[Sociological aspects of transgenrism]. / Aspects sociologiques des transidentités.

The surgery of trans people is not apprehended by most of plastic surgeons as a simple surgery for the purpose of morphological transformation. At the same time, the French trans population does not benefit from adequate surgical coverage. Over the past few years, French regulations have simplified the process of reassignment surgeries. In addition, we have witnessed a fairly rapid increase in requests for transition surgery with accelerated and sometimes atypical courses. In recent years, a number of specialists have warned the medical community about the risks of slippage due to a lack of psychological monitoring of certain people beginning a transition process. Quite recently, hybrid transition paths have also appeared which, from a surgical point of view, are no longer limited to ensuring that a native assigned female patient can take on the most masculine appearance possible or the reverse. In this manuscript, we expose the biological, historical and societal place of transidentity and then address the reasons for the warnings of a certain category of the medical population while reassuring the surgical community on the benefits of reassignment surgeries in a controlled context. We end by proposing a few ways to improve the care course of trans people applicable in France.

[Burns caused by nitrous oxide cylinder misuse]. / Brûlures par l'usage détourné du protoxyde d'azote en bonbonne.

In recent years, we have seen an increase in the frequency of the misuse of nitrous oxide as a narcotic. The risks associated with its use are now well-known, such as neurological and psychiatric risks. In this study, we report our experience with specific thigh burns when using nitrous oxide canisters for narcotic purposes. PATIENTS AND METHODS: Between November 2021 and August 2022 we treated 4 patients burned during a nitrous oxide use accident. RESULTS: We report the cases of three women and one man with an average age of 28. Two of them were treated in addictology. We observed an average delay before consultation of a healthcare professional of 7days. The burns were all rounded and deep, localized at the level of the thighs. For three of the patients (one having been lost to sight), a split thickness skin graft was performed within an average of 32days. CONCLUSIONS: The non-medical use of nitrous oxide represents a real public health problem in addition to the adverse effects of the substance itself. Prevention and health security measures seem to be becoming essential.

Thermal and chemical burns caused by e-cigarette battery explosions.

INTRODUCTION: E-cigarettes have become the main alternative to traditional cigarettes. An increasing number of explosive accidents with e-cigarettes have been described over the past years. Through our experience of sixteen consecutive cases, we wanted to acquire a better understanding of the origins and to specify the principles of management for these particular new burns. METHODS: A retrospective study was conducted to review all cases of burns related to e-cigarettes referred to our burn center from April 2014 through May 2019. Several key data were collected in relation to the patients, the circumstances and characteristics of the burns, their treatment and follow-up. RESULTS: In the past five years, sixteen patients were burned by e-cigarette explosions. They were all males with an average age of 41 years. They all had second or third degree burn injuries. The average burned area was 5% TBSA. The areas that were burned were the hands, buttocks, thorax, thighs and genital areas, and were always related to clothes pocket location. Eight patients described an increase in pain after cooling, suggesting significant contamination of the burn by lithium-ion deposits. Six required surgical management with excision and split-thickness skin graft. The others healed spontaneously in several weeks. CONCLUSIONS: Burns by e-cigarette lithium batteries explosion have a double mechanism (thermal and chemical). Carrying cigarettes in a pocket close to the body is a significant risk factor to which the male population is particularly exposed. Early debridement is recommended when possible while initial cooling does not seem helpful and is sometimes painful.

Vascularization of the superficial circumflex iliac perforator flap (SCIP flap): an anatomical study.

INTRODUCTION: The superficial circumflex iliac artery perforator flap (SCIP) has gained widespread popularity as local or free flap to cover soft tissue defects. However, there are numerous anatomical variations in terms of size, location and reliability of its perforators This cadaveric study aimed to focus on the anatomical bases of this flap. MATERIALS AND METHODS: A bilateral dissection of seven cadavers was performed to harvest 14 flaps. Superficial circumflex iliac artery parameters, number, length and diameters of perforators were measured. Correspondent perforasomes were highlighted through semi-selective injections. RESULTS: The major perforator of the superficial branch had a mean caliber of 2.0 mm, and a mean length of 1.8 mm. The major perforator of the deep branch had a mean caliber of 2.1 mm and a mean length of 1.43 mm. The mean area of the superficial pattern perforasome was 178.6 cm2 and the mean measured surface of the deep pattern perforasome was 156.2 cm2. The descending branches of the deep branch anastomosing with the ascending branch of the lateral circumflex femoral artery were found in three cases. CONCLUSION: Several anatomical variations were observed in this anatomical study, but major perforators supplying large perforasomes were always found.

