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[New findings in the etiopathogenesis of ulcers and reevaluation of therapy].

The etiopathogenesis of ulcer disease is comprehensive and many experimental and clinical data failed to prove the primary cause of the disease. Although much has been learned concerning the pathophysiological mechanism which appear important in the development of ulcer disease, our present knowledge of the etiology of this disease is incomplete. Depression of the gastric acid secretion still remains the main treatment approach, although the cytoprotective drugs are interesting therapeutic challenge. Etiology of the peptic ulcer disease is not solved yet, but the defense mechanisms of the gastric mucosa are much more clear what will lead to better understanding of the defense mechanisms in the gastric cancer. Omeprazole is an interesting new drug healing peptic ulcer in almost 100% of the patients. A philosophic question may be asked: "Do we need to know the etiology of the disease in order to be able to treat it properly?" Omeprazole heals the ulcer and, in fact, we do not know its etiology. In the cost-benefit ratio, the most widely used drugs are still H2-receptor antagonists and sucralfate, and omeprazole is reserved for the patients with resistant ulcer disease, Zollinger-Ellison syndrome and severe reflux esophagitis.

Humans↗

New findings on the genetic influences on alcohol use and dependence.

PURPOSE OF REVIEW: Alcohol dependence is a complex disorder with a well documented highly hereditary nature. This article reviews the recent advances in our understanding of the direct and indirect genetic influences on alcohol use and dependence. RECENT FINDINGS: Recent findings can be summarized as follows: (a) twin studies have defined and estimated the risks of general and specific alcohol-related vulnerabilities. (b) Linkage studies have provided largely inconsistent findings, though several chromosomal regions have been implicated. (c) Quantitative trait loci analyses in animals have identified that the Mpdz gene predisposes to alcohol dependence and withdrawal. (d) Examination of family-based samples has identified several genes including GABRA2 and CHRM2 thought to be associated with alcohol dependence. SUMMARY: Despite great advances in understanding of genetic vulnerability in alcohol use disorders, only two gene complexes, ADH and ALDH2, have been identified as having defined effects on alcohol use and liability to dependence in humans. New genes associated with increased risks for the disorder will certainly be added to this list in the near future. Neurobiological analyses of the effects of these genes will surely contribute to further understanding of the cause of alcohol dependence and the interindividual differences in risks.

Alcoholism↗

[New findings in orthopedic pathology].

The term orthopedic pathology refers to bone- and joint-affecting diseases which are important for the orthopedic surgeon. In the report presented here, emphasis is placed on the membrane-associated proteolysis, which is essential for the degradation of the extracellular matrix. Matrix-degrading processes play a role not only in arthrosis but also in rheumatoid arthritis. Moreover, they are strongly associated with the problem of loosening of protheses, which is of utmost importance for the orthopedic surgeon. In these processes, major roles are played by the plasminogen activator system, plasmin, different matrix metalloproteinases, including the membrane type matrix metalloproteases and different cathepsins. A deeper insight into the function of these proteins and their influence on the matrix degradation in joint diseases will open the way for new diagnostic and therapeutic strategies. Investigations into a large number of chondrosarcomas have shown that for this type of bone lesions, urokinase plasminogen activator and cathepsin B are prognostic parameters that are independent of the differentiation grade. Also, in this context, investigations into the membrane-bound proteases will be of great practical and diagnostic value.

Arthroplasty, Replacement↗

[New findings in the study of schizophrenia].

The paper gives a survey on the results of research on etiology and course of schizophrenia. The results of etiological research have not, as yet, progressed so far as to provide measures of primary prevention, whereas the results of research into the course of schizophrenia have already led to practical consequences for therapy resp. rehabilitation of schizophrenic patients. In future, with a decrease in the number of long-stay hospitalizations, the number of schizophrenic out-patients, resp. of prolonged periods of out-patient treatments will increase accordingly. Thus hitherto known influencing factors and treatment strategies will also be due to change. According to present knowledge, etiology, psychopathology, course and outcome of schizophrenia represent a very complex and variable, multifactorially initiated process, in which illness-related and environment-related factors concur. Drafts of new models and instruments for the assessment of this process and subsequent disabilities as well as methodological difficulties herewith are reported.

