Miracle-dz/UniFAR-FTUs huggingface dataset:
Diagnostic accuracy of a uniform research case definition for TBM in children: a prospective study.

BACKGROUND Bacteriological confirmation of tuberculous meningitis (TBM) is problematic, and rarely guides initial clinical management. A uniform TBM case definition has been proposed for research purposes. METHODS We prospectively enrolled patients aged 3 months to 13 years with meningitis confirmed using cerebrospinal fluid analysis at Tygerberg Hospital, Cape Town, South Africa. Criteria that differentiated TBM from other causes were explored and the accuracy of a probable TBM score assessed by comparing bacteriologically confirmed cases to 'non-TBM' controls. RESULTS Of 139 meningitis patients, 79 were diagnosed with TBM (35 bacteriologically confirmed), 10 with bacterial meningitis and 50 with viral meningitis. Among those with bacteriologically confirmed TBM, 15 were Mycobacterium tuberculosis culture-positive and 20 were culture-negative but positive on GenoType(®) MTBDRplus or Xpert(®) MTB/RIF; 18 were positive on only a single commercial nucleic acid amplification test. A probable TBM score provided a sensitivity of 74% (95%CI 57-88) and a specificity of 97% (95%CI 86-99) compared to bacteriologically confirmed TBM. CONCLUSION A probable TBM score demonstrated excellent specificity compared to bacteriological confirmation. However, 26% of children with TBM would be missed due to the limited accuracy of the case definition. Further prospective testing of an algorithm-based approach to TBM is advisable before recommendation for general clinical practice.
Preoperative activation and intraoperative stimulation of language-related areas in patients with glioma.

OBJECTIVE Evaluation of the accuracy of preoperative localization of language-related cortex by magnetic resonance imaging-guided positron emission tomography. METHODS Patients with gliomas in the left dominant hemisphere were examined preoperatively with magnetic resonance imaging-guided positron emission tomography and intraoperatively by electrical stimulation of cortex. RESULTS A verb generation task yielded more intense and better lateralized local increases of cerebral blood flow in the positron emission tomographic examination than did a naming task. Significant correspondence of preoperative and intraoperative findings was observed for the verb generation task. Cortical sites with aphasic disturbance during electrical stimulation had a significantly higher cerebral blood flow increase during preoperative activation than did sites without intraoperative language impairment. Areas with cerebral blood flow increases above an optimum threshold had 73% sensitivity and 81% specificity to predict aphasic disturbance during intraoperative stimulation. CONCLUSION The data suggest that with further technical improvements, imaging of language function may become a preoperative diagnostic tool for patients with tumors close to language-related brain structures.
Development of Methionyl-tRNA Synthetase Inhibitors as Antibiotics for Gram-Positive Bacterial Infections

ABSTRACT Antibiotic-resistant bacteria are widespread and pose a growing threat to human health. New antibiotics acting by novel mechanisms of action are needed to address this challenge. The bacterial methionyl-tRNA synthetase (MetRS) enzyme is essential for protein synthesis, and the type found in Gram-positive bacteria is substantially different from its counterpart found in the mammalian cytoplasm. Both previously published and new selective inhibitors were shown to be highly active against Gram-positive bacteria with MICs of ≤1.3 μg/ml against Staphylococcus, Enterococcus, and Streptococcus strains. Incorporation of radioactive precursors demonstrated that the mechanism of activity was due to the inhibition of protein synthesis. Little activity against Gram-negative bacteria was observed, consistent with the fact that Gram-negative bacterial species contain a different type of MetRS enzyme. The ratio of the MIC to the minimum bactericidal concentration (MBC) was consistent with a bacteriostatic mechanism. The level of protein binding of the compounds was high (>95%), and this translated to a substantial increase in MICs when the compounds were tested in the presence of serum. Despite this, the compounds were very active when they were tested in a Staphylococcus aureus murine thigh infection model. Compounds 1717 and 2144, given by oral gavage, resulted in 3- to 4-log decreases in the bacterial load compared to that in vehicle-treated mice, which was comparable to the results observed with the comparator drugs, vancomycin and linezolid. In summary, the research describes MetRS inhibitors with oral bioavailability that represent a class of compounds acting by a novel mechanism with excellent potential for clinical development.
Drug delivery by red blood cells: vascular carriers designed by mother nature