Complex abdominopelvic reconstruction by combined tensor fascia latae and superficial circumflex iliac artery perforator flaps.

BACKGROUND: Extensive full thickness abdominopelvic defects pose a difficult challenge to surgeons. Autologous tissues are versatile and can provide a satisfying reconstructive option for this type of defects. The tensor fascia latae (TFL) and superficial circumflex iliac perforator (SCIP) flaps provide a large area of vascularized tissue and their use in reconstructive surgery is well-known. In this report, the authors present the experience of using combined TFL and propeller SCIP flaps for covering large abdominal and pelvic defects. METHODS: Four patients underwent reconstruction of soft-tissue abdominopelvic defects by combined TFL and SCIP flaps. Three were men and one woman, aged from 52 to 76 years. The etiologies of the defects were tissue loss after tumor resection in 3 cases and necrotizing fasciitis in the fourth case. Defect dimensions ranged from 32 × 20 cm to 45 × 17 cm. An acoustic handheld Doppler was utilized to detect perforator vessels, then TFL and SCIP flaps were elevated at the same time by 2 surgical teams. Donor sites of the flaps were closed primary except for one TFL flap donor site. The latter one was treated with negative pressure therapy and finally with a split-thick skin graft. RESULTS: The size of the TFL flaps ranged from 25-38 × 10-14 cm. Concerning the SCIP flaps, the dimensions ranged from 18-32 × 12-18 cm. The average flap dimensions were 30.25 × 11.75 cm for the TFL and 26.75 × 14 cm for the SCIP. Two TFL flaps presented a necrosis of the distal tip. All the other flaps survived entirely. Complete healing was achieved in all patients. Patients were followed for an average of 4 months postoperatively (ranging between 2 and 8 months). CONCLUSIONS: Combined TFL and SCIP flaps may represent an alternative reconstructive procedure for large abdominopelvic defects in well-selected cases.

[Radical treatment of hidradenitis suppurativa: Comparison of the use of the artificial dermis and pedicled perforator flaps]. / Traitement radical de la maladie de Verneuil : comparaison de l'utilisation du derme artificiel et des lambeaux perforants pédiculés.

OBJECTIVES: The objective of this study was to compare the use of artificial dermal and perforator flap after radical surgery of severe axillary and perineal hidradenitis suppurativa disease. PATIENTS AND METHODS: The data on postoperative outcomes, scar assessment (POSAS) and quality of life (DLQI, SF-36) were collected during consultation or by phone call. Forty-seven patients were included in our study between January 2015 and September 2017, including 27 patients in the artificial dermal group and 20 patients in the perforator flap group. RESULTS: The quality of life assessment by the SF-36 questionnaire showed a significant increase in quality of life in both groups (P<0.05), higher in the perforating flap group (P<0.001). The DLQI questionnaire showed a decrease in the impact of MV on quality of life in both groups, which was greater in the perforator flap group (P<0.05). The scarring assessment by the POSAS patient and observer questionnaire showed a better overall opinion in the perforator flap group (P<0.001). In the perforator flap group, the total hospital stay and healing time was shorter (P<0.001) and the return to work was faster (P<0.001). CONCLUSION: The artificial dermis and the perforator flaps are very useful coverage solutions after radical surgery of hidradenitis suppurativa. The use of perforator flaps, however, seems more interesting while simplifying the post-operative course.

Antibody targeting of claudin-1 as a potential colorectal cancer therapy.

