[Complex fronto-orbital reconstruction with a PEEK prosthesis and skin expansion: about a case]. / Reconstruction fronto-orbitaire complexe avec prothèse en PEEK et expansion cutanée : à propos d'un cas.

INTRODUCTION: Reconstructions of the fronto-orbital area remain a challenge to the reconstructive surgeon, due to the functional and esthetic impact. OBSERVATION: The authors present a case of a complex fronto-orbital reconstruction with a PEEK (PolyEtherEtherKetone) implant, associated with a skin expansion. DISCUSSION: With a follow-up of over three years, the cosmetic result is excellent. The authors believe that this technique is reliable, fast with long-term good results.

Assessment of deep brain stimulation candidacy during the COVID-19 pandemic: Lessons learned and future directions for neuropsychologists.

ObjectiveNeuropsychological assessment is integral to the pre-surgical deep brain stimulation (DBS) workup for patients with movement disorders. The COVID-19 pandemic quickly affected care access and shifted healthcare delivery, and neuropsychology has adapted successfully to provide tele-neuropsychological (teleNP) DBS evaluations during this time, thus permanently changing the landscape of neuropsychological practice. Method: In this paper, we discuss the lessons learned from the pandemic and we offer care management guidelines for teleNP and in-person evaluations of pre-DBS populations, with exploration of the feasibility of the different approaches for uninterrupted care access. Results: We summarize the strengths and weaknesses of these care models and we provide future directions for the state of clinical neuropsychological practice for DBS programs, with implications for broader patient populations. Conclusions: A better understanding of these dynamics will inform and educate the DBS team and community regarding the complexities of performing DBS neuropsychological evaluations during COVID-19 and beyond.

The global pandemic has permanently changed the state of practice for pre-DBS neuropsychological evaluations.

The evaluation and management of patients with movement disorders has evolved considerably due to the COVID-19 pandemic, including the assessment of candidates for deep brain stimulation (DBS) therapy. Members of the Neuropsychology Focus Group from the Parkinson Study Group Functional Neurosurgical Working Group met virtually to discuss current practices and solutions, build consensus, and to inform the DBS team and community regarding the complexities of performing DBS neuropsychological evaluations during COVID-19. It is our viewpoint that the practice of neuropsychology has adapted successfully to provide tele-neuropsychological pre-DBS evaluations during the global pandemic, thus permanently changing the landscape of neuropsychological services.

FACT-MNG: tumor site specific web-based outcome instrument for meningioma patients.

To formulate Functional Assessment of Cancer Therapy-Meningioma (FACT-MNG), a web-based tumor site-specific outcome instrument for assessing intracranial meningioma patients following surgical resection or stereotactic radiosurgery. We surveyed the relevant literature available on intracranial meningioma surgery and subsequent outcomes (38 papers), making note of which, if any, QOL/outcome instruments were utilized. None of the surgveyed papers included QOL assessment specific to tumor site. We subsequently developed questions that were relevant to the signs and symptoms that characterize each of 11 intracranial meningioma sites, and incorporated them into a modified combination of the Functional Assessment of Cancer Therapy-Brain (FACT-BR) and SF36 outcome instruments, thereby creating a new tumor site-specific outcome instrument, FACT-MNG. With outcomes analysis of surgical and radiosurgical treatments becoming more important, measures of the adequacy and success of treatment are needed. FACT-MNG represents a first effort to formalize such an instrument for meningioma patients. Questions specific to tumor site will allow surgeons to better assess specific quality of life issues not addressed in the past by more general questionnaires.

Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement.

In a model of male sterility (MTp53) owing to enforced p53 expression in spermatocytes II and spermatids of transgenic mice, we focused on the role of caspases. Most of them are expressed in all differentiation stages, but only the transcriptional levels of caspase-2 and caspase-3 are modified in MTp53 germ cells. In normal testis, cleaved caspase-3 and caspase-9 are detected during the elongation of spermatids. Despite this constitutive presence of caspases during terminal differentiation, calpains are the main effectors of germ cell loss in MTp53 testes: calpain 1 RNA levels are increased, caspase-3-like activity is markedly decreased while calpain activity is higher and the calpain inhibitor E64d ((2S, 3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester) reduces TUNEL labeling in MTp53 testis, whereas pancaspase inhibitor zVADfmk (N-benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone) has no effect. Our work suggests that despite the presence, and potent involvement, of caspases in male haploid cell maturation, calpains are the executioners of the death of terminally differentiating germ cells.

