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Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is a comparably seldom but fatal entity. The definition of cardiogenic shock - unlike e. g. septic shock - is not uniform. Immediate revascularization is central to the patient's prognosis in AMI-CS. Patients who continue to meet the criteria of shock despite revascularization should be hemodynamically phenotyped to allow guidance of personalized subsequent therapy. Antiplatelet medication is the cornerstone for maintaining myocardial (re)perfusion. In hypotension, norepinephrine should be used as the first-line vasopressor, depending on afterload and after compensation for possible hypovolemia. Dobutamine is recommended to increase inotropy, possibly augmented or substituted by calcium sensitizers such as levosimendan. PDE-III (phosphodiesterase enzyme type III)-inhibitors should be used with restraint in myocardial infarction. Dopamine is no longer recommended in Europe. A sasodilator may be an option in highly selected patients with AMI-CS. This review will provide a detailed updated overview on pharmacological treatment modalities and indications in individual patients.

BackgroundThe role of club cells in the pathology of idiopathic pulmonary fibrosis (IPF) is not well understood. Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum-based redox chaperone required for the functions of various fibrosis-related proteins; however, the mechanisms of action of PDIA3 in pulmonary fibrosis are not fully elucidated.ObjectivesTo examine the role of club cells and PDIA3 in the pathology of pulmonary fibrosis and the therapeutic potential of inhibition of PDIA3 in lung fibrosis.MethodsRole of PDIA3 and aberrant club cells in lung fibrosis was studied by analyses of human transcriptome dataset from Lung Genomics Research Consortium, other public resources, the specific deletion or inhibition of PDIA3 in club cells and blocking SPP1 downstream of PDIA3 in mice.ResultsPDIA3 and club cell secretory protein (SCGB1A1) signatures are upregulated in IPF compared with control patients. PDIA3 or SCGB1A1 increases also correlate with a decrease in lung function in patients with IPF. The bleomycin (BLM) model of lung fibrosis showed increases in PDIA3 in SCGB1A1 cells in the lung parenchyma. Ablation of Pdia3, specifically in SCGB1A1 cells, decreases parenchymal SCGB1A1 cells along with fibrosis in mice. The administration of a PDI inhibitor LOC14 reversed the BLM-induced parenchymal SCGB1A1 cells and fibrosis in mice. Evaluation of PDIA3 partners revealed that SPP1 is a major interactor in fibrosis. Blocking SPP1 attenuated the development of lung fibrosis in mice.ConclusionsOur study reveals a new relationship with distally localised club cells, PDIA3 and SPP1 in lung fibrosis and inhibition of PDIA3 or SPP1 attenuates lung fibrosis.

Highlights • EBV reactivation was observed in patients with COVID-19. • NK + and CD8 + T cell reduction was related to the severity of COVID-19 infection. • An increase of B cells in patients with severe symptoms was documented., Objectives The immunologic profile and opportunistic viral DNA increase were monitored in Italian patients with COVID-19 in order to identify markers of disease severity. Methods A total of 104 patients infected with SARS-CoV-2 were evaluated in the study. Of them, 42/104 (40.4%) were hospitalized in an intensive care unit (ICU) and 62/104(59.6%) in a sub-intensive care unit (SICU). Human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), Parvovirus B19 and Human Herpesvirus 6 virus reactivations were determined by real-time PCR, and lymphocyte subpopulation counts were determined by flow cytometry. Results Among opportunistic viruses, only EBV was consistently detected. EBV DNA was observed in 40/42 (95.2%) of the ICU patients and in 51/61 (83.6%) of the SICU patients. Comparing the two groups of patients, the EBV DNA median level among ICU patients was significantly higher than that observed in SICU patients. In parallel, a significant reduction of CD8 T cell and NK count in ICU patients as compared with SICU patients was observed (p

It has long been appreciated that the endoplasmic reticulum (ER) and mitochondria, organelles important for regular cell function and survival, also play key roles in pathogenesis of various lung diseases, including asthma, fibrosis, and infections. Alterations in processes regulated within these organelles, including but not limited to protein folding in the ER and oxidative phosphorylation in the mitochondria, are important in disease pathogenesis. In recent years it has also become increasingly apparent that organelle structure dictates function. It is now clear that organelles must maintain precise organization and localization for proper function. Newer microscopy capabilities have allowed the scientific community to reveal, via 3D imaging, that the structure of these organelles and their interactions with each other are a main component of regulating function and, therefore, effects on the disease state. In this review, we will examine how 3D imaging through techniques could allow advancements in knowledge of how the ER and mitochondria function and the roles they may play in lung epithelia in progression of lung disease.