BACKGROUND: Metastatic colorectal cancer (mCRC) is one of the major causes of cancer-related death. Despite the substantial progress in mCRC management, it remains important to identify new therapeutic options and biological markers for personalized medicine. Here, we investigated the expression of claudin-1 (CLDN1), a major tight junction transmembrane protein, in the different colorectal cancer (CRC) molecular subtypes and then assessed the anti-tumor effect of a new anti-CLDN1 monoclonal antibody (mAb). METHODS: Gene expression profiling and immunochemistry analysis of normal and tumor tissue samples from patients with stage IV CRC were used to determine CLDN1 gene expression. Then, the 6F6 mAb against CLDN1 extracellular part was generated. Its effect on CRC cell cycle, proliferation, survival and migration was assessed in vitro, using a 3D cell culture system, flow cytometry, clonogenic and migration assays. In vivo, 6 F6 mAb efficacy was evaluated in nude mice after subcutaneous xenografts or intrasplenic injection of CRC cells. RESULTS: Compared with normal mucosa where it was almost exclusively cytoplasmic, in CRC samples CLDN1 was overexpressed (p < 0.001) and mainly localized at the membrane. Moreover, it was differentially expressed in the various CRC molecular subtypes. The strongest expressions were found in the consensus molecular subtype CMS2 (p < 0.001), the transit-ampliflying (p < 0.001) and the C5 subtypes (p < 0.001). Lower CLDN1 expression predicted a better outcome in the molecular subtypes C3 and C5 (p = 0.012 and p = 0.004, respectively). CLDN1 targeting with the 6 F6 mAb led to reduction of survival, growth and migration of CLDN1-positive cells. In preclinical mouse models, the 6F6 mAb decreased tumor growth and liver metastasis formation. CONCLUSION: Our data indicate that CLDN1 targeting with an anti-CLDN1 mAb results in decreased growth and survival of CRC cells. This suggests that CLDN1 could be a new potential therapeutic target.

Leech therapy in flap salvage: Systematic review and practical recommendations.

INTRODUCTION: Medicinal leeches have been part of the therapeutic armamenterium of plastic surgeons for more than 50 years. While their use in hand surgery is a matter of course, their use in salvage of flaps with venous congestion remains facultative depending on teams. MATERIALS AND METHODS: We conducted a systematic review of leech therapy for flap salvage between 1960 and 2015, analyzing 121 articles and subsequently taking into consideration 41 studies. In parallel, we collected data from 43 patients for whom leach therapy had recently been applied in treatment of venous insufficiency in pedicled or free flaps after revision surgery had failed to improve flap vascularization, or in cases where flap revision was not appropriate. The data collected pertained to relevant indications, treatment procedure, efficacy, adjuvant therapies, side effects and complications. RESULTS: For this indication, the success rate of leech therapy ranged from 65 to 85% (83.7% in our series) according to the situations encountered. Optimal frequency of application ranged from 2 to 8hours, while average overall duration ranged from 4 to 10 days. The number of leeches to be applied can be determined depending on volume of the flap. In 50% of the cases reported in the literature, the patients required transfusion. Antibiotic prophylaxis against Aeromonas is highly advisable. A ciprofloxacin and trimethoprim-sulfametoxazole combination currently appears as the most relevant prophylactic antibiotherapy. CONCLUSION: Hirudotherapy is a reliable treatment in cases of patent venous insufficiency of pedicled or free flaps (or when revision surgery is not recommended). Even though the relevant literature is highly heterogeneous, we have attempted to put forward a specific protocol bringing together dosage, delivery route, frequency of administration and appropriate prophylactic antibiotherapy. An algorithm for treatment and management of venous congestion and a practical information sheet have been placed at the disposal of plastic surgery teams.

[Cutaneous loxoscelism, about an exceptional observation of 9 consecutive cases]. / Le loxoscelisme cutané, à propos d'une observation exceptionnelle de 9 cas consécutifs.