The yeast KEX-2-processing endoprotease is active in the Golgi apparatus of transfected NIH 3T3 fibroblasts.

Proteolytic processing of polyprotein precursors at pairs of basic amino acids is a prerequisite for the generation of bioactive peptide hormones. While the mammalian endoproteases responsible for these cleavages are yet to be identified, this function has been unequivocally assigned in yeast to the product of the KEX-2 gene. To study the molecular mechanisms involved in polyprotein processing, we have transfected the yeast KEX-2 gene into mouse NIH 3T3 fibroblasts and established a new cell line (called 2N-DK) where the KEX-2 endoprotease is permanently expressed. Immunofluorescence studies show that the KEX-2 enzyme is retained within the Golgi of the 2N-DK cells. The evidence for this cellular location is supported by measurement of intracellular and extracellular KEX-2 enzyme activity. In this permanently transfected cell line, KEX-2 activity is exclusively intracellular, in contrast to the situation previously described in transiently infected cell lines, where extracellular KEX-2 activity was detected. Furthermore, infection of 2N-DK cells with a recombinant retrovirus expressing a cDNA coding for porcine proopiomelanocortin (POMC) resulted in the synthesis of POMC and its efficient processing into beta-lipotropin and beta-endorphin, two of its physiologically authentic maturation products. These results suggest that in the fibroblast cell line 2N-DK, proteolytic processing of POMC by KEX-2 endoprotease occurs in the Golgi apparatus.

METABOLIC EFFECTS OF MARIJUANA USE AMONG BLACKS.

BACKGROUND: Increased legalization of marijuana has resulted in renewed interest in its effects on body weight and cardiometabolic risk. Conflicting data exist regarding marijuana effects on body weight, waist circumference as well as lipid profiles, blood pressure and cardiovascular disease. Furthermore, there is a dearth of data available on this effect in the black population. OBJECTIVE: To assess the metabolic profile and cardiovascular risk factors as well as body weight and waist circumference among urban black marijuana users. METHODS: A cross sectional study design involving 100 patients seen in a Family Practice clinic at University hospital of Brooklyn, NY, USA, over a period of 3 months from January 2014 to March 2014. Participants were administered a questionnaire regarding marijuana use, and other associated behaviors. Socio-demographic, laboratory, and clinical data were collected. We report measures of central tendencies, and dispersion for continuous variables and the frequency of distribution for categorical variables. RESULTS: Of the 100 patients surveyed, 57% were females. The mean (±SEM) age of the entire cohort was 46.3 years±1.5; range, 19-78 years. The mean body mass index (BMI) was 29.6 kg/m2±0.73; SBP=128.0 mmHg±1.69; DBP=76.1 mmHg±1.17. Current marijuana users had the lowest waist circumference compared to former or never users respectively (32.9±0.66 vs. 35.9±0.88 vs. 33.4±0.74), p<0.01. Diastolic blood pressure in mmHg was significantly higher among former marijuana users compared to current or never users, (80.0±2.1 vs. 73.3±2.3 vs. 73.4±1.6), p<0.01. Current marijuana users showed a tendency (not statistically significant) towards lower total cholesterol, Triglycerides (TG), High Density Lipoprotein (HDL)-cholesterol, Low Density Lipoprotein (LDL)-cholesterol, body mass index (BMI) and systolic blood pressure, compared to former users or never users. CONCLUSION: Current marijuana use is associated with significantly lower waist circumference, compared to former users and never users. Except for diastolic BP that was significantly lower among current users, other metabolic parameters showed tendency towards favorable profile. Further studies are needed to characterize the metabolic effects and to elucidate mechanisms of actions of marijuana in view of its rapid rate of utilization in the USA and around the world.

High specificity of Müllerian-inhibiting substance signaling in vivo.

