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At least 181 records · Page 10Linked to original sources

Role of interleukin 6 in a murine model of Crohn's ileitis: are cytokine/anticytokine strategies the future for IBD therapies?

Although the precise causes of inflammatory bowel disease (IBD) have yet to be discovered, important therapeutic advances have resulted from the manipulation of cytokine function(s) using anticytokine/cytokine therapies, such as targeting of tumor necrosis factor. We discuss the future of this area of investigation in the context of preclinical experimentation using animal models of IBD. In particular, we pinpoint the roles played by interleukin 6 and its intracellular signalling pathways in the SAMP1/Yit murine model of Crohn's-like ileitis.

Animals↗

Plasma Proteome Signatures in Sickle Cell Anemia and the Effect of Hydroxyurea Treatment.

Sickle Cell Anaemia (SCA) is a monogenic blood disorder caused by a mutation in the β-globin gene, yet it presents with marked clinical variability. Although hydroxyurea (HU) is an established therapy, its precise mechanism of action remains incompletely understood. Plasma proteins represent valuable biomarkers for elucidating disease mechanisms and treatment responses. In this study, plasma proteome profiling of 31 healthy controls and 76 SCA patients identified 43 differentially abundant proteins (DAPs) that form a highly interconnected interaction network. Proteins with increased abundance in SCA were largely associated with immune and inflammatory responses, whereas those with reduced levels were linked to coagulation and proteolytic pathways. HU therapy was associated with elevated levels of haptoglobin (HP) and hemopexin (HPX), key mediators of free hemoglobin scavenging. We also identified several previously unreported plasma proteins altered in SCA, broadening the landscape of potential biomarkers and HU-responsive targets. Many DAPs significantly correlated with clinical indices, such as transfusion frequency, vaso-occlusive crises, white blood cell counts, and platelet counts, offering insights into disease mechanisms and potential utility in disease management. Notably, overlap with β-thalassemia-associated signatures suggests shared pathophysiological pathways between these hemoglobinopathies. Collectively, these findings provide a strong foundation for translational validation in larger, independent cohorts.

Humans↗

The effect of interferon and desferrioxamine on serum ferritin and hepatic iron concentrations in chronic hepatitis B.

BACKGROUND/AIMS: Recent reports indicate that an individual's iron status might affect the response rate achieved with Interferon therapy for the treatment of chronic viral hepatitis. METHODOLOGY: Forty individuals, 29 men and 11 women, with chronic viral hepatitis B, who had elevated serum ferritin levels, were randomized to receive either Interferon (IFN) 5 MU TIW SQ for 6 months alone (n=21) or Interferon in combination with repetitive cycles of desferrioxamine infused at a dose of 80 mg/kg per cycle (n=19) over 3 consecutive days in an effort to reduce their metabolically active iron pool during the course of IFN treatment. These cycles were continued until a serum ferritin level of less than 250 ng/ml (normal values <220 ng/ml) was achieved. Additionally, all desferrioxamine treated subjects were placed on a low iron containing diet. An interferon response was defined as normalization of the serum ALT and seroconversion from eAg positive to eAb positive. All other responses were defined as failures. RESULTS: The mean ages of the subjects in the 2 groups were 39+/-6 and 38+/-5 years. The initial serum ALT levels were 150+/-27 and 151+/-13 IU/l. The hepatic iron concentrations were 916+/-29 and 896+/-15 microg/g/dry liver weight. The serum ferritin levels were 386+/-12 and 393+/-18 ng/ml. None of these values differed significantly between the 2 treatment groups. The desferrioxamine treated group consisted of 14 men and 5 women. This group experienced a reduction in their serum ferritin to a level of 237+/-13 ng/ml as a result of the desferrioxamine treatment (p<0.05). Additionally, a reduction in their hepatic iron concentration, to a level 766+/-29 microg/g/dry liver weight, occurred with treatment (p<0.05). Twelve of the 19 (63%) desferrioxamine-treated subjects and 8 of the 21 (38%) control subjects experienced a normalization of their serum ALT levels with treatment (p<0.05). Thirteen of 19 (68%) of the desferrioxamine-treated subjects but only 8 of 21 (38%) of the IFN alone treated group seroconverted to anti-e positive (p<0.05). Moreover, a greater improvement in the hepatic histologic score and rate of HBV-DNA loss occurred in the desferrioxamine-treated group. CONCLUSIONS: Based upon these data, it can be concluded that desferrioxamine infusion to achieve a normal serum ferritin level enhances the likelihood of an individual with chronic hepatitis B responding to IFN therapy. The precise mechanism responsible for this phenomenon is not clear, but would appear to be due to a reduction in the hepatic free iron pool as reflected by sequential changes in the serum ferritin and hepatic iron concentrations.