INTRODUCTION: Loxosceles spiders are ubiquitous and responsible for many cases of envenomation in the world. The kind rufescens is present in the Provence and Occitan regions in France. During the summer 2015, we faced many Loxosceles rufescens cases of bites having led to extensive integumental necrosis whose features and singular evolution seems important to report. MATERIAL AND METHODS: We report the cases of nine patients who experienced a spider bite in the summer of 2015 in the Languedoc Roussillon. RESULTS: Of nine patients, eight patients had skin necrosis and five required surgical care. Five patients had a fever and had five other general signs such as important asthenia, joint pain, nausea and dizziness. CRP was very low normal in all patients. Finally, five of the nine patients reported a residual pain. DISCUSSION: L. rufescens is a small spider (7 to 15mm in diameter) having a cytotoxic venom. Loxoscelism diagnosis is usually made by removing a front necrotic skin lesion. Of systemic loxoscelism that have been described, some American species had fatal outcomes. The treatment remains controversial with various options: surgery, antibiotics, antihistaminics, antivenom. CONCLUSION: The diagnosis must be made in endemic areas when confronted to a necrosic integumentary infectious rapidly progressive, unresponsive to antibiotic treatment associated with atypical general signs.

Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial.

BACKGROUND: This trial evaluated the feasibility and efficacy of combined sorafenib and irinotecan (NEXIRI) as second- or later-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC), who had progressed after irinotecan-based chemotherapy. METHODS: In Phase I, in a 3+3 dose escalation schedule, patients received irinotecan (125, 150 or 180 mg m(-2) every 2 weeks), in combination with 400 mg sorafenib b.d. The primary end point was the maximum-tolerated dose of irinotecan. In Phase II, the primary end point was disease control rate (DCR). Secondary end points were progression-free survival (PFS), overall survival (OS) and toxicity. RESULTS: Phase I included 10 patients (median age 63 (49-73)); no dose-limiting toxicity was seen. In Phase II, 54 patients (median age 60 (43-80) years) received irinotecan 180 mg m(-)(2) every 2 weeks with sorafenib 400 mg b.d. Nine patients (17%) remained on full-dose sorafenib. The DCR was 64.9% (95% CI, 51-77). Median PFS and OS were 3.7 (95% CI, 3.2-4.7) and 8.0 (95% CI, 4.8-9.7) months, respectively. Toxicities included Grade 3 diarrhoea (37%), neutropenia (18%), hand-foot syndrome (13%) and Grade 4 neutropenia (17%). CONCLUSION: The NEXIRI regimen showed promising activity as second- or later-line treatment in this heavily pretreated mCRC population (ClinicalTrials.gov NCT00989469).

TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy.

Recent studies have suggested that activation of the EGFR pathway leads to malignant transformation only if the p53 protein is inactivated. Therefore, we evaluated the impact of TP53 mutations on cetuximab-based chemotherapy (CT) sensitivity in combination with KRAS mutations that have been associated with cetuximab resistance. KRAS and TP53 status were assessed in tumours from 64 metastatic colorectal cancer patients treated with cetuximab-based CT and correlated to clinical response using the Fisher's exact test. Times to progression (TTPs) according to gene status were calculated using the Kaplan-Meier method and compared with log-rank test. TP53 mutations were found in 41 patients and were significantly associated with controlled disease (CD), as defined as complete response, partial response or stable disease (P=0.037) and higher TTP (20 vs 12 weeks, P=0.004). Remarkably, in the subgroup of 46 patients without KRAS mutation, but not in patients with KRAS mutation, TP53 mutations were also associated with CD (P=0.008) and higher TTP (24 vs 12 weeks, P=0.0007). This study suggests that TP53 mutations are predictive of cetuximab sensitivity, particularly in patients without KRAS mutation, and that TP53 genotyping could have a clinical interest to select patients who should benefit from cetuximab-based CT.

Proteomic analysis of RCL2 paraffin-embedded tissues.

