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PubMed2025

Integration of Genetic Information to Improve Brain Age Gap Estimation Models in the UK Biobank.

Neurodegeneration occurs when the body's central nervous system becomes impaired as a person ages, which can happen at an accelerated pace. Neurodegeneration impairs quality of life, affecting essential functions, including memory and the ability to self-care. Genetics play an important role in neurodegeneration and longevity. Brain age gap estimation (BrainAGE) is a biomarker that quantifies the difference between a machine learning model-predicted biological age of the brain and the true chronological age for healthy subjects; however, a large portion of the variance remains unaccounted for in these models, attributed to individual differences. This study focuses on predicting the BrainAGE more accurately, aided by genetic information associated with neurodegeneration. To achieve this, a BrainAGE model was developed based on MRI measures, and then the associated genes were determined with a Genome-Wide Association Study. Subsequently, genetic information was incorporated into the models. The incorporation of genetic information yielded improvements in the model performances by 7% to 12%, showing that the incorporation of genetic information can notably reduce unexplained variance. This work helps to define new ways of determining persons susceptible to neurological aging decline and reveals genes for targeted precision medicine therapies.

Humans↗

PubMed2004

Pathology of melanocytic lesions: new, controversial, and clinically important issues.

Patients with primary cutaneous melanocytic lesions rely not only on the knowledge, skills, and experience of their treating clinician but also on the fundamentally important input of their pathologist for accurate diagnosis and appropriate management. Free and precise communication between pathologists and surgeons is important and undoubtedly improves patient care, particularly when managing difficult or complicated cases. To provide both patient and surgeon with the necessary information they require to make the most appropriate decisions, the pathology report should include all pathologic factors that are important in determining the patient's prognosis and management. Use of a synoptic format for pathology reporting of melanomas can facilitate this. Recent studies have established that the dermal mitotic rate of a primary cutaneous melanoma is a major prognostic determinant, and have shown that its assessment and that of other important histopathologic prognostic variables are reproducible between pathologists. Sentinel node (SN) biopsy has provided a minimally invasive procedure that can accurately predict the regional node status of melanoma patients. It is well demonstrated that the use of immunohistochemical stains assists in the detection of melanoma micrometastases in SNs, although it remains unclear which is the optimal pathologic protocol for SN evaluation and whether there is a role for reverse transcriptase polymerase chain reaction (RT-PCR) in SN assessment. False negative SN biopsies may occur as a result of errors in lymphatic mapping or sentinel lymphadenectomy, or because of a deficiency in the process of histopathologic evaluation. Recent studies have shown that the likelihood of non-SN involvement when the SN is positive correlates mostly with the extent of SN involvement, in particular the tumor penetrative depth (defined as the maximum distance of melanoma cells from the inner margin of the SN capsule). It appears that assessment of the micromorphometric features of positive SNs may be useful in predicting which patients have a low probability of having metastatic tumor in non-SNs, and therefore in selecting patients who potentially may be spared a completion lymph node dissection. It is likely that future advances in our understanding of the molecular biology of melanoma will provide new insights into tumor classification, improve diagnostic accuracy and prognostic ability, and lead to the development of more precisely targeted therapies.

Biopsy, Fine-Needle↗

PubMedDate not supplied

31P NMR spectroscopy of a xenografted hypopharynx carcinoma: effects of tumor growth and treatment with cisplatin on the tumor phosphorus metabolism, histology and cytokinetics.

