Biomedical subjects

Paul Hofman

Publications and source records attributed to Paul Hofman.

At least 37 records · Page 2Linked to original sources

PubMed2006

The pathology induced by highly active antiretroviral therapy against human immunodeficiency virus: an update.

The use of highly active antiretroviral therapy (HAART) has considerably improved the quality of life and has increased the survival of HIV-infected individuals. Although HAART can successfully suppress viral replication in the long term, it is not without significant toxicity, which can seriously compromise treatment effectiveness. Moreover, the rapid rate of virus mutation and subsequent emergence of drug-resistant HIV variants threaten the longer-term efficacy of HIV treatment. The most common adverse effects caused by HAART include a metabolic syndrome with lipodystrophy, hyperlipidemia and insulin resistance, deterioration in the clinical status due to various exaggerated local and systemic inflammatory reactions during the immunerestoration disease, and various hepatic, peripheral and cardiac muscle, kidney, bone, bone marrow, retinal, ear, and skin toxicities. The heterogeneity in the organs affected by the different drugs and the morphological features observed in tissues in HAART-treated patients raise possible explanations including differential distribution or activation of these agents. Antiretroviral drugs from new classes, as well as new drugs from existing classes with favorable resistance and side effect profiles are in various stages of development. However, new tissue disorders will be certainly described in the future in patients treated with these drugs. The different pathophysiology of the main adverse effects and the less common known side effects of antiretroviral therapy against HIV are described here, with special emphasis on the histological features induced by HAART.

Antiretroviral Therapy, Highly Active↗

PubMed2006

A comparison between functional and radical sinus surgery in an experimental model of maxillary sinusitis.

PURPOSE OF THE STUDY: To compare functional and radical surgery in a maxillary sinusitis' treatment during in vivo experiments in rabbits. METHODS: An experimental chronic maxillary sinusitis was induced in 21 New Zealand white rabbits by inducing mucosal trauma combined with an injection of Streptococcus pneumoniae, and a maxillary sinus ostium occlusion during 28 days. Functional surgery (FS) by reopening the natural ostium and radical surgery (RS) by reopening the natural ostium were performed in association with removal of the sinus mucosa. They were macroscopically and histologically evaluated 15 days, 1 month and 2 months after the surgery. RESULTS: FS had diminished chronic inflammatory criteria (lymphoid and plasma cells) faster that RS ([15 days (p = 0.016)]; [1 month (p = 0.03)]; [2 months (p = 0.03)]). Mucosa fibrosis was more important after RS ([15 days (p = 0.016)]; [1 month (p = 0.03)]; [2 months (p = 0.016)]). CONCLUSION: FS accelerates healing with less fibrosis that RS in pathological mucosa altered by a chronic inflammation.

Animals↗

PubMed2005

A new role for the oncogenic high-mobility group A2 transcription factor in myogenesis of embryonic stem cells.

The high mobility group type A-2 (HMGA 2) transcription factor is involved in proliferation and differentiation, mainly during embryogenesis. Its activated form (HMGA 2/T) presents oncogenic activities both in vivo and in vitro. However, its precise role during embryogenesis is unknown. We investigated its role during the commitment of mouse embryonic stem (ES) cells by constructing cell lines expressing either wild type (wt) or HMGA 2/T forms of the gene. Following differentiation, control and wt HMGA 2 ES cells did not display myotubes; whereas HMGA 2/T ES cell lines massively formed contractile myotubes. Furthermore, as opposed to control cells, HMGA 2/T ES cells highly expressed the muscle myosin heavy chain (MHC) marker. Interestingly, in experimental conditions inhibitory for myogenesis, we observed a strong expression of MyoD and myogenin in HMGA 2/T cells. By contrast, commitment into adipocyte, neuron, and cardiomyocyte lineages was not affected. Teratocarcinomas induced by HMGA 2/T ES cell lines presented numerous skeletal muscle-differentiated tissues that were not observed in wt HMGA 2 or control tumours. Finally, rapamycin, an inhibitor of the mTOR kinase, downregulated endogenous HMGA-2 expression and inhibited myogenesis. This effect was prevented by overexpression of exogenous HMGA-2. Our results reveal a novel function of HMGA-2 in skeletal muscle differentiation.