Histopathological diagnosis in most of the world's hospitals is based upon formalin-fixed and paraffin-embedded (FFPE) tissues. Although this standard fixation and embedding procedure keeps the tissue in excellent form for morphological and immunohistological analysis, FFPE is inappropriate for nucleic acids and protein studies. We investigated the potential value of RCL2, a new non-toxic fixative, for sparing proteins preserved in paraffin-embedded tissues. Normal colonic mucosa tissue was fixed in RCL2 prior to paraffin embedding (RCL2P), and then processed for quality and quantity of protein conservation, as compared to frozen and FFPE tissues using complementary proteomic analysis approaches. Using 4 different protein extraction protocols, RCL2P tissue consistently showed the highest protein yield. Similar protein patterns were observed with RCL2P and frozen tissues using mono and bi-dimensional electrophoresis. Moreover, membrane, cytoplasmic and nuclear proteins, as well as phosphorylated proteins, were successfully detected using western-blot. Furthermore, protein patterns observed by mass spectrometry analysis after laser-captured microdissection were found to be identical for frozen and RCL2-fixed tissues. At last, immunohistochemistry using various antibodies showed comparable results between both tissue storage methods. We concluded that RCL2 has great potential for performing both morphological and molecular analyses on the same archival paraffin-embedded tissue sample, and can be a new method for investigating protein biomarkers.

Proteomics-based identification of HSP60 as a tumor-associated antigen in early stage breast cancer and ductal carcinoma in situ.

The detection of autoantibodies in cancer patients has been shown to constitute an excellent tool for early diagnosis. Because breast cancer still lacks early diagnostic markers, we investigated novel tumor-associated antigens and related autoantibodies in sera from patients with early stage breast cancer compared to autoimmune disease, other cancers, and healthy volunteers, using a proteomics-based approach. Among the 26 protein antigens specifically recognized by early stage breast cancer sera, we focused on Heat Shock Protein 60 (HSP60). Using ELISA, we investigated the frequency of autoantibodies directed against this protein in the sera of 240 individuals, comprising patients with either ductal carcinoma in situ (DCIS) ( n = 49) or early stage breast cancer ( n = 58), other cancers ( n = 20), autoimmune disease ( n = 20), and healthy subjects ( n = 93). Autoantibodies directed against HSP60 were present in 16/49 (31%) early stage breast cancer and 18/58 (32.6%) DCIS patients, compared to 4/93 (4.3%) healthy subjects. In particular, autoantibodies were present in 11/23 patients (47.8%) with high-grade DCIS, compared to 5/26 (19.2%) with low-grade DCIS. HSP60 mRNA levels were significantly higher in primary breast cancer compared to healthy breast tissues. Using immunohistochemistry, we found that HSP60 expression gradually increases from normal through DCIS to invasive tissues. Our results indicate that HSP60 autoantibodies may be of interest in terms of clinical utility for the early diagnosis of breast cancer and more particularly in DCIS. Moreover, HSP60 overexpression during the first steps of breast carcinogenesis may be functionally correlated to tumor growth and/or progression.

Efficient DNA electrotransfer into tumors.

DNA transfer to tumor cells of antiproliferative genes or of genes coding for immunomodulatory or antiangiogenic products is a promising approach for cancer therapy. However, intratumoral injection of plasmid DNA either naked or associated to chemical vectors results in a low level of gene expression. Recently, electrically mediated gene transfer has been described to strongly increase foreign gene expression in various tissues. We confirm and extend these observations using long duration electric pulses for several murine and human tumor models, using a reporter gene encoding for luciferase. After plasmid intratumoral injection, eight electric pulses of 20-ms duration were delivered at a frequency of 1 Hz through two flat parallel stainless steel electrodes placed at each side of the tumor. Optimal gene transfer was obtained using a voltage-to-distance ratio comprising between 400 and 600 V/cm. Two days after electrotransfer, we obtained a 10- to 1200-fold increase in gene expression over the naked DNA injection alone, leading to the expression of 0.6 to 300 ng luciferase per tumor. Moreover, histological results using beta-Gal reporter gene injected in H1299 tumor indicate that electrotransfer leads to a substantial increase in the percentage of beta-Gal positive cells. These results confirm the wide potential of electrotransfer for gene therapy in cancer.