Importance of the field: Vascular delivery of several classes of therapeutic agents may benefit from carriage by red blood cells (RBC), for example, drugs that require delivery into phagocytic cells and those that must act within the vascular lumen. The fact that several protocols of infusion of RBC-encapsulated drugs are now being explored in patients illustrates a high biomedical importance for the field. Areas covered by this review: Two strategies for RBC drug delivery are discussed: encapsulation into isolated RBC ex vivo followed by infusion in compatible recipients and coupling therapeutics to the surface of RBC. Studies of pharmacokinetics and effects in animal models and in human studies of diverse therapeutic enzymes, antibiotics and other drugs encapsulated in RBC are described and critically analyzed. Coupling to RBC surface of compounds regulating immune response and complement, affinity ligands, polyethylene glycol alleviating immune response to donor RBC and fibrinolytic plasminogen activators are described. Also described is a new, translation-prone approach for RBC drug delivery by injection of therapeutics conjugated with fragments of antibodies providing safe anchoring of cargoes to circulating RBC, without need for ex vivo modification and infusion of RBC. What the reader will gain: Readers will gain historical perspective, current status, challenges and perspectives of medical applications of RBC for drug delivery. Take home message: RBC represent naturally designed carriers for intravascular drug delivery, characterized by unique longevity in the bloodstream, biocompatibility and safe physiological mechanisms for metabolism. New approaches for encapsulating drugs into RBC and coupling to RBC surface provide promising avenues for safe and widely useful improvement of drug delivery in the vascular system.
Benzhexol-dependence resulting from self-medication for intermittent explosive disorder

Objective. Recent observations in Iraq during the period of sanction suggest the existence of benzhexol prescribing linked to its calming effects on explosive behaviours. This inspired our group to research the existence of this practice and the characteristics of those involved in it. Method. All patients from the psychiatric service in Merjan Hospital, Al Hilla City, Babylon Governate, Iraq, who had a prescription for benzhexol between January 1991 and December 2000, were identified. All participants received their diagnosis based on the clinical criteria of the DSM-IV, after taking a comprehensive medical and psychiatric history, mental state examination and collateral information from family members. The patients were evaluated by the same qualified consultant psychiatrist at the initial assessment and all through the period of follow-up. Results. In the 10-year period under study, 354 patients were prescribed benzhexol. A total of 190 patients diagnosed as intermittent explosive disorder (IED) and 164 suffering from severe mental disorders or personality disorders were excluded from the study. The average age of the IED group was 29.5 years. On direct questioning, the main reason patients gave most frequently for using benzhexol was to control the aggressive outbursts (N=92, 48.4), to get high (N=49, 25.8), to relax (N=26, 13.7), to get rid of boredom (N=23, 12.1). In total, the whole group were prescribed benzhexol, at an average dose of 12.5 mg/day (range 2–20 mg/day). At the time of final assessment the mean dose of prescribed benzhexol had fallen slightly to 12 mg/day (2–20 mg/day), with 10 patients being benzhexol free. Of the 190, three patients had a diagnosis of obsessive compulsive disorders, 36 patients had a diagnosis of benzodiazepines dependence, and a further five had a diagnosis of alcohol dependency syndrome. Eighty percent felt satisfied with the effect of the drug and 95 were not motivated to stop it. Conclusions. There are a significant number of patients who are routinely prescribed benzhexol as a replacement therapy. The main original reason for starting it is to control outbursts and improves their reaction to stress situations. This growing issue raises the need for awareness, by both public and medical practitioners, of the potential adverse effects of benzhexol and its untoward consequences.
Protective effect of Acorus calamus against acrylamide induced neurotoxicity