Adult↗

[Use of the Nd-YAG laser in the treatment of tumors in the area of the craniocervical transition].

The primary symptom in patients with tumors in the region of the foramen magnum is persistent neck pain. With the use of microneurosurgical techniques and additional laser therapy, favorable operative results can be obtained. The same holds true for patients harboring difficult to approach lesions such as ventrally located tumors of the craniocervical junction or with brain stem tumors. The advantages of the Nd-Yag-laser therapy are: precise denaturation of tumor tissue with predictable depth effect; adequate delineation of tumors due to different tissue absorption properties; excellent coagulation in the presence of highly vascularized tumors; surgery markedly facilitated due to laser induced shrinkage of tumors.

Adult↗

Carbon dioxide laser treatment for condylomata acuminata venereal infections.

Condylomata acuminata virus accounts for a significant number of venereal infections in the western world and constitutes a major public health problem. Unfortunately, conventional therapeutic measures have given inconsistent and largely unsuccessful results for the elimination of genital warts. A 3.5-year experience with 110 women using the carbon dioxide (CO2) laser for evaporation of viral warts is presented. Six patients (5.5%) developed recurrent lesions and were retreated. Several patients were staged for 2 or 3 treatments because of extensive condylomata; this occurred especially during pregnancy and other altered states of immunity. The principal advantages of CO2 laser therapy are precision, which results in sparing of normal tissue; probable elimination of the infective agent; and rapid healing without scar formation. Sixty-three patients had atypical cytology associated with condylomata acuminata; this finding suggests an association with lower genital tract neoplasia.

Adolescent↗

Bio-identical steroid hormone replacement: selected observations from 23 years of clinical and laboratory practice.

To maximize the safety and efficacy of human hormone replacement therapy, it is suggested that exact molecular copies of human hormones ("bio-identical" hormones) be administered in physiologic quantities and proportions, following physiologic timing and routes of administration. It is also suggested that physicians return to the practice of monitoring hormone therapy by precise laboratory measurement levels of the hormones administered. This paper also presents clinical and laboratory data concerning appropriate proportions of bio-identical estrogens, the physiologic and supraphysiologic nature of commonly employed doses, estrogen levels achieved by varying routes of administration, and the significant effects of iodine on estrogen metabolism and cobalt on estrogen excretion.

Cobalt↗

[Current state of blood transfusion in Yugoslavia and its perspectives].

The current situation of the transfusion service in this country has been characterised by small-scale operational level, the lack of regional system and basic components of a single service. There is a great variety in the medical and expert point of view starting from the lack of elementary hygienic and technical conditions, down to developed institutions of the European level. This activity has been characterised for the last ten years or so by an effort to win blood-givers at all cost, to enhance production of intravenous solutions which in some factories have obtained factory production volume, to determine basic blood groups and a very modest diagnostics for haemolitic diseases of newly born children. A large number of doctors--transfusiologists have obtained specialists' titles, but without any prospects to change the present status of their work: blood conservation, efforts to win blood-givers and determine blood groups. The differentiation between transfusiologists and clinic-engaged personnel has been increasing, thus making the transfusiologists to be far from the problems of modern haematology and clinical therapy. Observing the situation and status of transfusiology in the developed countries of Western Europe, it is possible to state that the transfusiology is developing in the direction of cooperation and team-work with doctors engaged in clinics. Therefore, cooperation with doctors engaged in clinics should be cultivated and organise team work. The intermediary role of doctors-transfusiologist in the cycle of health improvement should be avoided by all means. 90% of packed blood in this country is consumed in the form of full blood or dry plasma and only 10% in the form of desired derivatives, instead of the contrary case, since the precisely set therapy using new haemostatic medicaments is an economical imperative. The electronic data processing of blood-givers enables doctors-transfusiologists to deal with these problems since this is much cheaper and more efficient than when it was done by the doctor. Application of plactic casings, its industrial production, use of multi-channel electronic systems when determining the blood-groups and anti-bodies, makes this more of a technical than medical problem dealt by doctors. Production of intravenous solutions and plasma drying requires an inter-republican integration into a powerful industrial group, similar to that in Great Britain. Our transfusiologist should in future be engaged in business done by pathologists related to problems of blood patho-physiology, similar to the activities done in USA and other Anglo-Saxon countries. Integration of American Association of Blood Banks with the Association for organs and tissue transplation in USA only underlines this...