A xenografted hypopharynx carcinoma growing subcutaneously in nude mice was studied by in vivo 31P NMR spectroscopy during uninfluenced growth and following treatment with cisplatin (CDDP). Parallel to the NMR experiments, the cytokinetic and histological changes in the tumor were investigated. The most significant change in the growing tumor was a decline in the level of phosphocreatine (PCr), whereas the tumor pH did not change. Following treatment with CDDP (4, 8 and 12 mg/kg), a dose-dependent decrease in the level of phosphomonoesters (PME) took place, whilst no dose dependence could be observed for the increase of PCr. the pH shifted to alkaline only after administration of the highest CDDP dose. Tumor cytokinetics revealed a cell arrest at the G1/S boundary 24 h after chemotherapy. At this time, the histological sections showed a dilatation of capillaries, whereas first necroses appeared on day 3. The proliferative activity of the tumor showed a sharp decline 24 h after CDDP application, followed by a revival of cell proliferation that was proportional to the dose applied between days 5 and 7. This increase in proliferative activity was paralleled by a marked increase in the PME/phosphodiesters ratio. Thus, in the tumor investigated the PME were the best indicators of tumor response to therapy. A precise correlation between the cytokinetic data and the re-energization of the tumor was not possible because histological changes, which may contribute to improved tumor energy status took place at the same time.

Animals↗

PubMedDate not supplied

Adjuvant systemic therapy for early breast cancer.

Systemic therapy (chemotherapy or hormonal therapy) as an adjuvant to modalities of local control is now an integral part of the management of almost all patients with primary breast cancer metastatic to axillary lymph nodes. In addition, recent data suggest an expanding role for such treatments in patients without axillary involvement. Although some node-negative patients should probably not receive adjuvant therapy, the precise criteria to be used for selection are still under active discussion in the literature. Of the two types of systemic treatment, it is generally accepted that chemotherapy is indicated for premenopausal patients and that tamoxifen is useful for postmenopausal patients whose tumors contain estrogen or progesterone receptors. The recent analysis of several studies has suggested that chemotherapy may add to the benefits of tamoxifen in some postmenopausal patients as well. A possible role for tamoxifen in younger patients is being evaluated. For patients at relatively low risk of systemic relapse (i.e., those with zero to three involved axillary lymph nodes), no chemotherapy regimen has yet shown an advantage over 6 months of cyclophosphamide, methotrexate and 5-fluorouracil. For patients at high risk, however, doxorubicin-based regimens have demonstrated benefits. High-dose chemotherapies, some involving autologous bone marrow support, are being investigated for patients with ten or more involved nodes who are at very high risk of the eventual development of stage IV disease.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Evaluation of a prototype steerable angioscopic laser catheter in a canine model: a feasibility study.

To overcome some of the persisting technical problems related to laser angioplasty, a new catheter was designed and investigated in a canine model. This 5F catheter contained a deflectable tip for steerability, an angioscope, and a laser fiber. Catheter steerability, angioscopic function, and the effects of a 480 nm flash lamp pumped pulsed dye laser on normal canine vessel walls were evaluated. Steering, angioscopic guidance, and application of laser energy were easy and fast to perform in a bloodless vessel segment. Maintaining a condition of bloodlessness at the target site, critical to angioscopic guidance, proved to be the most difficult part in this prototype evaluation. It was noted that the 480 nm pulsed dye laser did not cause macroscopic alterations or perforations to the normal vessel wall. We conclude that a relatively simple deflection mechanism of a small-caliber angioscope provides the kind of aiming ability requisite for precise endovascular therapy. Complete bloodlessness of the area is necessary for both viewing and laser ablation at 480 nm.

Angioplasty, Balloon, Laser-Assisted↗

PubMed1998

[Fungal infection].

Untreated dermatological mycoses are easy to diagnose. Once treatment with corticosteroids has been initiated the diagnosis of a mycosis can be difficult. In the immunosuppressed patient (AIDS patients) typical dermatological manifestations can be lacking. Systemic antimycotic therapy requires precise detection of the pathogen concerned. Mistakes still made in surgical practice are incision of a tumour in the case of tinea profunda and the extraction of nails affected by fungi. In the healthy person yeasts are transient organisms present in the mouth and intestinal tract in contrast, the mouth and intestinal tract of patients in risk make up a reservoir of candida infection that can affect the internal organs. Cryptococcosis and aspergillosis are inhaled mycoses. Factors predisposing to mycoses influence the duration and the outcome of the course of illness. The most important of these factors in surgical practice is the immunosuppression. Systemic mycoses are difficult to recognize. In many cases organ mycoses can be diagnosed by CT. Continuous investigations of diagnostic cultures and serological tests can contribute to the diagnosis. Only cryptococcosis can be ascertained early by specific antigen demonstration in the serum. For this reason continuous serological testing for cryptococci is essential in AIDS patients.