Diagnosis, Differential↗

New findings in beta-lactam and metronidazole resistant Bacteroides fragilis group.

Beta-lactam antibiotics and 5-nitroimidazoles have been extensively used against anaerobic bacteria. However, antibiotic resistance is increasingly common among anaerobic Gram-negative bacilli. The classical mechanisms of resistance to beta-lactams are, (1) production of beta-lactamases; (2) alteration of penicillin-binding proteins (PBPs); and (3) changes in outer membrane permeability to beta-lactams. The 5-nitroimidazole molecule is a prodrug whose activation depends upon reduction of the nitro group in the absence of oxygen. Decreased uptake and altered reduction are believed to be responsible for metronidazole resistance. Five nim genes (A, B, C, D and E) have been identified in Bacteroides fragilis group spp. that confer resistance to 5-nitroimidazole antibiotics. Knowledge of the status and the mechanisms of resistance is critical for both the selection of antimicrobial therapy and the design of new antimicrobial agents. The purpose of this article is to review the mechanisms for and the prevalence of beta-lactam and metronidazole resistance in strains belonging to the B. fragilis group.

Anti-Bacterial Agents↗

New findings on transcription regulation across different HIV-1 subtypes.

Transcriptional activation of gene expression in HIV-1 is controlled by the interaction of sequence-specific transcription factors with the long terminal repeat (LTR) of the provirus. The identification and characterization of cellular proteins involved in the process has provided a basic understanding about both general eukaryotic and HIV-1 proviral transcription regulation. The HIV-1 epidemic is expanding worldwide with an increasing number of distinct viral subtypes as well as intersubtype recombinant viruses. LTR-specific sequence variability among different HIV-1 variants could affect LTR binding to cellular and/or viral factors, influencing the extent of transcription. In vitro assays have demonstrated subtype-specific functional differences between the LTR regions of distinct HIV-1 subtypes. This observation could have consequences on the biology of the different HIV-1 clades and influence HIV-1 disease progression. Finally, the knowledge of the molecular mechanisms of transcription regulation events could help in the search for new compounds targeting the critical steps of viral transcription.

Anti-HIV Agents↗

Tissue interactions and antlerogenesis: new findings revealed by a xenograft approach.

Tissue interactions play a pivotal role in organogenesis. Here we describe a xenograft approach to investigate how heterotypic tissue interactions control antler formation in deer. Deciduous antlers grow from the apices of permanent protuberances, called pedicles. Histogenesis of pedicles depends on the antlerogenic periosteum (AP). Pedicles and growing antlers are made up of interior osseocartilage (a mixture of bone and cartilaginous tissue) and exterior skin. In a previous study we hypothesised that pedicle growth may result from mechanical interactions between the interior and exterior components whereas antler generation from a pedicle would involve molecules communicating between the interior and exterior components. To test this hypothesis, we subcutaneously transplanted AP of red deer (Cervus elaphus), either alone or with future pedicle skin, onto nude mice. The results showed that under the nude mouse skin, subcutaneously xenografted AP alone not only could form pedicle-shaped protuberances but also could differentiate into well-organised pedicle-like structures. The overlying mouse skin accommodated the expansion of the grafted AP by initial mechanical stretching and subsequent formation of new skin. Nude mouse skin was not capable of participating in antler tissue formation. However, grafted deer skin together with AP may have successfully rescued this failure after wounding, which highlights the necessity of the specificity of the overlying skin for antler tissue generation. Therefore, we conclude that it is the interaction between the antlerogenic tissue and the overlying skin that results in antlerogenesis: reciprocal mechanical interactions cause pedicle formation, whereas reciprocal instructive interactions induce first antler generation.

Animals↗

The treatment of advanced gastric cancer: new findings on the activity of the taxanes.