Animals↗

PubMed2005

DNA microarrays.

Until recently, diagnostic and prognostic assessment of diseased tissues in a Pathology laboratory relied on histological and immunohistological studies. DNA microarray technology now allows the simultaneous analysis of up to thousands of different genes in histological or cytological specimens. Thus, the microarray techniques offer opportunities for the pathologist to obtain 'molecular signatures' of the state of activity of diseased cells in patient tissue samples, providing new information, such as the biological staging of tumors, a risk assessment of pre-malignant lesions, resistance to, and side effects of, treatment, molecular mechanisms in neurodegeneration and inflammation, and detection of micro-organisms. However, despite the great promise of this revolutionary technology, there are several issues that may undermine the power of the DNA microarray approach. After a short summary of the different forms of microarray and the contribution of this technology to understanding human disease, this short review focuses on the potential pitfalls and the important issues that must be considered when using a DNA microarray. Although this new approach shows great potential, the successful application of gene arrays to diagnostic and prognostic problems requires thoughtful interpretation and a strong correlation with other data, such as clinical, histopathological and immunohistochemical findings.

Animals↗

PubMed2005

[Antiretroviral treatments-related lipodystrophy syndrome: clinico-pathological findings].

Effective therapies are available that can stop or slow down the progression of HIV infection. Highly active antiretroviral therapy (HAART) is a combination of antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors. Among the side effects due to these drugs, lipodystrophy is a pathology characterized by fat wasting in face and limbs, accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), insulin resistance, and lactic acidemia. The main clinical features include peripheral fat loss (presumed lipoatrophy in the face, limbs, and buttocks) and central fat accumulation (within the abdomen, breasts, and over the dorsocervical spine, so-called "buffalo hump"). Histopathological features disclose a peculiar type of involutional lipodystrophy. Skin biopsies generally show thinning of the subcutaneous fat, associated with fibrosis, lipogranuloma and sometimes vessel proliferation. There is still an open debate concerning the precise responsibility of HAART as well as the metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. There is no proven therapy for any component of lipodystrophy syndrome.

Acquired Immunodeficiency Syndrome↗

PubMed2005

[Histological diagnosis of lung bacterial necrotizing infections: a study of four fulminant cases].

We report the clinical and histopathological features of four cases of pulmonary bacterial infections associated with extensive necrosis, which were fatal within a few hours (two cases of group A Streptococcus, one case of Staphyloccocus aureus and one case of Haemophilus influenzae infection). These bacterial infections are extremely severe conditions due to the production of necrotizing toxins. Histological findings are distinctive, showing extensive hemorrhagic necrosis, widespread layers of bacteria, and very few or no inflammatory cell components. These dramatic infections are extremely rare, occuring with no apparent underlying disease, both in immunodeficient and immunocompetent patients. The main differential diagnosis is a viral infection, difficult to diagnose on histological examination alone. The diagnosis is based on histological and microbiological results.

Acute Disease↗

PubMed2005

Lateralized anterior mesiotemporal lobe activation: semirandom functional MR imaging encoding paradigm in patients with temporal lobe epilepsy--initial experience.

