: Positively-mated female Sprague-Dawley rats (n=24) were treated from day 6 to day 20 of gestation with vehicle (control), melamine 300 mg/kg/day (group-1) or melamine 450 mg/kg/day (group 2). On day 21, the numbers of foetal resorptions and dead foetuses were recorded. Thereafter, pups were examined for external anomalies, and various growth parameters were measured. RESULTS: A remarkable increase in the number of resorptions was observed in group-2 compared to the other two groups. A significant increase in foetal weight and placental weight was seen in group-2 compared to control. Head length and placental diameter were low in group-1 compared to control. The ratio between crown-rump length and head length was significantly greater in group 2 compared to control indicating asymmetrical intrauterine growth restriction. The only influence observed in group 1 compared to control was a decrease in placental diameter. No gross foetal malformations or changes in umbilical cord length, crownrump length or biparietal diameter were observed in both melamine-treated groups. CONCLUSIONS: Maternal exposure to melamine during pregnancy increased the incidence of resorption and resulted in asymmetrical intrauterine growth restriction.

Analyzing the outcome of early versus prolonged extubation following cardiac surgery.

OBJECTIVES: This study considered the factors associated with prolonged ventilation and the effects of reduced extubation times on patient recovery, intensive care unit stay, and overall hospital stay. MATERIALS AND METHODS: A retrospective study was performed, including 86 consecutive patients who underwent cardiac surgery from August 2006 to January 2007. The patients were divided into two groups following intensive care unit admission: Group A, duration of intubation <4 h (n=34); Group B, duration of intubation >4 h (n=52). RESULTS: Two deaths occurred in 86 patients, and overall hospital mortality was 2.32%. Patients in Group A were younger (33.2+/-12 versus 45.8+/-13 years; p=0.001) and had better preoperative left ventricular ejection fraction (LVEF) (62.4+/-9.8 versus 44.6+/-9.4; p=0.003) than those in Group B. Moreover, Group A patients had a shorter intensive care unit length of stay (1.7+/-0.5 versus 2.2+/-0.8 days; p=0.006) and were discharged earlier than Group B patients (2.7+/-2.4 versus 4.01+/-3.96; p=0.014). CONCLUSIONS: Early extubation offers a substantial advantage in terms of accelerated recovery, shorter intensive care unit, and hospital stay, suggesting that efforts to reduce extubation times are cost-effective.