Immediate-Onset Linear Effluvium Associated With High-Density Hair Transplantation: A Series of 28 Cases. / Efluvio en línea de aparición inmediata asociado a trasplante capilar de alta densidad: descripción de 28 casos.

We describe 28 patients who experienced effluvium with previously unreported features shortly after hair transplant surgery. Notable features were as follows: a) a linear morphology; b) immediate onset (1-3 days); c) association with dense-pack grafting in areas of receding hairline at the temples (Mickey Mouse pattern); d) a progressive increase in the diameter of the hair loss line (wave-like pattern); e) in some cases, subsequent concentric linear effluvium on the crown (donut pattern); and f) other forms of previously unreported immediate-onset effluvium. The linear morphology could be the result of dense packing, which can cause perilesional hypoxia and loss of miniaturized hairs around the recipient area. Since linear hair loss can cause patient concern about graft failure, we recommend taking images of transplanted and nontransplanted areas immediately after surgery and warning patients in advance about these transient effects, which are fully reversed in 3 months.

Biomarkers of cell damage, neutrophil and macrophage activation associated with in-hospital mortality in geriatric COVID-19 patients.

BACKGROUND: The risk for symptomatic COVID-19 requiring hospitalization is higher in the older population. The course of the disease in hospitalised older patients may show significant variation, from mild to severe illness, ultimately leading to death in the most critical cases. The analysis of circulating biomolecules involved in mechanisms of inflammation, cell damage and innate immunity could lead to identify new biomarkers of COVID-19 severity, aimed to improve the clinical management of subjects at higher risk of severe outcomes. In a cohort of COVID-19 geriatric patients (n= 156) who required hospitalization we analysed, on-admission, a series of circulating biomarkers related to neutrophil activation (neutrophil elastase, LL-37), macrophage activation (sCD163) and cell damage (nuclear cfDNA, mithocondrial cfDNA and nuclear cfDNA integrity). The above reported biomarkers were tested for their association with in-hospital mortality and with clinical, inflammatory and routine hematological parameters. Aim of the study was to unravel prognostic parameters for risk stratification of COVID-19 patients. RESULTS: Lower n-cfDNA integrity, higher neutrophil elastase and higher sCD163 levels were significantly associated with an increased risk of in-hospital decease. Median (IQR) values observed in discharged vs. deceased patients were: 0.50 (0.30-0.72) vs. 0.33 (0.22-0.62) for n-cfDNA integrity; 94.0 (47.7-154.0) ng/ml vs. 115.7 (84.2-212.7) ng/ml for neutrophil elastase; 614.0 (370.0-821.0) ng/ml vs. 787.0 (560.0-1304.0) ng/ml for sCD163. The analysis of survival curves in patients stratified for tertiles of each biomarker showed that patients with n-cfDNA integrity < 0.32 or sCD163 in the range 492-811 ng/ml had higher risk of in-hospital decease than, respectively, patients with higher n-cfDNA integrity or lower sCD163. These associations were further confirmed in multivariate models adjusted for age, sex and outcome-related clinical variables. In these models also high levels of neutrophil elastase (>150 ng/ml) appeared to be independent predictor of in-hospital death. An additional analysis of neutrophil elastase in patients stratified for n-cfDNA integrity levels was conducted to better describe the association of the studied parameters with the outcome. CONCLUSIONS: On the whole, biomarkers of cell-free DNA integrity, neutrophil and macrophage activation might provide a valuable contribution to identify geriatric patients with high risk of COVID-19 in-hospital mortality.

Multidisciplinary approach and multimodal therapy in resected pancreatic cancer. Observational study.

OBJECTIVE: Analysis and evaluation of a multidisciplinary approach, postoperative results and survival of a group of patients with resected pancreatic cancer after a multimodal therapy. DESIGN: DESCRIPTIVE, prospective and observational study. PATIENTS: Between January 2004 and December 2004, 124 patients with pancreatic cancer were evaluated. In 30 patients pancreatic resection was performed, and they are the object of this study. Results of preoperative evaluation, postoperative morbidity and mortality, and long term survival were studied. RESULTS: Diagnostic evaluation was completed in ambulatory basis in 20% of the patients. In 63% of cases, admission was done in the same day of surgery. In 3 patients (9%), tumor resection was not achieved, therefore, concordance between radiological and surgical resectability rate was 91%. Resectability rate was 24.1%. Surgical Mortality was 3.3%, with a global morbidity rate of 56.6%. Survival at one, two, three and, four years was 76.2%, 56.3%, 43%, y 27.3% respectively. CONCLUSIONS: Technological development and coordination of efforts in multidisciplinary teams offer an accurate evaluation of tumor involvement, and may reduce the number of laparotomies without tumor resection. The application of a systematic and generalized multimodal treatment in pancreatic cancer is progressively showing a tendency of progressive increase in resectability and survival rates in pancreatic cancer.

