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The article presents a case study of a 37-year-old male diagnosed with irreversible cerebellar toxicity. Topics discussed include the medical record of the patient, the diagnosis of his irreversible cerebellar toxicity through magnetic resonance imaging, his physical examinations, his treatment through chemotherapy, and an overview of the disease.

Aims: Formic acid has recently been detected in maternal blood and umbilical cord blood of infants born to alcohol abusing mothers. This toxic metabolite of methanol requires folate for detoxification. We hypothesized that formic acid produced in the maternal circulation will transfer across the placenta and will be toxic to the placenta. Our objectives were, first, to determine whether formic acid transfers across the human placenta and whether it is toxic to the placenta and second, to determine whether folate can decrease transplacental transfer of formic acid and mitigate toxicity. Methods: Dual perfusion of a single placental lobule ex vivo was used to characterize the transfer of formic acid across the placenta. After a 1-h control period, formic acid (2 mM) was introduced into the maternal circulation with (n = 4) or without folate (1 μM) (n = 4) and was allowed to equilibrate for 3 h. Results: Formic acid transferred rapidly from the maternal to the fetal circulation, and transfer was not altered with the addition of folate. Compared with the control period, there was a significant decrease in hCG secretion (P = 0.03) after addition of formic acid. The addition of folic acid to the perfusate mitigated the decrease in hCG. Conclusions: Formic acid rapidly transfers across the placenta and thus has the potential to be toxic to the developing fetus. Formic acid decreases hCG secretion in the placenta, which may alter steroidogenesis and differentiation of the cytotrophoblasts, and this adverse effect can be mitigated by folate. [ABSTRACT FROM AUTHOR]

Despite the positive impact of newer chemotherapeutic agents on responses and survival in patients with solid tumors, challenges in recurrent and metastatic solid tumors include acquired drug resistance, poor responses and poor tolerance by the patient. Use of antiangiogenic agents appears to be a logical, rational and effective approach. Of these agents, thalidomide has shown to specifically inhibit endothelial cell growth in various experimental animals. The advantages of thalidomide include the convenience of the oral route of administration and low toxicity profile. Furthermore, thalidomide has been found to be effective in cancer cachexia syndrome, chronic nausea, insomnia, profuse sweating and pain, which are often part of advanced malignancies. In this case report of six patients, we present encouraging responses to thalidomide used in a dose of 200 mg in patients with refractory solid tumors. [ABSTRACT FROM AUTHOR]

Abstract: Objectives : To determine the effects of metabolism and protein binding on the relationship between administered dose, blood levels of R methadone and biological response by measuring the free and protein-bound forms of the R and S enantiomers of methadone and EDDP, its metabolite. Design and methods : To measure free and total drug, trough levels were collected from 45 methadone clients. To measure free methadone, samples were filtered using ultrafiltration with a MW weight cut-off of 10,000 and extracted using liquid–liquid extraction. The solvent was evaporated and samples reconstituted in mobile phase for analysis by LC/MS/MS. Total analyte was determined by extracting unfiltered samples. Enantiomeric separation of methadone and EDDP was by chiral chromatography. Results : The presence of unmetabolized methadone suggested that none of the patients were very fast metabolizers. R and S forms were metabolized at the same rate at all administered doses. Free R methadone levels correlated both with methadone dose and with the total amount of R methadone. The free fraction of R methadone (%free R) was higher at lower doses than at high doses, varied from 5 to 25% and was inversely proportional to the total dose of administered drug in a relationship that was logarithmic and non-linear. Conclusions : By measuring the free, biologically active form of the drug, we were unable to account for the large variations in dose required between different patients to prevent the onset of withdrawal symptoms. The reason for the large range in dosage may be multifactorial. [Copyright &y& Elsevier]