PURPOSE: To prospectively demonstrate anterior mesiotemporal lobe (MTL) activation in healthy volunteers by using a semirandom memory-encoding paradigm and to prospectively compare lateralized functional magnetic resonance (MR) imaging activation with intracarotid amobarbital procedure (IAP) memory test results in patients with temporal lobe epilepsy (TLE) who were scheduled to undergo surgery. MATERIALS AND METHODS: The study was approved by a local ethics committee, and written informed consent was obtained from all subjects. Eight healthy volunteers and 18 patients with TLE who were scheduled for surgery were included in the functional MR imaging study involving the use of a memory-encoding paradigm with variable epoch lengths. Subjects were instructed to memorize new pictures that were mixed among pictures that they had seen before. Data analysis entailed computations of the contrast between the MTL activation induced by the new pictures and the MTL activation induced by the old pictures and of the lateralization index, defined as the relative difference in the number of activated voxels between the left and right MTLs. Lateralization indexes were compared between the patients and the volunteers and statistically correlated with the patients' IAP memory test results. To study deviations from perfect correspondence between the functional MR imaging- and IAP-derived lateralization indexes, orthogonal regression analysis was applied. Proportional relations for the patients with left-sided TLE and for those with right-sided TLE were calculated separately. RESULTS: The memory paradigm consistently activated the posterior and anterior MTL structures in both the healthy volunteers and the patients. Regression analysis revealed that functional MR imaging activation was stronger than the IAP results when it was lateralized to the contralateral MTL. This analysis also revealed a significant (P < .001) correlation between the functional MR imaging results and the IAP results in the patients with right-sided TLE but not in those with left-sided TLE (P > .1). CONCLUSION: The functional MR imaging memory-encoding paradigm consistently yielded MTL activation in the volunteers and the patients with TLE, but lateralized functional MR imaging activation was in concordance with the IAP results in only those patients with right-sided TLE.

Adult↗

PubMed2005

The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis.

Hyperplasia of adipose tissue is critical for the development of obesity, but molecular mechanisms governing normal or pathological recruitment of new adipocytes remain unclear. The extracellular signal-regulated kinase (ERK) pathway plays a pivotal role in many essential cellular functions, such as proliferation and differentiation. Using ERK1(-/-) mice, we investigated the role of this isoform in adipose tissue development. Mice lacking ERK1 have decreased adiposity and fewer adipocytes than wild-type animals. Furthermore, ERK1(-/-) mice challenged with high-fat diet are resistant to obesity, are protected from insulin resistance, and have a higher postprandial metabolic rate. To get insights into cellular mechanisms implicated in reduced adiposity in ERK1(-/-) animals, we analyzed adipocyte differentiation in ERK1(-/-) cells. Compared with wild-type control cells, mouse embryo fibroblasts and cultures of adult preadipocytes isolated from ERK1(-/-) adult animals exhibit impaired adipogenesis. An inhibitor of the ERK pathway does not affect the residual adipogenesis of the ERK1(-/-) cells, suggesting that ERK2 is not implicated in adipocyte differentiation. Our results clearly link ERK1 to the regulation of adipocyte differentiation, adiposity, and high-fat diet-induced obesity. This suggests that a therapeutic approach of obesity targeting specifically the ERK1 isoform and not ERK2 would be of particular interest.

Adipocytes↗

PubMed2004

The fetal, neonatal, and infant environments-the long-term consequences for disease risk.

The developmental origins of health and disease can be understood by reference to the fundamentals of developmental plasticity. It is essential to distinguish between those environmental effects acting during development that are disruptive from those that have adaptive value. The latter are likely to underpin programming and the developmental origins of adult disease. It is suggested that greater disease risk is created by a mismatch between the environment predicted during the plastic phase of development and the actual environment experienced in the postplastic phase. This plastic phase extends from conception to after birth at least for some systems. It is not necessary to invoke a particular mechanism in the neonatal or infant period. There is increasing evidence that prematurity can be associated with long-term consequences, and this is to be anticipated from conceptual considerations. Different preventative strategies may be relevant in different populations.

Adaptation, Physiological↗

PubMed2004

A voxel-based morphometric study to determine individual differences in gray matter density associated with age and cognitive change over time.