Role of p53 codon 72 arginine allele in cell survival in vitro and in the clinical outcome of patients with advanced breast cancer.

BACKGROUND: The p53 codon 72 polymorphism, which results in either an arginine or proline residue, plays a different role in vitro and in vivo in cell survival and drug resistance. We verified, in vitro, the impact of the arginine allele on cell survival under normoxia and hypoxia, and investigated in vivo the role of p53 codon 72 arginine homozygosity in the clinical outcome of advanced breast cancer patients. METHODS: Tumors at advanced stages grow in vivo in a hypoxic environment, and we mimicked such conditions in vitro using p53 null breast cancer cells transfected with either the arginine or proline allele. We also analyzed in vivo the p53 codon 72 genotype status of advanced breast cancer patients. RESULTS: In vitro transfection of the arginine allele induced higher cell death under normoxia, whereas cell death was greater in proline-transfected cells under hypoxia. The arginine allele upregulated BCRP-I, a hypoxia response gene, which increases drug resistance. Metastatic breast cancer patients homozygous for arginine had a significantly shorter time to progression and overall survival than those with heterozygous arginine/proline tumors. CONCLUSION: We provide a molecular explanation for the association of the arginine allele with tumor aggressiveness and treatment resistance in advanced breast cancer.

Efluvio en línea de aparición inmediata asociado a trasplante capilar de alta densidad: descripción de 28 casos / Immediate-Onset Linear Effluvium Associated With High-Density Hair Transplantation: A Series of 28 Cases

Describimos 28 pacientes que desarrollaron una forma de efluvio postrasplante capilar con características no descritas en la literatura: a) morfología lineal; b) aparición inmediata (1-3 días); c) asociación con ‘dense packing’ en entradas (‘signo de Mickey Mouse’); d) progresión del diámetro de la línea (patrón ‘wave-like’); e) posible adición posterior de efluvio lineal concéntrico a vértex (‘signo del Donut’), y f) además de otros efluvios tampoco publicados por su inmediatez de aparición. La morfología lineal podría ser el resultado de la alta densidad colocada en nuestros pacientes, provocando hipoxia perilesional y efluvio de las unidades foliculares miniaturizadas que rodean la zona receptora. Debido a que la línea alopécica provoca inseguridad a los pacientes sobre una posible no colocación de injertos, recomendamos iconografía postoperatoria inmediata demostrando unión de áreas trasplantada y no trasplantada, así como la explicación previa al paciente de este fenómeno transitorio y completamente reversible en 3 meses (AU)

We describe 28 patients who experienced effluvium with previously unreported features shortly after hair transplant surgery. Notable features were as follows: a) a linear morphology; b) immediate onset (1-3 days); c) association with dense-pack grafting in areas of receding hairline at the temples (Mickey Mouse pattern); d) a progressive increase in the diameter of the hair loss line (wave-like pattern); e) in some cases, subsequent concentric linear effluvium on the crown (donut pattern); and f) other forms of previously unreported immediate-onset effluvium. The linear morphology could be the result of dense packing, which can cause perilesional hypoxia and loss of miniaturized hairs around the recipient area. Since linear hair loss can cause patient concern about graft failure, we recommend taking images of transplanted and nontransplanted areas immediately after surgery and warning patients in advance about these transient effects, which are fully reversed in 3 months (AU)

[Translated article] Immediate-Onset Linear Effluvium Associated With High-Density Hair Transplantation: A Series of 28 Case / Efluvio en línea de aparición inmediata asociado a trasplante capilar de alta densidad: descripción de 28 casos