Female transgenic mice that ectopically express high levels of human Müllerian-inhibiting substance (hMIS) under the control of the mouse metallothionein (MT) promoter lack a uterus, oviducts, and ovaries. The loss of the uterus and oviducts is consistent with the known activities for MIS. However, it is not clear if the loss of the ovaries in these transgenic females is caused by interactions of MIS with its normal receptor signaling pathway or by abnormal interactions with other transforming growth factor-beta (TGF-beta) super family receptor signaling pathways. To address this question, female mice carrying the MT-hMIS transgene that were also homozygous for a targeted deletion of the MIS type II receptor gene were generated. Although these females had high levels of circulating hMIS, they had normal reproductive tracts and ovaries with germ cells. In addition, these females were able to become pregnant and gave birth to pups. These findings demonstrate that all of the abnormalities of the reproductive system that are found in female transgenic mice that ectopically express high levels of hMIS are caused by signaling through the MIS type II receptor. These in vivo data demonstrate a high specificity for MIS and its receptor.

The role of anti-Müllerian hormone in gonadal development.

Anti-Müllerian (AMH), a member of the transforming growth factor beta produced by immature Sertoli cells and, to a lesser degree, by granulosa cells from birth to the end of reproductive life, does not affect gonadal determination but has a negative effect upon gonadal development in both sexes. It blocks meiosis in fetal ovaries, leading to loss of germ cells and subsequent fibrous degeneration, and inhibits the transcription of aromatase and LH receptor. AMH also affects the development and function of the adult testis by blocking the differentiation of mesenchymal into Leydig cells and by independently decreasing the expression of steroidogenic enzymes.

Investigation of a possible role of the amino-terminal pro-region of proopiomelanocortin in its processing and targeting to secretory granules.

Proopiomelanocortin (POMC) is a polyprotein which is targeted to the regulated secretory pathway of neuroendocrine cells where it undergoes tissue-specific proteolysis to yield peptides such as adrenocorticotropic hormone, beta-lipotropin and beta-endorphin. The pro-region of POMC is 49 amino acid long with two disulfide bonds between cysteine residues 2 and 24 and 8 and 20. These cysteine residues are conserved across the species. The pro-region contains no known hormonal sequence. Sorting to the regulated secretory pathway is thought to involve targeting signals encoded in the structure of secretory proteins. In the present study, we have examined the possibility that the disulfide bridges located in the NH2-terminal portion of the pro-region of POMC are essential for maintaining a determinant involved in the sorting of POMC to the regulated secretory pathway. Using site-directed and deletion mutagenesis of the porcine POMC cDNA, we created mutants in which one or both disulfide bridges were disrupted or in which the first 26 amino acid residues of the pro-region were deleted. Recombinant retroviruses carrying the mutated POMC cDNAs were used to infect Neuro2A cells. Immunofluorescence and immunoelectron microscopy studies performed on infected cells revealed that the unmutated and mutated POMC-immunoreactive peptides were localized in dense-core vesicles at the tips of cellular extensions. Analysis of the POMC-immunoreactive peptides extracted from the infected Neuro2A cells indicated that the mutated precursors in which one disulfide bridge was disrupted (POMC-S2 or POMC-S8) were stored and processed as efficiently as the unmutated POMC. By contrast, the mutated precursor in which both disulfide bridges were disrupted (POMC-S2,8) did not accumulate in intracellular compartments to the same extent as unmutated POMC. Moreover, this mutant was very inefficiently processed and no release could be observed upon stimulation of the cells with K+/Ca2+. These results suggest that POMC-S2,8 entered the regulated secretory pathway less efficiently than the unmutated precursor. However, when both disulfide bridges were removed from the precursor from the precursor by deletion of the first 26 amino acid residues of POMC, the truncated precursor (POMC delta 1-26) behaved as the unmutated POMC. Taken together our results indicate that the NH2-terminal portion of the pro-region including both disulfide bridges can be deleted without affecting the targeting of the molecule to secretory granules. However, when the entire POMC sequence is expressed in Neuro2A cells, the proper folding of the NH2-terminal region might be important for efficient processing and targeting.