Proton-sensing G Protein Coupled Receptors (GPCRs) sense changes in the extracellular pH to effect cell signaling for cellular homeostasis. They tend to be overexpressed in solid tumors associated with acidic extracellular pH, and are of direct interest as drug targets. How proton-sensing GPCRs sense extracellular acidification and activate upon protonation change is important to understand, because it may guide the design of therapeutics. Lack of publicly available experimental structures make it challenging to discriminate between conflicting mechanisms proposed for proton-binding, as main roles have been assigned to either an extracellular histidine cluster or to an internal carboxylic triad. Here we present a protocol to derive and evaluate structural models of the proton-sensing GPR68. This approach integrates state-of-the-art homology modeling with microsecond-timescale atomistic simulations, and with a detailed assessment of the compatibility of the structural models with known structural features of class A GPCRs. To decipher structural elements of potential interest for protonation-coupled conformational changes of GPR68, we used the best-compatible model as a starting point for independent atomistic simulations of GPR68 with different protonation states, and graph computations to characterize the response of GPR68 to changes in protonation. We found that GPR68 hosts an extended hydrogen-bond network that inter-connects the extracellular histidine cluster to the internal carboxylic triad, and which can even reach groups at the cytoplasmic G-protein binding site. Taken together, results suggest that GPR68 relies on dynamic, hydrogen-bond networks to inter-connect extracellular and internal proton-binding sites, and to elicit conformational changes at the cytoplasmic G-protein binding site., Competing Interests: G.S. and H.N. are employees of Boehringer Ingelheim Pharma GmbH & Co. KG., (© 2023 The Authors.)

Strawberry (Fragaria × ananassa Duch.) production is a major aspect of the agricultural economy in Turkey's Mediterranean region, offering high rates of employment and farm revenue. The effects of treatment of the exogenous amino acid on yield, quality, and physiological diversity for strawberry production was analyzed considering the economic aspects. To achieve this, 4 different irrigation regimes (IR (irrigation) 125, IR100, IR75, IR50) with proline treatment was tested. The total berry yield, photosynthesis and leaf water potential (LWP) significantly decreased as irrigation application rates declined. The IR125 treatment with proline (PIR125) produced the highest overall berry production. The use of proline significantly increased berry production by 23%. Exogenous proline generated 3.5 kg/1 m 3 greater yields than control in terms of irrigation water use efficiency (IWUE). Under the IR50 conditions, the treatment of proline yielded a 32% higher than the control. Moreover, proline significantly increased fruit soluble solids content (SSC) by 6.4%. The production system achieves the highest cost-benefit ratio (CBR) under PIR125 whereas the lowest cost-benefit ratio under IR50. When each scenario was considered at individually, it was evident that the more water used the more efficient high tunnel strawberry production. The fact that proline generated an increase in CBR in all four irrigation regimes proves this amino acid's economic effectiveness. As a result, PIR125 is recommended for the highest efficiency and CBR in Mediterranean environment. However, it has been discovered that using proline to alleviate this problem in areas where water is limited could be quite helpful., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Three decades of research, both in vitro and in vivo, have demonstrated the conformational heterogeneity that is displayed by the amyloid β peptide (Aβ) in Alzheimer's disease (AD). Understanding the distinct properties between Aβ conformations and how conformation may impact cellular activity remain open questions, yet still continue to provide new insights into protein misfolding and aggregation. In particular, there is interest in the group of soluble oligomeric prefibrillar Aβ species comprising lower molecular weight oligomers up to larger protofibrils. In the current study, a number of strategies were utilized to separate Aβ protofibrils and oligomers and show that the smaller Aβ oligomers have a much different conformation than Aβ protofibrils. The differences were consistent for both Aβ40 and Aβ42. Protofibrils bound thioflavin T to a greater extent than oligomers, and were highly enriched in β-sheet secondary structure. Aβ oligomers possessed a more open structure with significant solvent exposure of hydrophobic domains as determined by tryptophan fluorescence and bis-ANS binding, respectively. The protofibril-selective antibody AbSL readily discerned conformational differences between protofibrils and oligomers. The more developed structure for Aβ protofibrils ultimately proved critical for provoking the release of tumor necrosis factor α from microglial cells. The findings demonstrated a dependency on β-sheet structure for soluble Aβ aggregates to cause a microglial inflammatory response. The Aβ aggregation process yields many conformationally-varied species with different levels of β-structure and exposed hydrophobicity. The conformation elements likely determine biological activity and pathogenicity., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Sepsis is a serious medical condition characterized by bacterial infection and a subsequent massive systemic inflammatory response. In an effort to identify compounds that block lipopolysaccharide (LPS)-induced inflammation reported herein is the development of simple Lipid-A analogues that lack a disaccharide core yet still possess potent antagonistic activity against LPS. The structure of the new lead compound was developed based on predictive computational experiments. LPS antagonism by the lead compound was not straightforward, and a biphasic effect was observed suggesting a possibility of more than one binding site. An IC 50 value of 13 nM for the new compound was determined for the possible high affinity site. The combination of computational, synthetic, and biological studies revealed new structural determinants of these simplified analogues. It is expected that the acquired information will aid future design of LPS targeting glycopharmaceuticals.