Exposure of rats to acrylamide (ACR) caused hind limb paralysis in 58% of the animals on day 10 and decreased behavioural parameters, namely distance travelled, ambulatory time, stereotypic time and basal stereotypic movements compared with the control group. These rats also had a decrease in the reduced glutathione (GSH) content and glutathione‐S‐transferase (GST) activity in the corpus striatum and an increase in striatal dopamine receptors, as evident by an increase in the binding of 3H‐spiperone to striatal membranes. Treatment with the ethanol:water (1:1) extract of the rhizomes of Acorus calamus (AC‐002) increased the GSH content and GST activity in the corpus striatum while insignificant changes were observed in other parameters. Rats treated with ACR and AC‐002 in combination had a lower incidence of paralysis (18%) compared with those treated with ACR alone on day 10 of the experiment. The rats also showed a partial recovery in other behavioural parameters. The levels of GSH content and GST activity increased in the corpus striatum, while the dopamine receptors decreased compared with the ACR treated rats. The results suggest that the neurobehavioural changes produced by ACR may be prevented following treatment with Acorus calamus rhizomes. Copyright © 2002 John Wiley & Sons, Ltd.
Resting metabolic rate and anthropometric measurements in male sleep apnea patients.

OBJECTIVE Obstructive Sleep Apnea Syndrome (OSAS) is a common sleep-related breathing disorder. Associations among Apnea-Hypopnea Index (AHI), Resting Metabolic Rate (RMR), body habitus differences, and otorhinolaryngologic abnormality may clarify the characteristics of patients with OSAS. In order to test this hypothesis, we aimed to compare the RMR, Modified Mallampati Scores (MMS), anthropometric measurements and body composition of male OSAS patients with simple snorers and to investigate the association among these parameters. METHODS MMS were calculated, overnight polysomnography was performed, body mass index, neck, shoulder, chest, waist, hip and abdomen circumferences, body fat amount and ratio, lean body weight, body water amount and RMR were measured for all of the patients. PATIENTS Ninety-eight male patients with suspected OSAS were included in the study. RESULTS Fifty-one patients were diagnosed as OSAS and 47 patients were diagnosed as simple snorers. RMR, total body water, neck, shoulder and chest circumferences were significantly higher in OSAS patients than the simple snorers. The majority of the simple snorers was seen to have a MMS of stage 2 whereas OSAS patients had MMS of stages 3 and 4. AHI was significantly correlated with neck, shoulder, chest circumferences, total body water amount, MMS and RMR. Chest girth was found as the most important single predictor of sleep apnea in multivariate analysis. CONCLUSION We suggest that the increased RMR and chest circumference might have occurred due to the condition resulting from the elevated AHI in patients with OSAS. Mallampati score should be routinely evaluated in OSAS patients.
Late morbidity in upper limb function and quality of life in women after breast cancer surgery.

BACKGROUND Breast cancer is the most common malignancy in Brazilian women. In recent years, there has been great progress in and an increasing number of breast-conserving surgical techniques; however, immediate or late morbidity after surgery, in the form of functional impairment and pain, remains a significant clinical problem. OBJECTIVE To investigate the relationship between late upper limb functional impairment and the quality of life in women subjected to breast cancer surgery. METHOD A total of 81 women participated in the study, with the length of time since surgery ranging from one to five years. A survey of upper limb complaints reported by patients was conducted, and the questionnaires Disabilities of the Arm, Shoulder, and Hand (DASH) and the European Organization for Research and Treatment of Cancer (EORTC QLQC-30 and BR23) were applied. RESULTS The correlation between the DASH score and the length of time since surgery determined that the longer the time since surgery, the greater the difficulties in functionality of the upper limb (r=0.459; p<0.0001). A statistically significant correlation was observed between the DASH score and health-related quality of life. CONCLUSION Late functional impairment had a significant impact on upper limb function in everyday life and health-related quality of life for women who underwent breast cancer surgery.
Nuclear Localization of Hepatitis B Core Antigen and Its Relations to Liver Injury, Hepatocyte Proliferation, and Viral Load