AIDS-Related Opportunistic Infections↗

PubMed2007

[Perioperative coagulation management controlled by thrombelastography. Clinical implementation illustrated by reference to a case of acquired coagulopathy following aortic stab injury].

Uncontrolled bleeding is one of the main reasons for a lethal outcome of severe trauma. Loss, consumption and dilution of clotting factors and platelets induce a complex acquired coagulopathy. Beside surgical control of bleeding, early and precise coagulation therapy is essential for successful treatment. We report on a patient whose life-threatening bleeding and perioperative coagulopathy after a knife injury to the aorta was successfully treated by surgical control of the bleeding and subsequent targeted coagulation therapy with factor concentrates and fresh-frozen plasma. The coagulopathy was diagnosed and managed by means of bed-side thrombelastography.

Adult↗

PubMed2004

Proximal renal tubular dysfunction in primary distal renal tubular acidosis.

Low-molecular-weight (LMW) proteinuria has been described in patients with primary distal renal tubular acidosis (dRTA). However, other proximal renal tubular dysfunctions have rarely been reported. In this report we describe reversible and multiple proximal renal tubular cell dysfunctions in a patient with dRTA. A 4-year-old girl was admitted to our hospital for investigation of short stature and proteinuria. Laboratory studies revealed a hyperchloremic metabolic acidosis without aciduria, hypokalemia, hypouricemia with uricosuria, hypercalciuria, LMW proteinuria, phosphaturia, and generalized aminoaciduria. The patient was diagnosed as having dRTA with multiple proximal renal tubular dysfunctions. All proximal renal tubular dysfunction subsided 1.5 years after starting alkali therapy. The precise pathogenic mechanisms underlying the development of multiple proximal renal tubular dysfunctions in dRTA remained unclear. However, proximal renal tubular endosomal dysfunction resulting from a profound intracellular acidosis caused by vacuolar H+-ATPase dysfunction or hypokalemic nephropathy might contribute to the development of proximal renal tubular dysfunctions in patients with dRTA.

Acidosis, Renal Tubular↗

PubMed2001

Medium-chain triglyceride-rich enteral nutrition is more effective than low-fat enteral nutrition in rat colitis, but is equal in enteritis.

BACKGROUND: Although enteral nutrition (EN) therapy for Crohn's disease has been confirmed to be as effective as steroid therapy, the precise mechanism responsible for the effects of EN remains unclear, although some of the therapeutic effects of EN are believed to be due to a low dietary fat content. In order to elucidate the influence of fat in EN, it is important to investigate not only the quantity of fat, but also the source of the fat. METHODS: We compared two enteral nutritional formulae: Elental (Ajinomoto) (elemental diet; ED), which contains only 1.5% fat, provided as long-chain triglycerides (LCT), versus Twinline (Snow Brand Milk Products) (TL), which contains a high percentage of fat (20.4%), provided mainly as medium-chain triglycerides (MCT). These formulae were tested on rat enteritis and rat colitis induced by trinitrobenzene sulfonic acid (TNBS). RESULTS: Both ED and TL reduced the manifestations of enteritis. TL had a stronger anti-inflammatory effect than ED for colitis. TL also had nutritional advantages as compared with ED, as shown by the total serum protein in the TL group being significantly higher than that in the ED group. CONCLUSION: The results indicate that intraluminal MCT is suitable as a fat energy source during intestinal inflammation in rats. We suggest that Twinline may be more useful to improve nutritional status and to reduce the mucosal inflammation in rat colitis, but that Twinline is equal in effect to Elental for rat enteritis.