Luteinizing hormone-dependent activity and luteinizing hormone-independent differentiation of rat fetal Leydig cells.

Addition of 5x10(-2) U/ml recombinant luteinizing hormone (LH) to testes from fetuses at 16.5 day post conception (dpc) cultured for 5 days increased the number of Leydig cells by 34% and the acute LH-stimulated testosterone production by 600%. To determine whether these positive effects of LH in vitro are physiologically relevant in vivo, fetuses were decapitated on days 16.5 pc (before the onset of LH expression in the hypophysis) or 18.5 pc (before the surge of LH in the fetal plasma) and removed at 21.5 dpc. The number of fetal Leydig cells per testis and the acute LH-stimulated testosterone production by the testes ex vivo were unaltered by decapitation. Since, in all groups, the number of Leydig cells doubled between 16.5 and 18.5 dpc and between 18.5 and 21.5 dpc, these results suggest that neither the appearance of new fully differentiated fetal Leydig cells nor the maintenance of differentiated functions in existing fetal Leydig cells depend on LH during late fetal life, although this hormone is present in the plasma. Decapitation reduced the testosterone concentrations in the plasma (-56%) and in the testis in vivo (-67%) and the basal testosterone secretion of the testis ex vivo (-70%). This suggests that LH is required to maintain the physiological activity of the Leydig cell during late fetal life. However, the decrease of the in vivo testosterone production after decapitation was not sufficient to impair the growth of the Wolffian ducts and the lengthening of the anogenital distance. In conclusion, during late fetal life in the rat, Leydig cells are LH-independent for their functional differentiation and LH-dependent for their activity.

Glutathione elevation and its protective role in acrolein-induced protein damage in synaptosomal membranes: relevance to brain lipid peroxidation in neurodegenerative disease.

Oxidative stress may be a hallmark of several neurodegenerative disorders, including Alzheimer's disease (AD) Huntington's, and Parkinson's diseases as well as amyotrophic lateral sclerosis. Acrolein is a highly reactive product of lipid peroxidation that is elevated in the brains of persons with AD. This alkenal potentially can react with proteins by Michael addition to alter their structure and function. In the present study, we used electron paramagnetic resonance in conjunction with a protein-specific spin label to monitor synaptosomal membrane protein conformational alterations induced by acrolein. A dose-dependent increased conformational alteration was observed. Consistent with this finding, protein carbonyl levels from protein-bound acrolein were significantly elevated. However, pretreatment of synaptosomes with glutathione ethyl ester (GEE) significantly ameliorated both the conformational alterations and protein carbonyls induced by acrolein. Based on this success, we tested the hypothesis that elevated levels of endogenous glutathione (GSH) would offer protection against acrolein-induced oxidative stress. In-vivo elevation of GSH (215% over control, P<0.04) was produced by i.p. injection of N-acetylcysteine (NAC), a known precursor of GSH. Synaptosomes were treated with vehicle or 2 nM acrolein, the level of this alkenal found in AD brain. In contrast to synaptosomes from control animals, which had significantly increased protein carbonyl levels following addition of 2 nM acrolein, synaptosomes that were isolated from NAC-treated rodents and treated with 2 nM acrolein showed no increased carbonyl levels compared to untreated controls. These results demonstrate protection by increased in-vivo GSH levels against acrolein-induced oxidative stress at levels found in AD brain and are consistent with the notion that methods to increase endogenous GSH levels in neurodegenerative diseases associated with oxidative stress may be promising.

White phosphorus poisoning of waterfowl in an Alaskan salt marsh.

The cause of the yearly death of an estimated 1,000 to 2,000 migrating dabbling ducks (Anas spp.) and 10 to 50 swans (Cygnus buccinator and C. columbianus) has remained a mystery for the last ten years in Eagle River Flats (ERF), a 1,000 ha estuarine salt marsh near Anchorage, Alaska, used for artillery training by the U.S. Army. We have gathered evidence that the cause of this mortality is the highly toxic, incendiary munition white phosphorus (P4). The symptoms of poisoning we observed in wild ducks included lethargy, repeated drinking, and head shaking and rolling. Death was preceded by convulsions. Farm-reared mallards dosed with white phosphorus showed nearly identical behavioral symptoms to those of wild ducks that became sick in ERF. White phosphorus does not occur in nature but was found in both the sediments where dabbling ducks and swans feed and in the gizzards of all carcasses collected in ERF. We hypothesize that feeding waterfowl are ingesting small particles of the highly toxic, incendiary munition P4 stored in the bottom anoxic sediments of shallow salt marsh ponds.