Reported pin site infection rates in Kirschner wire fixation in the hand and wrist vary from 2% to 35%. In our unit we follow a strict pin site management protocol adapted from the Russian Ilizarov Scientific Centre. This study aims to identify if our current protocol reduces the incidence of pin site infection in hand and wrist surgery, and improves wire survival rates, to a level where exposed wires can be used safely. A retrospective review of 200 patients, treated with 369 percutaneous wires, in our hand surgery department over a 6-year period was carried out. Nine patients (4.5%) were diagnosed with a pin site infection with a wire survival rate of 99.5%.In our unit using our current protocol, results support the safe use of exposed wires with appropriate pin site care initiated in theatre. Adherence to this protocol allows wires to remain in-situ throughout treatment with minimal complications. Level of evidence: IV.

Background: Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and their endocrine-disrupting properties have focused growing attention regarding their teratogenic potential. We have recently documented that mothers of children born with hypospadias had been exposed to statistically higher levels of PBDE during pregnancy than mothers of healthy controls. However, it is not known which congeners of PBDE are associated with this putative teratogenic effect., Objectives: To identify PBDE congeners associated with increased risk for hypospadias., Study Methods: Hair samples from mothers were analyzed and compared between hypospadias cases and healthy controls for eight PBDE congeners using gas chromatography mass spectrometry (GC/MS). Polybrominated diphenyl ether levels were measured in the 0- to 3-cm segment closest to the skull of maternal hair as a proxy for in utero exposure of mothers who lived in the same environment for the duration of their pregnancy., Results: Median maternal hair levels of five PBDE congeners (28, 47, 99, 153, and 154) and of total PBDE (∑PBDE) were significantly higher among mothers of infants with hypospadias (n = 152) than among controls (n = 64). Apparent greater differences in the lower brominated congeners, especially in BDE-47 and BDE-99, may be due to the fact that they had been used in larger amounts, and their persistence properties confer longer exposure., Conclusions: The majority of the lower brominated PBDE congeners measured in maternal hair exhibited higher PBDE body burden during pregnancy in mothers of infants who were born with hypospadias., (Copyright © 2019 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Introduction: Advancing Quality (AQ) has high reliability and is effective at reducing unwarranted variation in care programme operated by the Advancing Quality Alliance (AQuA). Established in 2008, AQ aims to support NHS healthcare organisations toimprove the reliability of clinical practices so that every patient consistently
receives the highest quality care possible, every time. Our work with
dedicated clinical teams and managers aims to improve health outcomes for
patients and the population whilst reducing unwarranted variation in highly prevalent conditions., Methods: The population is identified retrospectively using ICD1-0 codes and a standardised data collection tool is used to assess management of people >60 years of age with a HFR, either on arrival to hospital or during their admission., Results: 7317 patients had a nutritional screen recorded using the MUST score between January 2015 and December 2016. In hospital mortality for patients receiving nutritional screen within 24 h was 6.1% compared to 9.3% for screens after 24 h, p < 0.001 (Fisher's exact test). Mortality rate for those patients without a risk score recorded was 9.4%.The number of patients receiving nutritional screen within 24 h, improved from 86% to 94%., Conclusion: Inpatient mortality was significantly lower in patients who had their MUST score within 24 h of admission. This is likely attributed to the improvement of the overall package of care if their assessment is performed early in those patients who are admitted to an orthopaedic or neck of femur ward. An early MUST score identifies nutritional deficiency and those at risk allowing measures can be taken to address malnutrition early during the inpatient stay., Competing Interests: None., (© 2019 Published by Elsevier B.V. on behalf of Professor P K Surendran Memorial Education Foundation.)