Globally, gastric cancer is one of the most common types of cancer and one of the most frequent causes of cancer-related death. Despite many advances in the diagnosis and treatment of this disease, the prognosis for gastric cancer remains poor, especially in more advanced stages. In metastatic disease, benefits in survival and quality of life have been demonstrated in patients with unresectable or metastatic gastric cancer receiving chemotherapy plus best supportive care versus best supportive care alone. The taxanes, which are among the most promising cytotoxic agents in clinical use, have shown encouraging activity in early-phase studies as single agents and in combination regimens in the treatment of advanced gastric cancer. Recently, interim results of a randomized phase III trial comparing the triplet of docetaxel, cisplatin, and 5-fluorouracil with a standard reference regimen of cisplatin and 5-fluorouracil were reported. Patients treated with the docetaxel-containing regimen had a statistically superior response rate and time to disease progression as well as a clinically significant prolongation of survival. This study underscores the importance of developing new therapeutic options for patients with advanced gastric cancer.

Antineoplastic Combined Chemotherapy Protocols↗

Feline retinal degeneration: clinical experience and new findings (1994-1997).

A retrospective case series of 26 cats with diffuse retinal degeneration is presented. The most common presenting complaints included bumping into objects, dilated pupils, and reluctance to jump. Ophthalmic examination findings were consistent with those reported in dogs with progressive retinal atrophy. Breed predilection of the Siamese cat was observed. Cats with primary retinal degeneration presented late in the clinical course of their disease, when vision loss was severe. Early symptoms such as night blindness and secondary ocular complications (i.e., cataract and retinal detachment), reported in dogs with progressive retinal degeneration, were not observed in this study. All cats showed excellent adaptive capabilities to blindness.

Animals↗

[New findings in type I diabetes].

The author present a review of contemporary views on the pathogenesis of type I diabetes, in particular with regard to recent research of European and non-European diabetelogical departments. In the aetiopathogenesis attention is drawn to genetic influences, external factor and stimuli, the importance of some virus groups (Picornidae, Mengo 2T virus, Coxsackie B5, cytomegaloviruses, congenital rubeola syndrome etc.). Special attention is paid to the autoimmune theory of type I diabetes, the importance of different types of anti- beta-cell antibodies, insulin antibodies, antibodies against protein 64-KD of the islets, pro-insulin antibody PAA, and other stimuli and interferences (oxidation stress, non-enzymatic glycosylation etc.). As to treatment, the author mentions immunosuppressive treatment (cyclosporin A, azathioprine, prednisone) and transplantation of the pancreas. The author presents his own experience with a group of 2040 diabetics; in a group of 253 juvenile diabetics he followed-up the development of micro- and macroangiopathic complications in the course of 25 years. He proved an increase of so-called late diabetic complications in particular vascular ones along with the lengthening period of diabetes, with advancing age during its clinical manifestation. In the conclusion the author draws attention to the importance of multi-centre studies and new laboratory techniques.

Diabetes Mellitus, Type 1↗

New findings on the Diels-Alder reactions. An analysis based on the bonding evolution theory.

Two Diels-Alder type reactions, i.e., normal electron demand (NED) between 1,3-butadiene (BD) and acrolein (Acr) and inverse electron demand (IED) between 2,4-pentadienal (PDA) and methyl vinyl ether (MVE), have been investigated using the bonding evolution theory (BET). BET combines topological analysis of the electron localization function (ELF) and catastrophe theory. Catalyst effect has been incorporated through Lewis acid BH3. The B3LYP hybrid HF/DFT method along with 6-31G(d), 6-311++G(d,p) basis sets have been used. All reactions yield two-stage mechanism and there is no topological evidence that they might be concerted with two bonds partially formed during transition structure. A formation of six-membered ring requires 10 (or 11) steps separated by two types of catastrophes: fold and cusp. The first "intermolecular" bond (C1-C6) is formed at 1.93, 1.92 A (NED) and 1.92, 1.97 A (IED). The six-membered ring is "closed" at 2.11, 2.13 A (NED) and 2.5, 2.6 A (IED) via formation of the second bond C4-C5. All reactions begin with "reduction" of C=C bonds to single C-C (cusp catastrophes). Subsequently, the nonbonding electron density is concentrated (fold catastrophes) on terminal C atoms. Finally the new bonds, C1-C6 and C4-C5, are established (cusp catastrophes). Both magnitude and regularity of the electron redistribution, happening during reactions enable us to distinguish two effects: (1) the "ring effect", where a large amount of electron density is regularly transferred from double C=C bonds to intermolecular regions and single C-C bonds, (2) the "side chain effect"--usually weaker and irregular--involving substituents' bonds. In the transition structure, well formed bonding basin V(C1,C6), is observed only for the PDA...BH3/MVE reaction. For other reactions only the nonbonding basins: V(C1) and V(C6), are found in the interaction region C1...C6.