Goals The aim of this study was to determine the factor(s) independently affecting the HBcAg expression pattern in HBV-infected livers. Background Subcellular localization of HBcAg have been found to be related to the activity of liver disease, hepatocyte proliferation rate and the level of HBV replication. Study A total of 98 patients with biopsy proven chronic hepatitis B were included. HBcAg and proliferative cell nuclear antigen (PCNA) were immunohistochemically detected. HBcAg expression and its relationship with histologic activity index, ALT levels, PCNA score and HBV DNA levels were investigated. Results Forty-three (44%) patients were positive for HBcAg staining, with most of them (37 patients) having nuclear localization. Forty-seven percent of patients with detectable HBV DNA had nuclear staining while none of the HBV DNA negative patients had nuclear staining (P < 0.0005). Patients with positive nuclear staining had lower HAI (<8) and a lower PCNA score (<353/1,000 cell) than those with negative staining (62% vs. 39% and 90% vs. 66%, respectively, P < 0.05). In multivariate analysis, both high HBV DNA level and low HAI (P < 0.0005 and P < 0.05, respectively) but not PCNA score, were independently associated with nuclear staining of HBcAg. Conclusions Our results suggest that viral load and the severity of liver damage but not the rate of hepatocyte proliferation independently affects the HBcAg expression pattern.
Insulin-like Growth Factor-2 Enhances Functions of Antigen (Ag)-specific Regulatory B Cells*

Background: Antigen-specific B cells (AgsBCs) are important in immune regulation. Results: AgsBCs express IGF2 receptor. IGF2 can drive AgsBCs to produce IL-10 and differentiate to regulatory B cells. Conclusion: IGF2 can enhance the immune suppressor function of AgsBCs. Significance: IGF2 has the potential to enhance immunotherapy of allergic disorders. Regulatory B cells (Bregs) are important in immune regulation. The factors that regulate Breg functions are less clear. Insulin-like growth factor 2 (IGF2) is capable of inducing hematopoietic stem cell differentiation. This study aimed to investigate the role of IGF2 in the development of Bregs and the enhancement of their function. In this study, the expression of IGF1 receptor (IGF1R) and IGF2R in ovalbumin (OVA)-specific B cells (OVAsBCs) was assessed by real time RT-PCR and Western blotting. The release of interleukin (IL)-10 from OVAsBCs and OVAsBC proliferation were assessed by enzyme-linked immunoassay and proliferation assay. The role of IGF2 in enhancing the function of OVAsBCs was tested with an intestinal allergic inflammation mouse model. The results showed that OVAsBCs expressed high levels of IGF2R. Exposure to both IGF2 and a specific antigen (Ag), OVA, markedly enhanced the expression of IL-10 in OVAsBCs as well as enhanced the IL-10+ OVAsBC proliferation. The concurrent exposure to IGF2 and specific Ag markedly induced the IL-10 promoter DNA demethylation via activating the STAT5 pathway. IGF2 also enhanced both the OVAsBC proliferation in vivo and the effect of Ag-specific immunotherapy on inhibiting allergic inflammation in the intestine. We conclude that OVAsBCs express high levels of IGF2R and that IGF2 increases the expression of IL-10 in OVAsBCs and enhances OVAsBC proliferation and the inhibitory effect on allergic inflammation.
Acute sleep‐promoting action of the melatonin agonist, ramelteon, in the rat