Strawberry has a unique status within the fruit species in terms of health and taste related compounds. This experimental study concerned the application of a bio-stimulant at various drip irrigation levels (IR125, IR100, IR75 and IR50). The effects of the bio-stimulant (seaweed extract) on the eating quality, i.e., the taste-related (TSS, fructose, glucose, sucrose and citric, malic, l-ascorbic acid), and health-related (antioxidant activity, total phenol, myricetin and quercetin) compounds were studied in two strawberry cultivars. The 'Rubygem' with its higher sugar and lower acid content has been more preferable than the 'Kabarla' cultivar. The bio-stimulant contributes to taste by improving the TSS, fructose, sucrose and also to health by increasing the quercetin content of the fruit which is associated to the cardiovascular properties and cancer reducing agents. The experiment conducted revealed significant increases only in the TSS contents and antioxidant activity under the IR50 and IR75 deficit irrigation treatments., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The impact of messaging campaigns on influencing urgent care- and emergent care-seeking behaviors, including the use of in-network providers, is not well-understood. Although out-of-network healthcare utilization can have negative financial consequences for patients in narrow network Affordable Care Act plans, individuals with time-sensitive medical conditions, and especially patients visiting the emergency department, may not think about out-of-network issues. Inappropriate or avoidable emergency department visits can also create unnecessary costs for patients., Objective: To evaluate the impact of 5 messaging strategies to educate individuals about the use of in-network providers and when care should be sought in the emergency department, urgent care center, or other sites of care., Methods: Using a retrospective analysis, individuals aged ≥18 years who were enrolled in an individually purchased Affordable Care Act-compliant Humana plan as of July 1, 2015, were randomized to 1 of 5 messaging arms (e-mail, magnet mailer with or without e-mail, and key-tag mailer with or without e-mail) or to a control group. The outreach was implemented and evaluated in 2 distinct, geographically defined populations of Orlando, Palm Beach, and Tampa, Florida (Population 1); and Atlanta, Georgia, and San Antonio and Austin, Texas (Population 2). The relative number of each emergency department, urgent care, and out-of-network visits during follow-up was modeled using negative binomial regression. Cox proportional hazard models were used to calculate the risk for ≥1 of each visit type (assessed separately) and high emergency department utilization (defined as ≥3 visits during follow-up) relative to the control, while accounting for variable follow-up time., Results: The relative numbers of each visit type assessed were not significantly different for any message group compared with the control in either population. The risk for an emergency department visit was 4% lower in the e-mail arm of Population 2 (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94-0.99; P = .005) and 7% lower in the e-mail/key-tag arm of Population 1 (HR, 0.93; 95% CI, 0.89-0.97; P = .001). The risk for high emergency department utilization was significantly reduced by the key-tag, magnet, and e-mail/key-tag strategies in Population 1, but no impact was found in Population 2., Conclusion: Despite the mixed results, the study provides new insights into how different messaging strategies could be used to educate patients and influence healthcare utilization decisions by people with health insurance.