Executive dysfunction in frontotemporal dementia is related to abnormalities in frontal white matter tracts.

Cognitive deficits in behavioral-variant frontotemporal dementia (bvFTD) and AD are linked to frontal and temporal lobe gray matter (GM) pathology. The aim of this study was to assess the relative contribution of white (WM) and GM abnormalities to cognitive dysfunction in bvFTD and AD. Fractional anisotropy (FA) for the corpus callosum, cingulum (Cg), and uncinate fasciculus (Unc) was determined in 17 bvFTD and 10 AD patients who underwent neuropsychological testing. Regressions were performed to assess the relative contribution of WM and GM abnormalities to cognitive deficits. Multiple regression analysis revealed that in bvFTD, the left anterior Cg FA was related to executive function, the right anterior Cg FA to visual-spatial attention and working memory, the right posterior Cg to visual-constructional abilities and the left Unc FA to Modified Trails Errors. After adding corresponding GM volumes, the left anterior Cg FA, the right anterior cingulate FA, the right posterior cingulate FA and the left uncinate FA remained significant predictors of the cognitive tasks. In the AD group, the left posterior Cg FA and right descending Cg FA were related to visual recall performance but did not remain significant predictors when GM volumes were added to the regression. These results suggest that reduced integrity of specific WM tracts contribute to cognitive deficits observed in bvFTD after accounting for GM atrophy. In AD, memory impairment was related to WM tract injury but this relationship was no longer observed when GM volumes were included.

Subthalamic nucleus deep brain stimulation in primary cervical dystonia.

OBJECTIVES: The globus pallidus internus (GPi) has been the primary target for deep brain stimulation (DBS) to treat severe medication-refractory dystonia. Some patients with primary cervical or segmental dystonia develop subtle bradykinesia occurring in previously nondystonic body regions during GPi DBS. Subthalamic nucleus (STN) DBS may provide an alternative target choice for treating dystonia, but has only been described in a few short reports, without blinded rating scales, statistical analysis, or detailed neuropsychological studies. METHODS: In this prospective pilot study, we analyzed the effect of bilateral STN DBS on safety, efficacy, quality of life, and neuropsychological functioning in 9 patients with medically refractory primary cervical dystonia. Severity of dystonia was scored by a blinded rater (unaware of the patient's preoperative or postoperative status) using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) preoperatively and 3, 6, and 12 months postsurgery. Lead location, medications, and adverse events were also measured. RESULTS: STN DBS was well-tolerated with no serious adverse effects. The TWSTRS total score improved (p < 0.001) from a mean (±SEM) of 53.1 (±2.57), to 19.6 (±5.48) at 12 months. Quality of life measures were also improved. STN DBS induced no consistent neuropsychological deficits. Several patients reported depression in the study and 3 had marked weight gain. No patients developed bradykinetic side effects from stimulation, but all patients developed transient dyskinetic movements during stimulation. CONCLUSIONS: This prospective study showed that bilateral STN DBS resulted in improvement in dystonia and suggests that STN DBS may be an alternative to GPi DBS for treating primary cervical dystonia. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that bilateral subthalamic nucleus deep brain stimulation results in significant improvement in cervical dystonia without bradykinetic side effects.

Early expression of the androgen receptor in the Sertoli cells of a marsupial coincides with downregulation of anti-Müllerian hormone at the time of urogenital virilization.