Journal Article↗

New findings of Neurospora in Europe and comparisons of diversity in temperate climates on continental scales.

The life cycles of the conidiating species of Neurospora are adapted to respond to fire, which is reflected in their natural history. Neurospora is found commonly on burned vegetation from the tropic and subtropical regions around the world and through the temperate regions of western North America. In temperate Europe it was unknown whether Neurospora would be as common as it is in North America because it has been reported only occasionally. In 2003 and 2004 a multinational effort surveyed wildfire sites in southern Europe. Neurospora was found commonly from southern Portugal and Spain (37 degrees N) to Switzerland (46 degrees N). Species collected included N. crassa, N. discreta, N. sitophila and N. tetrasperma. The species distribution and spatial dynamics of Neurospora populations showed both similarities and differences when compared between temperate Europe and western North America, both regions of similar latitude, climate and vegetation. For example the predominant species in western North America, N. discreta phylogenetic species 4B, is common but not predominant in Europe, whereas species rare in western North America, N. crassa NcB and N. sitophila, are much more common in Europe. The meiotic drive element Spore killer was also common in European populations of N. sitophila and at a higher proportion than anywhere else in the world. The methods by which organisms spread and adapt to new environments are fundamental ecosystem properties, yet they are little understood. The differences in regional diversity, reported here, can form the basis of testable hypotheses. Questions of phylogeography and adaptations can be addressed specifically by studying Neurospora in nature.

Climate↗

Idiopathic juxtafoveal retinal telangiectasis: new findings by ultrahigh-resolution optical coherence tomography.

OBJECTIVE: To investigate the capabilities of ultrahigh-resolution optical coherence tomography (UHR OCT); to compare with the commercially available OCT standard-resolution system, StratusOCT, for imaging of idiopathic juxtafoveal retinal telangiectasis (IJT); and to demonstrate that UHR OCT provides additional information on disease morphology, pathogenesis, and management. DESIGN: Retrospective, observational, interventional case series. PARTICIPANTS: Nineteen eyes of 10 patients diagnosed with IJT in at least one eye. METHOD: All patients were imaged with UHR OCT and StratusOCT at the same visit. A subset of patients was also imaged before and after treatment of IJT. MAIN OUTCOME MEASURES: Ultrahigh- and standard-resolution cross-sectional tomograms of IJT pathology. RESULTS: Using both standard- and ultrahigh-resolution OCT, we identified the following features of IJT: (1) a lack of correlation between retinal thickening on OCT and leakage on fluorescein angiography, (2) loss and disruption of the photoreceptor layer, (3) cystlike structures in the foveola and within internal retinal layers such as the inner nuclear or ganglion cell layers, (4) a unique internal limiting membrane draping across the foveola related to an underlying loss of tissue, (5) intraretinal neovascularization near the fovea, and (6) central intraretinal deposits and plaques. In 63% of cases, the presence of abnormal vessels and a discontinuity of the photoreceptor layer correlated with visual acuity. CONCLUSIONS: Ultrahigh-resolution OCT improves visualization of the retinal pathology associated with IJT and allows identification of new features associated with it. Some of these features, such as discontinuity of the photoreceptor layer, are revealed only by UHR OCT.

Adult↗

Bone regeneration: new findings and potential clinical applications.