Voxel-based morphometry (VBM) was used to examine the relation between age and gray matter density cross-sectionally and to study the association between gray matter density and longitudinal decline in performance on cognitive tests in healthy, non-demented elderly individuals. Participants were neuropsychologically tested at baseline and again after 3 years. Thirty-seven subjects (mean age 72.5 years) who showed a decline in cognitive test performance at follow-up were compared with 38 individually matched control subjects (mean age 71.8 years) whose performance did not change over time. Magnetic resonance imaging scans were acquired at follow-up and individual differences in regional gray matter density were examined with VBM. The largest age effects were found in various regions in the prefrontal cortex, the (medial) temporal lobes and the striate cortex. Longitudinal cognitive decline was associated with decreased gray matter density in prefrontal areas, the (medial) temporal lobes and the posterior parietal cortex. These findings suggest that prefrontal and temporal cortical regions are of particular relevance both in aging and age-related cognitive decline in healthy elderly individuals.

Adult↗

PubMed2004

Acid-sensing ion channel 2 is important for retinal function and protects against light-induced retinal degeneration.

pH variations in the retina are thought to be involved in the fine-tuning of visual perception. We show that both photoreceptors and neurons of the mouse retina express the H+-gated cation channel subunits acid-sensing ion channel 2a (ASIC2a) and ASIC2b. Inactivation of the ASIC2 gene in mice leads to an increase in the rod electroretinogram a- and b-waves and thus to an enhanced gain of visual transduction. ASIC2 knock-out mice are also more sensitive to light-induced retinal degeneration. We suggest that ASIC2 is a negative modulator of rod phototransduction, and that functional ASIC2 channels are beneficial for the maintenance of retinal integrity.

Acid Sensing Ion Channels↗

PubMed2004

Lessons for neuropsychology from functional MRI in patients with epilepsy.

This contribution aims to review the major findings of pre- and postsurgical functional magnetic resonance imaging (fMRI) in patients with refractory epilepsy from a neuropsychological perspective. We compared the contribution of fMRI with the intracarotid amytal procedure (IAP) with respect to functional mapping of language and memory in patients with therapy-resistant epilepsy. We conclude that using comprehensive language paradigms, fMRI has been able (1) to provide estimates of the degree of language lateralization including the degree of involvement of the nondominant hemisphere, (2) to provide information on the location of its activated network during expressive and receptive language, and (3) to help delineate eloquent language regions in the vicinity of the surgical target, thus preventing postoperative complications. The contribution of the frequently observed nondominant hemisphere activation to language should be explored and its clinical relevance determined. Evidence from fMRI studies is accumulating that reorganization of cognitive and motor function favors the activation of contralateral homotopic areas, although this process is far from understood. The exact functional contribution of atypical areas of activation should be investigated critically. In the presurgical evaluation process, detailed and reliable localization of language and memory functions of the individual patient is mandatory and should be the ultimate goal in the development of comprehensive clinical fMRI protocols.

Amobarbital↗

PubMed2004

[Disseminated pulmonary infection due to Cryptococcus neoformans in a non immunocompromised patient].

We report a case of a primary pulmonary infection due to Cryptococcus neoformans developed in a 40 Year old immunocompetent and HIV negative man. Radiologic findings consisted in diffuse, bilateral reticular and nodular opacities. Bronchoscopy was normal and bronchoalveolar lavage showed numerous macrophages without associated pathogens. A thoracovideoscopy with an open lung biopsy showed numerous cryptococci, free in the alveoli or located within the macrophages. They were associated with an inflammatory infiltrate in the interalveolar spaces, predominantly composed of mononuclear cells. Ultrastructural study showed yeasts with numerous intracytoplasmic organites, a nucleus, a wall and a thick capsule. Pulmonary cryptococcosis is rare in immunocompetent hosts and can be difficult to diagnose since clinicoradiologic features observed in this cryptococcal infection mimic other infectious or neoplastic diseases.