Animals↗

PubMed2005

Treatment strategies in movement disorders.

Strategies in treatment of movement disorders are discussed with the illustration of three patients with dystonia. Pharmacotherapy can be applied in two ways: (1) a precise directed therapy, or (2) a 'shotgun' approach. Botulinum toxin is successfully injected in focal and segmental forms of movement disorders. Stereotactic neurosurgery can be considered in pharmacotherapy-resistant dystonias, but also in other forms of movement disorders. Intrathecal baclophen treatment by continuous infusion is only indicated in severe forms of spasticity.

Adult↗

PubMed1987

Two forms of vasoconstriction in systemic hypertension.

Clinical, pharmacologic and biochemical evidence characterizes essential hypertension as a heterogeneous spectrum of pathophysiologic substances rather than the single entity it has long been presumed to be. Although the causes of essential hypertension remain obscure, 2 different mechanisms for long-term vasoconstriction that sustain diastolic hypertension in the experimental and clinical forms of primary aldosteronism and renovascular hypertension can also be identified and quantified among patients with essential hypertension. The first mechanism is renin independent, requires antecedent sodium retention and appears related to abnormal membrane transport of calcium. This vasoconstriction is identified by low plasma renin and ionized calcium and is correctable by sodium depletion or calcium channel or alpha blockade. The second vasoconstrictor mechanism is renin mediated and involves an increase in cytosolic calcium. This mechanism is quantifiable by the plasma renin level or the hypotensive response to an antirenin-system drug (converting enzyme inhibitor, beta blocker or saralasin). Depending on the state of sodium balance, these 2 mechanisms contribute reciprocally to maintenance of arteriolar tone in experimental models, in both normal and hypertensive people, and in patients with congestive heart failure. In these situations, at the extremes of the range of plasma renin values, one or the other mechanism predominates, whereas in the medium range of renin values both mechanisms can be operative. These interrelations provide a basis for applying more precisely tailored therapy and for stratifying patients pathophysiologically for further study.

Arteries↗

PubMed1996

Variation in prostate position relative to adjacent bony anatomy.

PURPOSE: In prostatic cancer, the prostate cannot be discerned from a portal image. Setup information is, therefore, obtained from bony anatomy. To perform high-precision conformal therapy, knowledge about the variation in distance between the prostate and adjacent bony anatomy during an external radiotherapy treatment is mandatory. This report is concerned with that variation. METHODS AND MATERIALS: Nine patients previously treated interstitially for prostatic cancer with implantation of 125I seeds, agreed to cooperate in a study. They underwent a number of simulations of external radiotherapy treatment. After the first patient setup, this setup was repeated five times for each patient as if the patient was treated by external radiotherapy. Simulator radiographs were made from each setup in the anterior-posterior and left-right lateral directions. The seeds were clearly visible in the simulator film images and reflect the position of the prostate. No bladder instructions were given and the filling of the rectum was not quantified. RESULTS: Variation in distance between the prostate and the bony anatomy was measured and is presented in one standard deviation of the normal distribution function: 0.8 mm lateral, 1.5 mm ventrodorsal, and 1.7 mm craniocaudal. CONCLUSIONS: The bone structure of the pelvis reflects fairly well the position of the prostate. The prostate is least mobile in a lateral direction and most mobile in the craniocaudal and ventrodorsal directions.

Brachytherapy↗

PubMed2026

Biomimetic mesoporous silica nanosphere ameliorate experimental autoimmune uveitis by delivering sCD83.