Blood Donors↗

[Muscular tensions of the back studied with telethermography: changes induced with static measures and auricular acupuncture. Preliminary report].

Thirty-six cases affected with scoliosis or scoliotic attitudes secondary to static trouble were examined. On all these cases a telethermography of the back was carried out demonstrating the presence of thermic asymmetry as regards to a normal map presenting hot areas on the side of the curve's concavity. The dysmorphosis secondary to static trouble cases was treated with millimetric rise whilst idiopathic scoliosis was treated with auricle therapy and precisely with the penetration of semipermanent steelplated needles of the bilateral external anthelis face. The exact point of penetration was determined by making use of the F frequency. All the cases treated have undergone long-term controls which document a return towards a normal telethermography. In the case of idiopathic scoliosis a significant modification in the thermography already after fifteen seconds of needle penetration was observed.

Acupuncture Therapy↗

A Biomimetic Dual-Targeting Nano-APA-Editor Reprograms the 3'UTR Landscape for Tongue Squamous Cell Carcinoma Therapy.

Targeting post-transcriptional dysregulation of tumor suppressors represents a new frontier in cancer therapy. Here, we identify the alternative polyadenylation (APA) regulator NUDT21 as a pivotal therapeutic target in oral squamous cell carcinoma (OSCC). NUDT21 is highly upregulated, correlating strongly with poor survival and advanced clinical stage. We outline a pathogenic mechanism whereby NUDT21 drives this phenotype by forcing a network of tumor suppressor transcripts, notably PTEN, into translationally-repressed, long-3'UTR isoforms. To therapeutically "re-engineer" this APA switch, we design a "Nano-APA-editor." This platform features an HMSN core with an sgRNA-NUDT21 payload and a hierarchical targeting strategy: a cancer-educated dendritic cell (DC) membrane for biomimetic camouflage and homotypic affinity, "gated" by a TA-aptamer for final precision. This system enables potent and selective NUDT21 silencing, driving a shift toward short-3'UTR isoforms. Consequently, the Nano-APA-editor effectively reinstates PTEN and associated suppressors and inhibits multiple malignant phenotypes in vitro. In an orthotopic OSCC model, it demonstrates profound tumor regression, outperforming conventional chemotherapy (PTX) with excellent biocompatibility. In vivo analysis confirmed target engagement (NUDT21-down) and functional restoration (PTEN-, WEE1-, TGF-&#x3b2;-up). This work validates a "post-transcriptional re-engineering" strategy, executed by a logically designed nanoplatform, as a powerful and safe modality for precision gene therapy.

Humans↗

State-of-the-art therapeutics: marginal-zone lymphoma.

Marginal-zone lymphomas comprise the mucosa-associated lymphoid tissue (MALT) type (extranodal marginal-zone lymphoma [EMZL]), the nodal marginal zone B-cell lymphoma (NMZL) and the splenic MZL (SMZL). EMZL is relatively common, whereas the remaining two entities are relatively rare disorders. EMZL, especially in its gastric localization, is the most studied MZL, and there are many data both on the underlying genetic lesions and on the role of infectious agents. These data have determined unique approach among all other lymphoma subtypes: the possibility of treating a subset of patients with antibiotics alone as first line of treatment. Indeed, there is compelling evidence that histologic regressions can be achieved in most gastric MALT lymphomas by eradicating Helicobacter pylori infection. However, molecular follow-up studies showed the persistence of the malignant clone in half of the cases in histologic remission after antibiotic treatment and transient, either histologic or molecular, relapses have been reported, too. Hence, a careful long-term follow-up is mandatory after antibiotic treatment. Radiotherapy, chemotherapy, anti-CD20 monoclonal antibodies are effective alternative therapies. The precise role of surgical resection should be redefined in view of the encouraging results of conservative approaches. Differently from EMZL, both SMLZ and NMZL often present with disseminated disease at diagnosis. The therapeutic approach comprises splenectomy, for SMZL, and chemotherapy, but with no consensus about the best treatment. This review addresses the current knowledge on the clinical features and therapeutic approaches for the individual MZLs.