Expression of Trk isoforms in brain regions and in the striatum of patients with Alzheimer's disease.

The TrkAII tyrosine kinase receptor differs from the TrkAI isoform by an insertion of six amino acids in the extracellular domain. We used RT-PCR to determine their respective distribution in rat and human brain. Only trkAII transcripts were detected in 12 rat brain regions, while both trkAI and trkAII transcripts were detected in the cerebellum and pituitary gland. In human, both trkAI and trkAII transcripts were detected in the frontal, temporal, and occipital cortex and thalamus, while only trkAI transcripts were detected in the hippocampus and cerebellum. In the caudate and putamen, trkAII transcripts were exclusively detected. Thereafter, we studied the expression of TrkA isoforms in the striatum of five patients with Alzheimer's disease (AD), four patients with non-AD dementia, seven patients with Parkinson's disease, and six paired nondemented elderly control individuals. In controls and non-AD patients, a constant expression of trkAII transcripts was detected within all striatum parts. In AD patients, a heterogeneous decrease in trkAII expression was observed in the caudate, putamen, and ventral striatum, resulting either in a drop of trkAII transcript levels or in a weak coamplification of trkAII and trkAI transcripts. The alteration of TrkAII gene expression paralleled those of choline acetyltransferase. Together with previous data, this suggests that the alteration of trk gene expression could contribute to a decrease in NGF binding sites and its protective effects on cholinergic neurons of AD patients.

An immunohistochemical study of the distribution of brain-derived neurotrophic factor in the adult human brain, with particular reference to Alzheimer's disease.

Brain-derived neurotrophic factor is a member of the family of neuronal differentiation and survival-promoting molecules called neurotrophins. Neuronal populations known to show responsiveness to the action of brain-derived neurotrophic factor include the cholinergic forebrain, mesencephalic dopaminergic, cortical, hippocampal and striatal neurons. This fact has aroused considerable interest in the possible contribution of an abnormal brain-derived neurotrophic factor function to the aetiology and physiopathology of different neurodegenerative disorders, such as Alzheimer's disease. This report describes the cellular and regional distribution of brain-derived neurotrophic factor in post mortem control human brain and in limited regions of the brain in patients with Alzheimer's disease, as was revealed by immunohistochemistry. Brain-derived neurotrophic factor is widely expressed in the control human brain, both by neurons and glia. In neurons, brain-derived neurotrophic factor was localized in the cell body, dendrites and axons. Among the structures showing the most intense immunohistochemical labeling were the hippocampus, claustrum, amygdala, bed nucleus of the stria terminalis, septum and the nucleus of the solitary tract. In the striatum, immunoreactivity was more intense in striosomes than in the matrix. Many labeled neurons were found in the substantia nigra pars compacta. The large putatively cholinergic neurons in the basal forebrain showed no immunoreactivity. The general pattern of labeling was similar in individuals with Alzheimer's disease. Brain-derived neurotrophic factor-immunoreactive material was found in senile plaques, and some immunoreactive cortical pyramidal neurons showed neurofibrillary tangles, suggesting that brain-derived neurotrophic factor may be involved in the process of neuronal degeneration and/or compensatory mechanisms which occur in this illness.

trkB messenger RNA expression in normal human brain and in the substantia nigra of parkinsonian patients: an in situ hybridization study.