Adult↗

PubMed2004

The value of polymerase chain reaction detection of Mycobacterium tuberculosis in granulomas isolated by laser capture microdissection.

AIMS: The aim of this study was to investigate the usefulness of polymerase chain reaction (PCR) detection of Mycobacterium tuberculosis in granulomas isolated by laser capture microdissection (LCM). METHODS: The PCR DNA amplification method was used to detect M. tuberculosis in granulomas microdissected from one section stained by haematoxylin and eosin (H&E) from a formalin-fixed paraffin-embedded specimen. The results were compared to those obtained from PCR performed from 10 whole paraffin sections of 5 micro m each, and with the histology, culture and the patient's clinical findings. RESULTS: Forty-nine formalin-fixed and paraffin-embedded samples from 49 patients with a histological suspicion of a mycobacterial infection were investigated. Using culture as the reference method, the sensitivity for the detection of M. tuberculosis was 92% and the specificity was 100% using PCR from microdissected granulomas and were similar to those obtained by using PCR from 10 whole sections. CONCLUSIONS: The PCR method of examination of microdissected granulomas from deparaffinised sections is a sensitive, specific and rapid method for the detection of M. tuberculosis in formalin-fixed and paraffin-embedded samples. The method is as sensitive as that using PCR on 10 whole tissue sections, thus making it suitable for small biopsies. However, although these methods reduce the delay in diagnosis, culture remains the gold standard for identification of mycobacteria in tissue. Culture also allows for the testing of antibiotic sensitivity of any isolated species, in this way determining appropriate treatment.

Animals↗

PubMed2004

Mediastinal neurogenic tumors and video-assisted thoracoscopy: always the right choice?

Neurogenic mediastinal tumors in adults are generally benign lesions and for this reason are ideal candidates for resection by video-assisted thoracoscopy (VAT). Usual contraindications to VAT are the dimension of the tumor (greater than 6 cm), its position (apex, posterior costodiaphragmatic angle), and/or the presence of intraspinal growth (the so-called "dumbbell tumors"). This study reviewed a single-institution 10-year experience approaching mediastinal neurogenic tumors routinely by VAT, even in cases of the above mentioned contraindications. From January 1992 to December 2002, 15 consecutive mediastinal neurogenic tumors were operated by VAT (11 females, mean age 43 years, range 16-67). Mean operating time was 99 minutes (range 60-180). No conversion thoracotomy was required. The 2 cases of "dumbbell tumor" in this series were treated by laminectomy followed by VAT. Two patients had a Claude-Bernard-Horner syndrome after removal of lesion at the level of T1-T2. Mean postoperative stay was 5.5 days. Histologic diagnosis was schwannoma in 12 cases (Antoni type A in 7 cases, type B in 4 cases, mixed type in 1 case) and neurofibroma in 3 cases. Results from this 10-year experience confirmed that VAT can be the standard approach for neurogenic tumors in adults without negative effect on radicality of resection and safety of the procedure.

Adolescent↗

PubMed2004

Pathogenesis of Helicobacter pylori infection.

Research in the last year has provided new insights into the function of the the cag-associated type IV secretion system and the vacuolating toxin VacA. A quite new aspect was disclosed by the finding that Helicobacter pylori in Mongolian gerbils colonizes a very distinct topology in the gastric mucous layer, obviously providing optimal conditions for long-term survival. Further research activities focused on H. pylori ammonia and metal metabolism as well as on bacterial stress defence mechanisms. Differential expression of approximately 7% of the bacterial genome was found at low pH suggesting that H. pylori has evolved a multitude of acid-adaptive mechanisms. VacA was shown to interrupt phagosome maturation in macrophage cell lines as well as to modulate and interfere with T lymphocyte immunological functions. Gastric mucosa as well as the H. pylori-infected epithelial cell line AGS strongly express IL-8 receptor A and B, which might contribute to the augmentation of the inflammatory response. Accumulating evidence implicates genetic variation in the inflammatory response to H. pylori in the etiology of the increased risk of gastric cancer after H. pylori infection. The chronic imbalance between apoptosis and cell proliferation is the first step of gastric carcinogenesis. In this regard, it was demonstrated that coexpression of two H. pylori proteins, CagA and HspB, in AGS cells, caused an increase in E2F transcription factor, cyclin D3, and phosphorylated retinoblastoma protein. Taken together, we now have a better understanding of the role of different virulence factors of H. pylori. There is still a lot to be learned, but the promising discoveries summarized here, demonstrate that the investigation of the bacterial survival strategies will give novel insights into pathogenesis and disease development.