Anti-Bacterial Agents↗

[Learning from the studies of twitcher mouse].

Twitcher mouse is a naturally occurring mouse model for human Krabbe disease, a lysosomal galactosyl-ceramidase deficiency. Therefore, this mouse provides us an excellent experimental model for studying the pathogenesis and effective therapies for Krabbe disease. First, we succeeded to clone cDNA of human galactosylceramidase from lymphocytes, and determined its sequence. Consequently, many mutations of Krabbe disease have been discovered. For the trial of gene therapy for twitcher mouse, a recombinant retrovirus vector containing human galactosylceramidase cDNA was constructed and targeted to bone marrow cells ex vivo. These cells were transplanted intraperitoneally into twitcher neonates. This protocol resulted in slightly better weight gain and increase in the enzymatic activity in the peripheral nerve in the gene therapy group, but the survival period was prolonged. These results suggest that the efficacy of viral transfection is critical for the gene therapy. In addition, in order to understand the pathogenesis of demyelinating process and to evaluate the gene therapy more precisely, we examined the pathophysiology of oligodendrocytes and their related cells in the nervous system of twitcher mouse. We introduced pi-glutathione-S-transferase immunostaining for the specific identification of oligodendrocytes. Using this method, the oligodendrocytes with multiple varicose processes were recognized in the early stages. With the progression of the disease, these cells became shrunk showing the ultrastructural and biochemical characteristics of apoptosis. This may provide a key to the future treatment of Krabbe disease.

Animals↗

Continuous emergency department monitoring of arterial saturation in adult patients with respiratory distress.

Continuous measurement of arterial oxygen saturation (SaO2) using pulse oximetry has become a common monitoring and management technique in critically ill hospitalized patients. To determine the impact of SaO2 monitoring on emergency patient management, we conducted a prospective uncontrolled clinical trial on 40 adult patients presenting to the emergency department with acute respiratory illness, such as emphysema, asthma, or pulmonary edema. Recorded data included hemograms, arterial blood gases, subsequent therapy, and response to treatment. Additionally, the "early warning" capability of SaO2 monitoring was analyzed by recording the severity and outcome of hypoxemic events during treatment. Mean duration of usage for the 40 oximeters in the ED was 1.8 hours; all probes functioned reliably over a wide range of systolic pressures (80 to 206 mm Hg), heart rates (40 to 180 beats per minute), and hematocrits (20% to 58%). There was good correlation between simultaneous pulse oximeter values and both directly measured SaO2 (r = 0.95) and saturations derived from measured arterial PaO2 (r = 0.94). The device detected several otherwise unrecognized drops in arterial saturation that were confirmed by laboratory analysis. Other clinical situations in which the pulse oximeter was found useful in the ED are reviewed. We conclude that continuous measurement of SaO2 can improve the monitoring of ED patients, increase the precision of therapy, detect hypoxemia during intubation, suctioning, and other treatments, and detect clinically unsuspected changes in arterial oxygenation.

Adult↗

Commissioning and quality assurance of an optically guided three-dimensional ultrasound target localization system for radiotherapy.