trkB is a high-affinity receptor for brain-derived neurotrophic factor, a neurotrophin acting on numerous cells, including dopaminergic neurons. Yet, little is known of its expression in the human brain. We report an in situ hybridization analysis of trkB messenger RNA, encoding the catalytic form of the receptor, in the human brain post mortem. Its expression was found to be widespread but heterogeneous among all the cerebral structures studied, the highest level being found in the cerebral cortex and the cerebellum. A strong but less intense staining was observed in the striatum, nucleus basalis of Meynert, hippocampus, tegmental pedonculopontinus nucleus and substantia nigra pars compacta. Combined immunohistochemistry for tyrosine hydroxylase and in situ hybridization for trkB messenger RNA showed that within the substantia nigra pars compacta a major proportion of dopaminergic neurons expressed trkB messenger RNA. Furthermore, we compared trkB messenger RNA expression in the mesencephalon of six control subjects and five patients with Parkinson's disease, a neurodegenerative disorder characterized by a severe loss of dopaminergic neurons. Despite the fact that the number of trkB messenger RNA-containing neurons was dramatically reduced in the substantia nigra pars compacta and ventral tegmental area of patients with Parkinson's disease, the level of trkB messenger RNA was unchanged in the remaining neurons in diseased brains. These results suggests that trkB is not involved in the process of neuronal death in Parkinson's disease. Furthermore, expression of brain-derived neurotrophic factor high-affinity receptor in patients could allow this neurotrophin to be used to prevent degeneration of surviving neurons at early stages of the disease.

Striatal expression of glutamic acid decarboxylase gene in Alzheimer's disease.

To examine potential alteration of GABAergic striatal neurons in Alzheimer's disease, we used quantitative in situ hybridization to analyze the messenger RNA coding for Mr 67,000 glutamic acid decarboxylase (GAD67 mRNA) in the striatum of five patients with Alzheimer's disease (AD) and nine matched control subjects. We found a 51-57% increase in the optical density of hybridization signal in the caudate nucleus and putamen, corresponding to a 30-42% increase in the number of neurons expressing a detectable amount of GAD67 mRNA. By contrast, no alteration was observed in the ventral striatum. The expression of GAD67 mRNA per neuron was similar in AD and control subjects both in the dorsal and ventral striatum. Taken together, our data indicate that, in AD, GABAergic neurotransmission is increased in the dorsal striatum but not in the ventral striatum. We suggest that this increased GABAergic neurotransmission may explain extrapyramidal signs often observed in AD.

Nuclear translocation of NF-kappaB in cholinergic neurons of patients with Alzheimer's disease.

NF-kappaB is a nuclear transcription factor involved in the control of numerous cellular functions, particularly regulation of survival. Translocation from the cytoplasm to the nucleus, an event essential for NK-kappaB activation, could be mediated through the low-affinity nerve growth factor receptor, p75, which has recently been shown to mediate cell death. In the human brain, p75 is exclusively expressed in cholinergic neurons of the basal forebrain. This population degenerates in Alzheimer's disease (AD). To investigate whether p75 could play a role in the vulnerability of these neurons via NF-kappaB activation, we studied the cellular distribution of NF-kappaB in the nucleus basalis of Meynert of four AD patients and four control subjects. The immunostaining observed both in AD patients and control subjects was limited to large, probably cholinergic, neurons. In AD, the proportion of neurons with nuclear NF-kappaB staining was significantly increased, suggesting an association between NF-kappaB functions and the process of cholinergic degeneration in AD.

Expression of Bcl-2 in adult human brain regions with special reference to neurodegenerative disorders.

The expression of the protooncogene bcl-2, an inhibitor of apoptosis in various cells, was examined in the adult human brain. Several experimental criteria were used to verify its presence; mRNA was analyzed by northern blot with parallel experiments in mouse tissues, by RNase protection, and by in situ hybridization histochemistry. Bcl-2 protein was detected by western blot analysis and immunohistochemistry. Two bcl-2 mRNA species were identified in the human brain. The pattern of distribution of bcl-2 mRNA at the cellular level showed labeling in neurons but not glia. The in situ hybridization signal was stronger in the pyramidal neurons of the cerebral cortex and in the cholinergic neurons of the nucleus basalis of Meynert than in the Purkinje neurons of the cerebellum. Both melanized and nonmelanized neurons were labeled in the substantia nigra. In the striatum, bcl-2 mRNA was detected in some but not all neurons. In the regions examined for Bcl-2 protein, the expression pattern correlated with the mRNA results. In patients with Alzheimer's and Parkinson's diseases, quantification of bcl-2 mRNA in the nucleus basalis of Meynert and substantia nigra, respectively, showed that the expression was unaltered compared with controls, raising the possibility that the expression of other components of apoptosis is modulated.