Abstract: Insomnia, which is severe enough to warrant treatment, occurs in ∼10% of the general population. It is associated with a range of adverse consequences for human health, economic productivity and quality of life. In animal and human studies, administration of melatonin has been reported to promote sleep, although there has been controversy regarding its effectiveness. The present study used a chronically implanted radiotelemetry transmitter to record electroencephalogram (EEG) and electromyogram (EMG) to enable discrimination of wake (W), nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep in un‐restrained rats. The acute action of melatonin and ramelteon, a melatonin agonist recently approved for long‐term treatment of insomnia in the USA, was examined. Radioligand binding assays on recombinant human MT1/MT2 receptors showed that both the melatonin and ramelteon were both high affinity, nonsubtype selective ligands. Both compounds acted as potent full agonists on a cellular model of melatonin action, the pigment aggregation response in Xenopus laevis melanophores. Both melatonin and ramelteon (10 mg/kg, i/p), administered close to the mid‐point of the dark phase of the L:D cycle, significantly reduced NREM sleep latency (time from injection to the appearance of NREM sleep). Both the drugs also produced a short‐lasting increase in NREM sleep duration, but the NREM power spectrum was unaltered. Neither drug altered REM latency, REM sleep duration nor power spectrum during REM sleep. In conclusion, ramelteon administration, like melatonin, exerted an acute, short‐lasting sleep‐promoting effect in the rat, the model most commonly used to evaluate the activity of novel hypnotic drugs.
Early Computed Tomography Hypodensity Predicts Hemorrhage After Intravenous Tissue Plasminogen Activator in Acute Ischemic Stroke

Parenchymal hypodensity is a proposed risk factor for hemorrhage after recombinant tissue plasminogen activator (TPA) thrombolysis for ischemic stroke. In Buffalo, NY, and Houston, TX, the authors reviewed 70 patients who were treated with intravenous TPA for acute middle cerebral artery (MCA) stroke. Two observers blinded to clinical outcome analyzed initial noncontrast head computed tomography (CT) scans. Basal ganglia CT hypodensity was quantitated in Hounsfield units (HUs). Contralateral‐ipsilateral difference in density was calculated using the asymptomatic side as a control. Ictus time to TPA averaged 2.5 hours. Six patients developed symptomatic intraparenchymal hematomas (2 fatal). The hemorrhage group had more severe basal ganglia hypodensity (mean 7.5 ± 1.4, range 6–10 HU) than the nonhemorrhage group (2.2 ± 1.4, range 0–9 HU) (P < .0001). The hemorrhage group had hypodensity of > 5 HU; the nonhemorrhage group had hypodensity of ≤4 HU, except 1 patient with hypodensity of 9 HU. In predicting hemorrhage, the positive predictive value of hypodensity > 5 HU was 86%; the negative predictive value was 100%. Prethrombolysis NIH Stroke Scale (NIHSS) deficit (P= .0007) and blood glucose (P= .005) were also higher in the hemorrhage group. Age, gender, smoking, hypertension, and ictus time to TPA infusion did not differ between the 2 groups. Logistic regression indicated that basal ganglia hypodensity was the best single predictor of hemorrhage. Hypodensity and NIHSS score together predicted all cases of hemorrhage. The authors conclude that basal ganglia hypodensity quantified by CT may be a useful method of risk stratification to select acute MCA stroke patients for thrombolytic therapy.
Toward a comprehensive developmental model for major depression in women.

OBJECTIVE Major depression is a multifactorial disorder with many etiologic variables that are interrelated through developmental pathways. The authors used structural equation modeling to generate a developmental model for the etiology of major depression in women. METHOD Data from 1,942 adult female twins, interviewed up to four times over a 9-year period, were used to construct a developmental model to predict depressive episodes in the year before the most recent interview. Eighteen risk factors in five developmental tiers were considered: 1) childhood (genetic risk, disturbed family environment, childhood sexual abuse, and childhood parental loss), 2) early adolescence (neuroticism, self-esteem, and early-onset anxiety and conduct disorder), 3) late adolescence (educational attainment, lifetime traumas, social support, and substance misuse), 4) adulthood (history of divorce and past history of major depression), and 5) the last year (marital problems, difficulties, and stressful life events). RESULTS The best fitting model included six correlations and 64 paths, provided an excellent fit to the data, and explained 52% of the variance in liability to episodes of major depression. The findings suggest that the development of risk for major depression in women results from three broad pathways reflecting internalizing symptoms, externalizing symptoms, and psychosocial adversity. CONCLUSIONS Major depression is an etiologically complex disorder, the full understanding of which will require consideration of a broad array of risk factors from multiple domains. These results, while plausible, should be treated with caution because of problems with causal inference, retrospective recall bias, and the limitations of a purely additive statistical model.