Recently, there has been proliferation of image-guided positioning systems for high-precision radiation therapy, with little attention given to quality assurance procedures for such systems. To ensure accurate treatment delivery, errors in the imaging, localization, and treatment delivery processes must be systematically analyzed. This paper details acceptance tests for an optically guided three-dimensional (3D) ultrasound system used for patient localization. While all tests were performed using the same commercial system, the general philosophy and procedures are applicable to all systems utilizing image guidance. Determination of absolute localization accuracy requires a consistent stereotactic, or three-dimensional, coordinate system in the treatment planning system and the treatment vault. We established such a coordinate system using optical guidance. The accuracy of this system for localization of spherical targets imbedded in a phantom at depths ranging from 3 to 13 cm was determined to be (average +/- standard deviation) AP = 0.2 +/- 0.7 mm, Lat = 0.9 +/- 0.6 mm, Ax = 0.6 +/- 1.0 mm. In order to test the ability of the optically guided 3D ultrasound localization system to determine the magnitude of an internal organ shift with respect to the treatment isocenter, a phantom that closely mimics the typical human male pelvic anatomy was used. A CT scan of the phantom was acquired, and the regions of interest were contoured. With the phantom on the treatment couch, optical guidance was used to determine the positions of each organ to within imaging uncertainty, and to align the phantom so the plan and treatment machine coordinates coincided. To simulate a clinical misalignment of the treatment target, the phantom was then shifted by different precise offsets, and an experimenter blind to the offsets used ultrasound guidance to determine the magnitude of the shifts. On average, the magnitude of the shifts could be determined to within 1.0 mm along each axis.

Equipment Failure Analysis↗

Tomotherapy.

Tomotherapy is delivery of intensity-modulated, rotational radiation therapy using a fan-beam delivery. The NOMOS (Sewickley, PA) Peacock system is an example of sequential (or serial) tomotherapy that uses a fast-moving, actuator-driven multileaf collimator attached to a conventional C-arm gantry to modulate the beam intensity. In helical tomotherapy, the patient is continuously translated through a ring gantry as the fan beam rotates. The beam delivery geometry is similar to that of helical computed tomography (CT) and requires the use of slip rings to transmit power and data. A ring gantry provides a stable and accurate platform to perform tomographic verification using an unmodulated megavoltage beam. Moreover, megavoltage tomograms have adequate tissue contrast and resolution to provide setup verification. Assuming only translational and rotational offset errors, it is also possible to determine the offsets directly from tomographic projections, avoiding the time-consuming image reconstruction operation. The offsets can be used to modify the leaf delivery pattern to match the beam to the patient's anatomy on each day of a course of treatment. If tomographic representations of the patient are generated, this information can also be used to perform dose reconstruction. In this way, the actual dose distribution delivered can be superimposed onto the tomographic representation of the patient obtained at the time of treatment. The results can be compared with the planned isodose on the planning CT. This comparison may be used as an accurate basis for adaptive radiotherapy whereby the optimized delivery is modified before subsequent fractions. The verification afforded tomotherapy allows more precise conformal therapy. It also enables conformal avoidance radiotherapy, the complement to conformal therapy, for cases in which the tumor volume is ill-defined, but the locations of sensitive structures are adequately determined. A clinical tomotherapy unit is under construction at the University of Wisconsin.

Dose Fractionation, Radiation↗

Effect of serum albumin on free fractions of phenobarbital and valproic acid in patients with convulsive seizures.

The free fractions of phenobarbital and valproic acid were assayed with Free-Level system I (Syva) and by an enzymatic immunoassay technique (EMIT) in 186 patients under chronic anti-convulsant therapy at precisely 2 hrs after they had taken the medicine at breakfast. The free fractions of PB ranged from 49 to 53% in monopharmacy and from 50 to 55% in polypharmacy. Those of VPA ranged from 10 to 12% in monopharmacy and from 8 to 11% in polypharmacy. The regression lines of the free fractions in PB monopharmacy and PB polypharmacy against serum albumin concentration indicated a negative correlation. There was no difference between the free fractions in PB monopharmacy and polypharmacy at the same albumin concentration. The regression lines of the free fractions in VPA monopharmacy and polypharmacy against serum albumin concentration indicated a negative correlation. The free fractions of VPA did not vary under a total VPA concentration of 80 micrograms/ml, while those of VPA above a total VPA concentration of 90 micrograms/ml increased with the total concentration, in the monopharmacy groups. On the other hand, free fractions of VPA in the polypharmacy groups did not vary with the total VPA concentration.