We describe 28 patients who experienced effluvium with previously unreported features shortly after hair transplant surgery. Notable features were as follows: a) a linear morphology; b) immediate onset (1-3 days); c) association with dense-pack grafting in areas of receding hairline at the temples (Mickey Mouse pattern); d) a progressive increase in the diameter of the hair loss line (wave-like pattern); e) in some cases, subsequent concentric linear effluvium on the crown (donut pattern); and f) other forms of previously unreported immediate-onset effluvium. The linear morphology could be the result of dense packing, which can cause perilesional hypoxia and loss of miniaturized hairs around the recipient area. Since linear hair loss can cause patient concern about graft failure, we recommend taking images of transplanted and nontransplanted areas immediately after surgery and warning patients in advance about these transient effects, which are fully reversed in 3 months (AU)

Describimos 28 pacientes que desarrollaron una forma de efluvio postrasplante capilar con características no descritas en la literatura: a) morfología lineal; b) aparición inmediata (1-3 días); c) asociación con ‘dense packing’ en entradas (‘signo de Mickey Mouse’); d) progresión del diámetro de la línea (patrón ‘wave-like’); e) posible adición posterior de efluvio lineal concéntrico a vértex (‘signo del Donut’), y f) además de otros efluvios tampoco publicados por su inmediatez de aparición. La morfología lineal podría ser el resultado de la alta densidad colocada en nuestros pacientes, provocando hipoxia perilesional y efluvio de las unidades foliculares miniaturizadas que rodean la zona receptora. Debido a que la línea alopécica provoca inseguridad a los pacientes sobre una posible no colocación de injertos, recomendamos iconografía postoperatoria inmediata demostrando unión de áreas trasplantada y no trasplantada, así como la explicación previa al paciente de este fenómeno transitorio y completamente reversible en 3 meses (AU)

Apoptosis-resistant phenotype in HL-60-derived cells HCW-2 is related to changes in expression of stress-induced proteins that impact on redox status and mitochondrial metabolism.

The onset of resistance to drug-induced apoptosis of tumour cells is a major problem in cancer therapy. We studied a drug-selected clone of promyelocytic HL-60 cells, called HCW-2, which display a complex resistance to a wide variety of apoptosis-inducing agents and we found that these cells show a dramatic increase in the expression of heat shock proteins (Hsps) 70 and 27, while the parental cell line does not. It is known that stress proteins such as Hsps can confer resistance to a variety of damaging agents other than heat shock, such as TNF-alpha, monocyte-induced cytotoxicity, and also play a role in resistance to chemotherapy. This elevated expression of Hsps is paralleled by an increased activity of mitochondrial metabolism and pentose phosphate pathway, this latter leading to high levels of glucose-6-phosphate dehydrogenase and, consequently, of glutathione. Thus, the apoptotic-deficient phenotype is likely because of the presence of high levels of stress response proteins and GSH, which may confer resistance to apoptotic agents, including chemotherapy drugs. Moreover, the fact that in HCW-2 cells Hsp70 are mainly localised in mitochondria may account for the increased performances of mitochondrial metabolism. These observations could have some implications for the therapy of cancer, and for the design of combined strategies that act on antioxidant defences of the neoplastic cell.

The different apoptotic potential of the p53 codon 72 alleles increases with age and modulates in vivo ischaemia-induced cell death.

A common arginine to proline polymorphism is harboured at codon 72 of the human p53 gene. In this investigation, we found that fibroblasts and lymphocytes isolated from arginine allele homozygote centenarians and sexagenarians (Arg+) undergo an oxidative-stress-induced apoptosis at a higher extent than cells obtained from proline allele carriers (Pro+). At variance, the difference in apoptosis susceptibility between Arg+ and Pro+ is not significant when cells from 30-year-old people are studied. Further, we found that Arg+ and Pro+ cells from centenarians differ in the constitutive levels of p53 protein and p53/MDM2 complex, as well as in the levels of oxidative stress-induced p53/Bcl-xL complex and mitochondria-localised p53. Consistently, all these differences are less evident in cells from 30-year-old people. Finally, we investigated the in vivo functional relevance of the p53 codon 72 genotype in a group of old patients (66-99 years of age) affected by acute myocardial ischaemia, a clinical condition in which in vivo cell death occurs. We found that Arg+ patients show increased levels of Troponin I and CK-MB, two serum markers that correlate with the extent of the ischaemic damage in comparison to Pro+ patients. In conclusion, these data suggest that p53 codon 72 polymorphism contributes to a genetically determined variability in apoptotic susceptibility among old people, which has a potentially relevant role in the context of an age-related pathologic condition, such as myocardial ischaemia.