Anti-Müllerian hormone (AMH), responsible for the regression of Müllerian ducts, is strongly expressed by eutherian fetal and postnatal Sertoli cells. Both AMH and testosterone levels are high during the period of fetal reproductive tract virilization which occurs largely in utero in eutherian mammals. Taking advantage of the fact that differentiation of the urogenital tract occurs after birth in marsupials, we studied the ontogeny and regulation of AMH in the tammar wallaby testis and related it to the expression of the androgen receptor in Sertoli cells. Testicular AMH expression was high between days 10-30 post partum, then fell to basal levels by day 60 and remained low until day 90, the oldest age examined. AMH expression was repressed by treatment of male pouch young with the potent androgen androstanediol. Thus, in the tammar, AMH expression decreases in response to androgen at the time of initial urogenital masculinization, in contrast to the situation in humans in which AMH is repressed by testosterone only at the time of puberty. The difference might be explained by the timing of androgen receptor expression which appears in tammar Sertoli cells at around day 40 of pouch life but only at a later developmental stage in eutherians.

11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration.

BACKGROUND: The PET tracer (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) specifically binds fibrillar amyloid-beta (Abeta) plaques and can be detected in Alzheimer disease (AD). We hypothesized that PET imaging with (11)C-PIB would discriminate AD from frontotemporal lobar degeneration (FTLD), a non-Abeta dementia. METHODS: Patients meeting research criteria for AD (n = 7) or FTLD (n = 12) and cognitively normal controls (n = 8) underwent PET imaging with (11)C-PIB (patients and controls) and (18)F-fluorodeoxyglucose ((18)F-FDG) (patients only). (11)C-PIB whole brain and region of interest (ROI) distribution volume ratios (DVR) were calculated using Logan graphical analysis with cerebellum as a reference region. DVR images were visually rated by a blinded investigator as positive or negative for cortical (11)C-PIB, and summed (18)F-FDG images were rated as consistent with AD or FTLD. RESULTS: All patients with AD (7/7) had positive (11)C-PIB scans by visual inspection, while 8/12 patients with FTLD and 7/8 controls had negative scans. Of the four PIB-positive patients with FTLD, two had (18)F-FDG scans that suggested AD, and two had (18)F-FDG scans suggestive of FTLD. Mean DVRs were higher in AD than in FTLD in whole brain, lateral frontal, precuneus, and lateral temporal cortex (p < 0.05), while DVRs in FTLD did not significantly differ from controls. CONCLUSIONS: PET imaging with (11)C-labeled Pittsburgh Compound-B ((11)C-PIB) helps discriminate Alzheimer disease (AD) from frontotemporal lobar degeneration (FTLD). Pathologic correlation is needed to determine whether patients with PIB-positive FTLD represent false positives, comorbid FTLD/AD pathology, or AD pathology mimicking an FTLD clinical syndrome.

Climate change. Increasing shrub abundance in the Arctic.

The warming of the Alaskan Arctic during the past 150 years has accelerated over the last three decades and is expected to increase vegetation productivity in tundra if shrubs become more abundant; indeed, this transition may already be under way according to local plot studies and remote sensing. Here we present evidence for a widespread increase in shrub abundance over more than 320 km of Arctic landscape during the past 50 years, based on a comparison of historic and modern aerial photographs. This expansion will alter the partitioning of energy in summer and the trapping and distribution of snow in winter, as well as increasing the amount of carbon stored in a region that is believed to be a net source of carbon dioxide.

Calcium antagonist radioprotectors do not reduce radiotherapeutic efficacy in three human tumor xenografts.

AIM: Calcium antagonists, which protect normal tissue as exemplified by bone marrow cells from radiation injury, were evaluated for radioprotection of tumor cells. MATERIALS AND METHODS: One Ewing's sarcoma and 2 colon carcinomas were grown as xenografts in immunosuppressed mice. The mice were treated with diltiazem, nifedipine, nimodipine and nitrendipine. The effect of whole body gamma-radiation on the growth of the subcutaneously implanted tumors was assessed. RESULTS: Growth delay or regression of the tumors in mice treated with the calcium antagonists prior to irradiation was not reduced as compared to only irradiated controls. CONCLUSION: The tested calcium antagonists, which are well tolerated and protect mice from death after lethal radiation, did not prevent the radiotherapeutic effect on 3 human tumors. This points to the possibility of differential radioprotection and thus to improve the therapeutic ratio in cancer radiotherapy.