Bone is a biologically privileged tissue in that it has the capacity to undergo regeneration as part of a repair process. Fracture healing is the most common and recognizable form of bone regeneration, but several other examples of bone regeneration have been observed in humans, suggesting that the ability to regulate bone regeneration as a therapeutic tool should be possible. Historically, efforts at limb lengthening have led to procedures for regenerating bone, such as the method of Ilizarov. This procedure, known as distraction osteogenesis, has applications in a variety of skeletal conditions, including the restoration of large skeletal defects, the transport of bone in cases of severe trauma with bone loss, and the correction of skeletal deformities. Fibrodysplasia ossificans progressiva is an example of how an abnormal metabolic condition can be viewed as evidence for the capacity of humans to regenerate large amounts of bone if the cellular and molecular signaling events are altered. Elucidation of the cellular and molecular basis for bone regeneration in humans - particularly the role of the human genome in relation to the expression of various growth factors and cytokines, such as the bone morphogenetic proteins - offers great potential for the treatment of orthopaedic conditions. Development of specific bone morphogenetic proteins as therapeutic substances to induce bone regeneration in patients is well under way. As methods for enhancing fracture healing, distraction osteogenesis, and other procedures are refined, the development of protein- and gene-based therapies for regulating bone formation should lead to a new era of orthopaedic practice.

Bone Morphogenetic Proteins↗

New findings in apple S-genotype analysis resolve previous confusion and request the re-numbering of some S-alleles.

Apple trees display gametophytic self-incompatibility which is controlled by a series of polymorphic S-alleles. To resolve the discrepancies in S-allele assignment that appeared in the literature, we have re-examined the identity of S-alleles known from domestic apple cultivars. Upon an alignment of S-allele nucleotide sequences, we designed allele-specific primer pairs to selectively amplify a single S-allele per reaction. Alternatively, highly similar S-alleles that were co-amplified with the same primer pair were discriminated through their distinct restriction digestion pattern. This is an extension of our previously developed allele-specific PCR amplification approach to reveal the S-genotypes in apple cultivars. Amplification parameters were optimised for the unique detection of the 15 apple S-alleles of which the nucleotide sequences are known. Both the old cultivars with a known S-genotype and a number of more common cultivars were assayed with this method. In most cases, our data coincided with those obtained through phenotypic and S-RNase analysis. However, three S-alleles were shown to relate to RNases that were previously proposed as being encoded by distinct S-alleles. For another S-allele the corresponding gene product has not been discriminated. Consequently, we propose the re-numbering of these four S-alleles. Furthermore, two alleles that were previously identified as S(27a) and S(27b) now received a distinct number, despite their identical S-specificity. To ease widespread future analysis of S-genotypes, we identified common cultivars that may function as a witness for bearing a particular S-allele. We discuss the assignment of new S-alleles which should help to avoid further confusion.

Alleles↗

New findings in apparent mineralocorticoid excess.

We report two female siblings (ages 4 and 9 years) and one 8-year-old male with the syndrome of apparent mineralocorticoid excess (AME) presenting with low renin hypertension and hypoaldosteronism. The deficiency of 11 beta-hydroxysteroid dehydrogenase results in a defect of the peripheral metabolism of cortisol (F) to cortisone (E). As a result, the serum cortisol half-life (T1/2) is prolonged, ACTH is suppressed, and serum F is normal. The specific diagnosis of the disorder was made by the decreased ratio of the urinary metabolites of E (tetrahydrocortisone, THE) and F (tetrahydrocortisol, THF). Continuous i.v. hydrocortisone administration caused an increase in blood pressure and decrease in serum potassium demonstrating the abnormal mineralocorticoid activity of cortisol in these patients. Addition of spironolactone resulted in a decrease in blood pressure, rise in serum potassium and a gradual increase in plasma renin activity. These studies suggest that an abnormality in cortisol action or metabolism results in cortisol behaving as a potent mineralocorticoid and causing the syndrome of AME.

Adrenocorticotropic Hormone↗

Heredity in Parkinson's disease: new findings.