p66(shc) is highly expressed in fibroblasts from centenarians.

p66(shc-/-) mice exhibit prolonged lifespan and increased resistance to oxidative and hypoxic stress. To investigate p66(shc) involvement in human longevity, p66(shc) mRNA and protein were evaluated in fibroblasts from young people, elderly and centenarians, exposed to oxidative or hypoxic stress. Unexpectedly, centenarians showed the highest basal levels of p66(shc). Oxidative stress induced p66(shc) in all samples. At variance, hypoxic stress caused p66(shc) reduction only in cells from centenarians. These changes occurred in absence of any modification of p66(shc) promoter methylation pattern. Intriguingly, in cells from centenarians, p66(shc) induction was affected by p53 codon 72 polymorphism. Thus, cells from centenarians present a peculiar regulation of p66(shc), suggesting that its role in mammalian longevity is more complex than previously thought.

The BB-paraoxonase genotype is associated with impaired brachial reactivity after acute hypertriglyceridemia in healthy subjects.

The possible relationship between paraoxonase (PON) gene polymorphism and brachial reactivity in healthy adult subjects in the presence of acute hypertriglyceridemia (HT), as a prooxidant factor, was investigated. In 101 healthy subjects the response to flow- induced vasodilatation was measured before and after Intralipid infusion. In the same subjects the A/B PON polymorphism was detected. The frequency was 0.545 for AA genotype, 0.356 for the AB genotype, and 0.099 for the BB genotype. At baseline all genotype groups had a similar increase in brachial artery diameter and flow. After Intralipid infusion, subjects sharing the BB genotype had a significant decrease vs. baseline values in changes in brachial artery diameter (P for trend < 0.001 vs. the other genotypes), but not in flow. In a subgroup of 55 subjects distributed among the 3 PON genotypes the same study protocol was repeated by buccal nitroglycerine administration to study the endothelium-independent vasodilatation. Again, subjects with the BB genotype had the worse vasodilation (P for trend < 0.001). Furthermore, subjects sharing the BB genotype had the lowest endothelium-independent and -dependent changes in diameter (P for trend < 0.001 vs. the other genotypes) independently of gender ratio, basal plasma triglycerides concentrations, and changes in plasma triglycerides concentrations. In conclusion, our study demonstrates that transient HT decreases vascular reactivity more in subjects with the PON BB genotype than in those with the other PON genotypes.

Paradoxes in longevity: sequence analysis of mtDNA haplogroup J in centenarians.

Previous studies have shown that mitochondrial DNA (mtDNA) haplogroup J is significantly over-represented in healthy centenarians with respect to younger controls, thus suggesting that this haplogroup predisposes to successful aging and longevity. On the other hand, the same haplogroup is reported to have elevated frequency in some complex diseases. To verify if centenarians clustered in a particular lineage within J we have sequenced the D-loop region from 18 centenarians and 18 younger controls, previously characterized to be J. Then the entire mtDNA molecule was sequenced in a sub-sample of nine centenarians to find possible functional mutations associated with haplogroup J in successful aging. No clustering of the J haplogroup mtDNA from centenarians was observed. In addition, most of the mutations found are known as disease-associated mutations. The general picture that emerges from the study is that the J haplogroup of centenarians is surprisingly similar to that found in complex diseases, as well as in Leber Hereditary Optic Neuropathy. This finding implies that the same mutations could predispose to disease or longevity, probably according to individual-specific genetic backgrounds and stochastic events. This data reveals another paradox of centenarians and confirms the complexity of the longevity trait.

Gene/longevity association studies at four autosomal loci (REN, THO, PARP, SOD2).

The possibility that four loci (REN, THO, PARP, SOD2) are associated with longevity was explored by comparing the genotypic pools of subjects older than 100 years with those of younger subjects matched for sex and geographic area (northern and southern Italy). The markers (all located within the respective gene) were HUMREN4; HUMTHO1; HUMPARP (gt)845nt; SOD2(C/T)401nt. In order to reduce the number of genotypes, multiallelic polymorphisms were recoded as diallelic according to allele size and frequency patterns (small: S, and large: L, alleles). A significant loss of LL homozygous genotypes was found at the THO locus in male but not in female centenarians with respect to matched controls. On the other hand no significant difference was found between case/control genotypic frequencies at REN, PARP, SOD2 loci. The latter loci therefore do not affect inter-individual variability in life expectancy (at least in terms of qualitative variants associated with the tested markers). However, the data is consistent with an association between the THO locus and longevity.