Adaptation, Physiological↗

PubMed2004

Escherichia coli cytotoxic necrotizing factor 1 inhibits intestinal epithelial wound healing in vitro after mechanical injury.

Cytotoxic necrotizing factor type 1 (CNF1) from Escherichia coli activates the small GTP-binding proteins of the Rho family (Rho, Rac, and Cdc42) by catalyzing their deamidation at a specific glutamine residue. Since RhoA, Rac, and Cdc42 play a pivotal role in cell migration during the early phase of wound repair, we investigated whether CNF1 was able to interfere with wound healing in intestinal epithelial monolayers (T84 cells). After mechanical injury, we found that CNF1 blocks epithelial wound repair within 48 h. This effect was characterized by cell elongation and filopodium formation on the leading edge, in association with permanent phosphorylation of the focal adhesion kinase (FAK) via Rho activation. Moreover, inhibition of Rho kinase with Y-27632 decreased CNF1-mediated permanent FAK phosphorylation, leading to complete restitution of wound repair within 24 h. In addition, we found that CNF1 induced upregulation of mitogen-activated protein kinases (MAPK) activation. Moreover, activation of Rac and MAPK by CNF1 increased matrix metalloproteinase 9 expression in wounded T84 monolayers. Taken together, these results provide evidence that CNF1 strongly impairs intestinal epithelial wound healing.

Amides↗

PubMed2004

Increased rate of apoptosis and diminished phagocytic ability of human neutrophils infected with Afa/Dr diffusely adhering Escherichia coli strains.

The proinflammatory effect of Afa/Dr diffusely adhering Escherichia coli (Afa/Dr DAEC) strains have been recently demonstrated in vitro by showing that polymorphonuclear leukocyte (PMN) transepithelial migration is induced after bacterial colonization of apical intestinal monolayers. The effect of Afa/Dr DAEC-PMN interaction on PMN behavior has been not investigated. Because of the putative virulence mechanism of PMN apoptosis during infectious diseases and taking into account the high level of expression of the decay-accelerating factor (DAF, or CD55), the receptor of Afa/Dr DAEC on PMNs, we sought to determine whether infection of PMNs by Afa/Dr DAEC strains could promote cell apoptosis. We looked at the behavior of PMNs incubated with Afa/Dr DAEC strains once they had transmigrated across polarized monolayers of intestinal (T84) cells. Infection of PMNs by Afa/Dr DAEC strains induced PMN apoptosis characterized by morphological nuclear changes, DNA fragmentation, caspase activation, and a high level of annexin V expression. However, transmigrated and nontransmigrated PMNs incubated with Afa/Dr DAEC strains showed similar elevated global caspase activities. PMN apoptosis depended on their agglutination, induced by Afa/Dr DAEC, and was still observed after preincubation of PMNs with anti-CD55 and/or anti-CD66 antibodies. Low levels of phagocytosis of Afa/Dr DAEC strains were observed both in nontransmigrated and in transmigrated PMNs compared to that observed with the control E. coli DH5alpha strain. Taken together, these data strongly suggest that interaction of Afa/Dr DAEC with PMNs may increase the bacterial virulence both by inducing PMN apoptosis through an agglutination process and by diminishing their phagocytic capacity.

Annexin A5↗