Adolescent↗

Clinical Actionability of Genetic Findings in Cerebral Palsy: A Systematic Review and Meta-Analysis.

IMPORTANCE: Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated. OBJECTIVE: To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies. DATA SOURCES: Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n&#x2009;=&#x2009;1345) or research (n&#x2009;=&#x2009;496) cohorts of CP were analyzed. A systematic literature review for evidence of effective therapies for specific genetic etiologies was performed. STUDY SELECTION: Nonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included. DATA EXTRACTION AND SYNTHESIS: Literature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach. MAIN OUTCOMES AND MEASURES: Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety and practicality of the intervention, and anticipated intervention efficacy on a scale from 0 to 3. RESULTS: Of 1841 patients with CP who underwent exome sequencing, 502 (27%) had pathogenic or likely pathogenic variants related to their phenotype. A total of 243 different genes were identified. In 1841 patients with identified genetic etiologies of CP, 140 (8%) had a genetic etiology classified as actionable, defined as prompting a change in clinical management. Also identified were 58 of 243 genes with pathogenic or likely pathogenic variants with actionable treatment options: 16 targeting the primary disease mechanism, 16 with specific prevention strategies, and 26 with specific symptom management. The level of evidence was also graded according to ClinGen criteria; 45 of 101 interventions (44.6%) had evidence class D or below. The potential interventions have clinical utility with 98 of 101 outcomes (97%) being moderate-high severity if left untreated and 63 of 101 interventions (62%) predicted to be of moderate-high efficacy. Most interventions (72 of 101 [71%]) were considered moderate-high safety and practicality. CONCLUSIONS AND RELEVANCE: The findings indicate that actionable genetic findings occurred in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety and practicality indicates moderate-high clinical utility of these genetic findings. Genetic sequencing can identify precision medicine interventions that provide clinical benefit to individuals with CP. The relatively limited evidence base underscores the need for additional research.

Humans↗

Comparison of a standard and a sensitive thromboplastin in monitoring low intensity oral anticoagulant therapy.

The greater precision in prothrombin time monitoring obtained using thromboplastins with low international sensitivity index (ISI) values are believed to result in improved patient care. The authors conducted a blinded prospective study of 84 random patients on low-intensity warfarin therapy who were monitored with either a sensitive (ISI, 1.3) or standard (ISI, 1.9) thromboplastin. For the patients monitored with standard and sensitive thromboplastins, respectively, no difference was found in the degree of anticoagulation (standard thromboplastin mean INR, 2.4 vs. 2.5, P = .37; sensitive thromboplastin mean INR, 2.6 vs. 2.6, P = .74; mean daily warfarin dose, 5.1 vs. 4.7 mg, P = .28) or efficacy (warfarin dosage adjustments, 117 vs. 116; clinic visits, 362 vs. 378; percentage of therapeutic INR determinations, 47% vs. 48%). In addition, no difference was found in bleeding prevalence or severity (.22 vs. .27 events per person-year observation). The authors concluded that monitoring anticoagulant therapy in the INR range of 2-3 with a standard thromboplastin may be comparable to monitoring with a more sensitive thromboplastin with respect to efficacy, safety, and degree of anticoagulation achieved.

Administration, Oral↗

Improvement of image quality in megavoltage computed tomography with second generation scanning mode.

Megavoltage computed tomographic (CT) scanning is a topic of interest in precision radiation therapy. It is useful in verifying and improving the accuracy of the patient's positioning. For this purpose, we developed a third generation mode megavoltage CT scanner. However, insufficient spatial resolution limits its clinical usefulness. A second generation mode megavoltage scanner using a turntable has been newly developed to investigate whether improvements in spatial sampling could result in image quality high enough for clinical use. Scanning is composed of 11 rotations and 12 translations of the table. The scanning beam is a 3 MV X-ray, and the detector consists of 75 elements of cadmium tungstate crystals combined with photodiodes. A spatial resolution of 0.5 mm and contrast resolution of approximately 5% were obtained. The image quality is inferior to that of conventional diagnostic CT scanners, but is estimated to be adequate for some clinical applications of radiation therapy. Based on the satisfactory results, a new third generation megavoltage CT scanner is under investigation.

Humans↗