The unexpected contribution of immunosenescence to the leveling off of cancer incidence and mortality in the oldest old.

In this paper the hypothesis that some features of immunosenescence might impact on the levelling off of cancer incidence and mortality in the oldest old will be considered. In fact, the term immunosenescence suggests that a progressive loss of immune system (IS) function occurs with aging. However, the age-related modifications of the IS can be more properly acknowledged as a 'remodeling' characterized by profound structural changes, which modify the functional properties of IS. We suggest that the expansion with age of natural killer cells (NK) and of T cells which progressively acquire phenotypes intermediate between T lymphocytes and NK cells, together with the age-related changes in the production of inflammatory/anti-inflammatory cytokines, such as INFgamma and IL-4, might create an environment unfavorable for neoplastic growth in the oldest old. In this perspective, studies on immunosenescence likely provide insights on mechanisms responsible for the individual capacity to escape from the life-threatening consequences of cancer outgrowth.

Mitochondria, aging and longevity--a new perspective.

A new perspective is emerging indicating that mitochondria play a critical role in aging not only because they are the major source and the most proximal target of reactive oxygen species, but also because they regulate stress response and apoptosis. Recent literature indicates that, in response to stress, a variety of molecules translocate to and localise in mitochondria. These molecules are likely to interact with each other, in order to mediate mitochondria/nucleus cross-talk and to regulate apoptosis. We surmise that an integration of signals in multimolecular complexes occurs at mitochondrial level. These phenomena can be of critical importance for human aging and longevity.

Immunogenetics of longevity. Is major histocompatibility complex polymorphism relevant to the control of human longevity? A review of literature data.

Literature data suggest that human longevity may be directly correlated with optimal functioning of the immune system. Therefore, it is likely that one of the genetic determinants of longevity resides in those polymorphisms for the immune system genes that regulate immune responses. Accordingly, studies performed on mice have suggested that the Major Histocompatibility Complex (MHC), known to control a variety of immune functions, is associated with the life span of the strains. In the last 25 years, a fair number of cross-sectional studies that searched for the role of HLA (the human MHC) genes on human longevity by comparing HLA antigen frequencies between groups of young and elderly persons have been published, but conflicting findings have been obtained. In fact, the same HLA antigens are increased in some studies, decreased in others and unchanged in others. On the whole, that could lead us to hypothesize that the observed age-related differences in the frequency of HLA antigens are due to bias. In our opinion, this hypothesis is real for most studies owing to major methodological problems. However, some studies that do not meet these biases have shown an association between longevity and some HLA-DR alleles or HLA-B8,DR3 haplotype, known to be involved in the antigen non-specific control of immune response. Thus, HLA studies in man may be interpreted to support suggestions derived from the studies on congenic mice on MHC effects on longevity. However, in mice the association may be by way of susceptibility to lymphomas whereas, in human beings, the effect on longevity is likely, via infectious disease susceptibility. Longevity is associated with positive or negative selection of alleles (or haplotypes) that respectively confer resistance or susceptibility to disease(s), via peptide presentation or via antigen non-specific control of the immune response.

Recent advances in human gene-longevity association studies.

This paper reviews the recent literature on genes and longevity. The influence of genes on human life span has been confirmed in studies of life span correlation between related individuals based on family and twin data. Results from major twin studies indicate that approximately 25% of the variation in life span is genetically determined. Taking advantage of recent developments in molecular biology, researchers are now searching for candidate genes that might have an influence on life span. The data on unrelated individuals emerging from an ever-increasing number of centenarian studies makes this possible. This paper summarizes the rich literature dealing with the various aspects of the influence of genes on individual survival. Common phenomena affecting the development of disease and longevity are discussed. The major methodological difficulty one is confronted with when studying the epidemiology of longevity involves the complexity of the phenomenon, which arises from the polygenic nature of life span and historical mortality change. We discuss this issue and suggest new methodological approaches.