Maternal alcohol consumption during gestation can cause serious injury to the fetus, and may result in a range of physiological and behavioral impairments, including increased seizure susceptibility, that are collectively termed fetal alcohol spectrum disorder (FASD). The cellular mechanisms underlying increased seizure susceptibility in FASD are not well understood, but could involve altered excitatory coupling of neuronal populations mediated by gap junction proteins. We utilized a mouse model of the prenatal alcohol exposure (PAE) to study the expression pattern of connexin (Cx) major components of gap junctions, and pannexin proteins, which form membrane channels, in the brain of 2-3weeks old PAE and control postnatal offspring. PAE during the first trimester-equivalent period of pregnancy in mice resulted in significant up-regulation of Cx30 mRNA and Cx30 total protein in the hippocampus of PAE animals compared to age-matched controls. Surface level expression of both dimeric and monomeric Cx30 were also found to be significantly up-regulated in both hippocampus and cerebral cortex of PAE animals compared to age-matched controls. On the membrane surface, the fast migrating form of Cx43 was found to be up-regulated in the hippocampus of PAE mice. However, we did not see any up-regulation of the phosphorylated forms of Cx43 on the membrane surface. These results indicate that the expression and processing of astrocytic connexins (Cx30, Cx43) are up-regulated in the brain of PAE offspring, and these changes could play a role in the cerebral hyperexcitability observed in these animals., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Prenatal alcohol exposure (PAE) can lead to long-lasting neurological alterations that may predispose individuals to seizures and neurobehavioral dysfunction. To date, there exists limited information regarding the underlying pathophysiological mechanisms. The hippocampal CA3 region generates excitatory population activity, called sharp waves (SPWs), that provide an ideal model to study perturbations in neuronal excitability at the network and cellular levels. In the present study, we utilized a mouse model of PAE and used dual extracellular and whole-cell patch-clamp recordings from CA3 hippocampal pyramidal cells to evaluate the effect of 1st trimester-equivalent ethanol exposure (10% v/v) on SPW activity and excitatory/inhibitory balance. We observed that PAE significantly altered in vitro SPW waveforms, with an increased duration and amplitude, when compared to controls. In addition, PAE slices exhibited reduced pharmacological inhibition by the GABA-A receptor antagonist bicuculline (BMI) on SPW activity, and increased population spike paired-pulse ratios, all indicative of network disinhibition within the PAE hippocampus. Evaluation of PAE CA3 pyramidal cell activity associated with SPWs, revealed increased action potential cell firing, which was accompanied by an imbalance of excitatory/inhibitory synaptic drive, shifted in favor of excitation. Moreover, we observed intrinsic changes in CA3 pyramidal activity in PAE animals, including increased burst firing and instantaneous firing rate. This is the first study to provide evidence for hippocampal dysfunction in the ability to maintain network homeostasis and underlying cellular hyperexcitability in a model of PAE. These circuit and cellular level alterations may contribute to the increased propensity for seizures and neurobehavioral dysfunction observed in patients with a history of PAE., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Intra-articular fractures of the proximal interphalangeal (PIP) joint are commonly treated with dynamic external fixation. Most commonly used is the Suzuki modification of the pins and rubber traction system (PRTS). There are a few other modifications of the PRTS external fixators. We present an alternative pin external fixator that is simple and effective., Methods: Under a suitable anesthesia and image intensification a true lateral view of the head of the proximal phalanx is obtained. A K-wire construct holds the affected digit out to length with the fracture reduced and Jurgan pin-balls hold the construct into position. Under image intensification the whole device is checked to ensure the joint and fracture is reduced and the joint is not over distracted. The PIP joint is also checked to ensure good range of motion. The device was checked in clinic at 1 week with radiographs. The wires are removed at 4 weeks followed by intensive hand physiotherapy., Results: Over 20 patients with intra-articular fractures of the proximal and middle phalangeal were treated with this technique. In all cases the fracture healed with good joint congruency. All patients achieved good range of motion of the PIP joint but with some restriction of full flexion (mean, 20 degrees). There was no loss of position or pin-site infections. There was good compliance with the treatment., Discussion: The main advantages of the technique we describe are: (1) the compact design, making it less cumbersome for the patient compared with other PRTS external fixators; (2) it is straightforward to assemble and the device is easy to adjust in clinic if there is any loss of reduction; (3) the pin-balls prevent sharp ends of the wire protruding causing morbidity to the patient; (4) there is less chance of loss of traction compared with traction devices using rubber bands. It is a dynamic device, which allows mobilization of the joints reducing stiffness.

Objective: To conduct a systematic review evaluating the effectiveness of a folate-fortified oral contraceptive preparation in increasing blood folate concentrations to levels providing optimal protection against neural tube defects (> 906 nmol/L)., Methods: We searched Medline, EMBASE, Web of Science, and the Cochrane Library for human studies published from inception to June 2013 that evaluated oral contraceptive use and folate status. Case-control studies, cohort studies, and clinical trials were included. Efficacy and bioequivalence data were evaluated from included studies., Results: Overall, efficacy and bioequivalence data for the folate-fortified oral contraceptive show that it is at least as effective as folic acid alone in raising blood folate concentrations, and that the concomitant administration of folate with the oral contraceptive component does not affect its absorption or kinetics., Conclusion: A folate-fortified oral contraceptive preparation provides an option for women to maintain blood folate levels, especially those who may be planning a family after the cessation of oral contraceptive therapy.