Autoimmune uveitis (AU) is an autoimmune disease that may lead to blindness, but there are currently no precise targeted therapies for its prevention and treatment. Dendritic cell (DC) is key cell involved in the pathogenesis of AU, and specific regulation of their state can help improve AU. In this work, mesoporous silica nanospheres were loaded with the immunomodulator soluble CD83 (sCD83) and subsequently camouflaged with dendritic cell (DC) membranes to fabricate the nanocarrier DCM@MSN/sCD83 for treating experimental autoimmune uveitis (EAU). Research results show that DCM@MSN/sCD83 effectively alleviated the symptoms of uveitis in EAU, reduced the proportion of CD4+CD25-T cell/CD4+CD25+T cell and the percentage of DC in the eyes and cervical lymph nodes. It also decreased the expression of STING in Müller cell. Furthermore, the efficacy of DCM@MSN/sCD83 was found to be primarily targeting DC, and promoted the expression of IL-10 and TGF-β1 in DC by activating the phosphorylated HIF/STAT3 pathway, to induce the production of CD4+CD25+ T. This effect is superior to nanomedicine loaded with dexamethasone. Moreover，DCM enabled the nanocarriers to efficiently cross the blood-eye barrier and reach cervical lymph nodes, thereby regulating peripheral immunity. This research indicate that cell membrane-modified nanoparticles targeting homologous cells can effectively improve treatment efficiency and duration, which is potential therapy strategy for uveitis.

Animals↗

PubMed2004

New concepts in reactive oxygen species and cardiovascular reperfusion physiology.

Increasingly complex behavior of free radicals and reactive oxygen species (ROS) are noted within biological systems. Classically free radicals and ROS were considered injurious, however current mechanisms describe both protective and deleterious effects. A burst of ROS has been well described with the first moments of reperfusion and is associated with injury. However ROS can also be protective as signal preconditioning protection and induce stress responses that lead to survival. ROS generation is appreciated to occur during ischemia despite the low oxygen tension, from a likely mitochondria source, and ROS-induced ROS release may amplify its signal. The burst of ROS seen during reperfusion may originate from a different cellular source than during ischemia and is not yet fully identified. ROS and cellular redox conditions regulate a large number of vital pathways (energy metabolism, survival/stress responses, apoptosis, inflammatory response, oxygen sensing, etc). While cellular systems may demonstrate reperfusion injury, whole organ and animal models continue to report contradictory results on reperfusion injury and the role of antioxidants as a therapy. Collectively, these data may offer insight into why clinical trials of antioxidants have had such mixed and mostly negative results. Future antioxidant therapies are likely to be effective but they must become: more specific for site of action, not have deleterious effects on other signaling pathways, be targeted to a specific reactive oxygen species or cellular compartment, and be "time sensitive" so they deliver the correct therapy at precisely the correct time in ischemia and reperfusion.

Animals↗

PubMed2026

Thirty years of adjuvant therapy: From treating risk to treating residual disease.

Over the past three decades, adjuvant therapy for solid tumours has evolved from treatment based predominantly on anatomical recurrence risk towards strategies informed by tumour biology, treatment response, and molecular residual disease. Cytotoxic chemotherapy and endocrine therapy established the curative potential of postoperative systemic treatment, while targeted agents and immunotherapy expanded its efficacy across malignancies. However, matching a drug to tumour biology does not establish whether residual cancer remains, and many patients receive treatment despite having been cured by surgery alone. This Perspective examines the transition from empirical risk reduction towards selective intervention against residual disease. Response-adapted perioperative strategies provide a dynamic assessment of treatment sensitivity and support postoperative escalation or omission in defined settings. Circulating tumour DNA offers a complementary approach, but its strong prognostic value must be distinguished from evidence that biomarker-directed treatment improves outcomes. Contrasting findings from randomised trials demonstrate that neither de-escalation after a negative result nor escalation after a positive result can be generalised across clinical contexts. Future studies should integrate anatomical risk, tumour genomics, pathological response, and longitudinal molecular assessment while prioritising absolute benefit, mature survival outcomes, irreversible toxicity, patient-reported outcomes, and equitable access. They should also distinguish durable eradication from temporary suppression and evaluate treatment omission with the same rigour as intensification. Progress in adjuvant oncology should ultimately be measured by additional cures achieved with less avoidable harm, through the smallest effective intervention supported by validated evidence.

Adjuvant therapy↗

PubMed2004

Delivering DNA from photocrosslinked, surface eroding polyanhydrides.