Multiple factors have been hypothesized over the last century to be causative or contributory for Parkinson's disease. Hereditary factors have recently emerged as a major focus of Parkinson's disease research. Until recently most of the research on the etiology of Parkinson's disease concentrated on environmental factors, and the possibility that genetic factors contribute significantly to the pathogenesis of Parkinson's disease has been neglected. However, it has become increasingly apparent that even in sporadic cases, the disease most likely reflects a combination of genetic susceptibility and an unknown environmental insult. Moreover, the identification of genes and proteins that may cause hereditary parkinsonism substantially contributes to our ability to understand the pathogenesis of Parkinson's disease and may help in the early identification of the disease and its treatment. The discovery of alpha-synuclein mutations in families with autosomal dominant Parkinson's disease sheds light on its role in sporadic Parkinson's disease. It seems that this protein tends to aggregate when the cellular milieu is altered [14-16]. The question as to the exact changes that cause its deposition remains open. One of the major possibilities is oxidative stress [16]. The role of these aggregates in neuronal cell death is also still unclear. Transgenic mice expressing wild-type human alpha-synuclein developed progressive accumulation of alpha-synuclein and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus and the substantia nigra. These alterations were associated with loss of dopaminergic terminals and motor impairments [24]. This finding suggests that accumulation of alpha-synuclein may play a causal role in sporadic Parkinson's disease as well. The parkin protein seems to be a crucial survival factor for nigral neurons [15]. The parkin protein is related to the ubiquitin pathway, which is important in the elimination of damaged proteins. Ubiquitin-mediated degradation of proteins plays a central role in the control of numerous processes, including signal transduction, receptor and transcriptional regulations, programmed cell death, and breakdown of abnormal proteins that may interfere with normal cell functions. Further studies on the function of Parkin protein and its relation to the ubiquitin pathway could elucidate at least one of the molecular mechanisms of nigral neuronal death. A mutation in the ubiquitin carboxy-teminal hydrolase L1 gene also implies the importance of the ubiquitin pathway in Parkinson's disease. Abnormal tau protein was found to be the cause of familial frontotemporal dementia and parkinsonism. It tends to form filamentous structures, which may lead to neuronal death. Elucidation of the molecular mechanism of neuronal death in this disease may contribute to our understanding of sporadic diseases with tau accumulation, such as corticobasal degeneration, progressive supranuclear palsy, Pick's disease, Alzheimer's disease and possibly also the pathogenesis of Parkinson's disease. Other genetic loci have been identified by linkage analysis of patients with familial parkinsonism. These loci conceal other genes and proteins that may be pivotal factors in the pathogenesis of Parkinson's disease. The discovery of genetic mutations in patients with parkinsonism may offer us new insights into the understanding of the pathways leading to neuronal death and development of Parkinson's disease. It may also help in the early identification of susceptible people to this disease and possibly in developing new treatment strategies.

Chromosome Mapping↗

Impact of gender and having children in the household on ambulatory blood pressure in work and nonwork settings: a partial replication and new findings.

Ambulatory blood pressure (ABP) has been shown to differ for men and women across work and nonwork settings. For men, ABP is higher at work than at home on workdays or on nonworkdays. For women, ABP levels in different settings depend on whether they have children in the household. Women without children at home exhibit the "male" pattern of higher ABP at work than at home. Women with children at home show either similar ABP levels in the two locations or higher ABP at home. These different patterns have been assumed to represent different stress levels in the two locations, but this assumption has rarely been tested. Also, few studies have examined ABP levels on a nonworkday in women or the effect of having children in the household for men. The present study monitored ABP in men and women during two workdays and one nonworkday. Comparisons were made between ABP levels in three settings (workday at work, workday at home, nonworkday) using mixed random effects regression models. Psychosocial variables (e.g. mood, stress) that might mediate the different ABP patterns were also assessed. ABP differences were analyzed by gender and whether children were living in the household using mixed random effects regression models. Results indicated that diastolic blood pressure was higher at work versus home for men with children and higher at work and on nonworkdays than at home for women without children. ABP did not differ across settings for women with children or men without children. These results were not mediated by mood or stress levels in the three settings.

Adult↗