Sustained delivery of DNA has the potential to enhance long-term gene therapy; however, precise control of a wide range of DNA release profiles may be needed. In this work, multifunctional anhydride monomers were photocrosslinked to produce hydrophobic, highly crosslinked polymer networks that degrade by surface erosion. Surface-eroding polymers can deliver molecules of a wide range of sizes at sustained, steady rates, which is advantageous for DNA delivery, where the high molecular weight may complicate control of the release profiles. When plasmid DNA was released from photocrosslinked polyanhydride matrices, DNA recovery was low (approximately 25%). Electrophoresis indicated that the plasmid DNA was released primarily in the relaxed and supercoiled forms, yet the relative fraction of released DNA in the supercoiled form decreased over time. To improve DNA recovery and reduce the damaging effects of polymer degradation, DNA was pre-encapsulated in alginate microparticles, which served as a temporary coating that quickly dissolved upon microparticle release from the polyanhydride matrix. As photocrosslinked polyanhydrides have highly predictable drug release profiles that depend on the polymer erosion rate and implant geometry and not on the entrapped molecule size, they can serve dual purposes in many biomaterial applications where structural support and drug release would be beneficial.

Alginates↗

PubMed2005

Upsetting the apple cart: a community anticoagulation clinic survey of life event factors that undermine safe therapy.

Anticoagulation therapy is a life-enhancing therapy for patients who are at risk for embolic events secondary to atrial fibrillation, valve replacement, and other comorbidities. Clinicians are motivated to decrease the amount of time that patients are either under- or over-anticoagulated, common conditions that decrease patient safety at either extreme. The primary purpose of this descriptive study was to examine the relationship between personal life event factors as measured by Norbeck's Life Events Questionnaire, core demographics such as age and income, and anticoagulation regulation. Although many factors affect anticoagulation therapy, the precise impact of life events, positive or negative, is unknown. The salient findings of this study (n = 202) showed a small, though statistically significant, inverse relationship (r = -0.184, P < .01) between negative life events and decreased time within therapeutic international normalized ratio. Total Life Event scores showed a statistically significant inverse relationship (r = -0.159, P < .05) to international normalized ratio time within therapeutic level. Lower income was inversely associated with higher negative Life Event scores (r = -0.192, P < .01). The findings demonstrate the need for strategies that address the potential impact of life events in conjunction with coexisting screening measures used in anticoagulation clinics. Implications for this study are limited by lack of methodology documenting concurrent social support factors and limitations of the research tool to reflect life event issues specific to outpatient seniors.

Adult↗

PubMed2026

"Updates on diagnostic and prognostic molecular biomarkers of CNS tumors".

The diagnosis and classification of central nervous system (CNS) tumors has undergone a paradigm shift over the past decade, evolving from a purely histology-based approach to an integrated framework that incorporates molecular and epigenetic features. This review summarizes recent updates in key genomic and epigenomic biomarkers across major CNS tumor categories, with a focus on their diagnostic, prognostic, and therapeutic implications. DNA methylation profiling has emerged as a valuable tool for tumor classification, subgrouping, and grading, complementing traditional histopathologic assessment. Across diffuse gliomas, newly characterized molecular alterations have refined grading criteria and clarified the boundaries between tumor types, including important caveats about the use of individual molecular features as sole diagnostic criteria. In ependymomas, medulloblastomas, atypical teratoid/rhabdoid tumors, meningiomas, pineal tumors, and embryonal tumors, methylation profiling now defines biologically and clinically meaningful subgroups that inform risk stratification and treatment selection. The emerging recognition of mismatch repair-deficient gliomas and fusion-driven tumor entities further underscores the expanding complexity of CNS tumor taxonomy. As molecular technologies continue to advance, the integration of genomic, epigenomic, histopathologic, and clinical data will be essential to improving diagnostic precision, guiding therapy, and ultimately enhancing patient outcomes.

Embryonal↗