CoronaVac is an inactivated SARS-CoV-2 vaccine that has been rolled out in several low and middle-income countries including Brazil, where it was the mainstay of the first wave of immunization of healthcare workers and the elderly population. We aimed to assess the T cell and antibody responses of vaccinated individuals as compared to convalescent patients. We detected IgG against SARS-CoV-2 antigens, neutralizing antibodies against the reference Wuhan SARS-CoV-2 strain and used SARS-CoV-2 peptides to detect IFN-g and IL-2 specific T cell responses in a group of CoronaVac vaccinated individuals (N = 101) and convalescent (N = 72) individuals. The frequency among vaccinated individuals, of whom 96% displayed T cell and/or antibody responses to SARS-CoV-2, is comparable to 98.5% responses of convalescent individuals. We observed that among vaccinated individuals, men and individuals 55 years or older developed significantly lower anti-RBD, anti-NP and neutralization titers against the Wuhan strain and antigen-induced IL-2 production by T cells. Neutralizing antibody responses for Gamma variant were even lower than for the Wuhan strain. Even though some studies indicated CoronaVac helped reduce mortality among elderly people, considering the appearance of novel variants of concern, CoronaVac vaccinated individuals above 55 years old are likely to benefit from a heterologous third dose/booster vaccine to increase immune response and likely protection.

Made available in DSpace on 2022-04-29T08:46:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Recurrence of COVID-19 in recovered patients has been increasingly reported. However, the immune mechanisms behind the recurrence have not been thoroughly investigated. The presence of neutralizing antibodies (nAbs) in recurrence/reinfection cases suggests that other types of immune response are involved in protection against recurrence. Here, we investigated the innate type I/III interferon (IFN) response, binding and nAb assays and T-cell responses to severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) with IFN gamma (IFNγ) enzyme-linked spot assay (ELISPOT) in three pairs of young adult monozygotic (MZ) twins with previous confirmed COVID-19, one of them presenting a severe recurrence four months after the initial infection. Twin studies have been of paramount importance to comprehend the immunogenetics of infectious diseases. Each MZ twin pair was previously exposed to SARS-CoV-2, as seen by clinical reports. The six individuals presented similar overall recovered immune responses except for the recurrence case, who presented a drastically reduced number of recognized SARS-CoV-2 T-cell epitopes on ELISPOT as compared to her twin sister and the other twin pairs. Our results suggest that the lack of a broad T-cell response to initial infection may have led to recurrence, emphasizing that an effective SARS-CoV-2-specific T-cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19. Human Genome and Stem Cell Research Center (HUG-CELL) Biosciences Institute Universidade de São Paulo, SP Laboratory of Immunology Heart Institute (InCor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), SP Institute for Investigation in Immunology Instituto Nacional de Ciência e Tecnologia - Iii-INCT, SP Division of Clinical Immunology and Allergy Department of Medicine Faculdade de Medicina da Universidade de São Paulo (FMUSP), SP Department of Microbiology Immunology and Parasitology Universidade Federal de São Paulo (UNIFESP/EPM), SP Department of Parasitology Biosciences Institute Universidade de São Paulo, SP School of Medicine Universidade Estadual Paulista (UNESP), SP Fleury Laboratory, SP School of Medicine Universidade Estadual Paulista (UNESP), SP

Influenza (IAV) neuraminidase (NA) is a glycoprotein required for the viral exit from the cell. NA requires disulfide bonds for proper function. We have recently demonstrated that protein disulfide isomerase (PDI)A3 is required for oxidative folding of IAV hemagglutinin (HA), and viral propagation. However, it not known whether PDIs are required for NA maturation or if these interactions represent a putative target for the treatment of influenza infection. We sought to determine whether PDIA3 is required for disulfide bonds of NA, its activity, and propagation of the virus. Requirement of disulfides for NA oligomerization and activity were determined using biotin switch and redox assays in WT and PDIA3−/− in A549 cells. A PDI specific inhibitor (LOC14) was utilized to determine the requirement of PDIs in NA activity, IAV burden, and inflammatory response in A549 and primary mouse tracheal epithelial cells. Mice were treated with the inhibitor LOC14 and subsequently examined for IAV burden, NA activity, cytokine, and immune response. IAV-NA interacts with PDIA3 and this interaction is required for NA activity. PDIA3 ablation or inhibition decreased NA activity, viral burden, and inflammatory response in lung epithelial cells. LOC14 treatment significantly attenuated the influenza-induced inflammatory response in mice including the overall viral burden. These results provide evidence for PDIA3 inhibition suppressing NA activity, potentially providing a novel platform for host-targeted antiviral therapies.

Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of Drp1 in lung epithelial cells leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM.

Background Tumor dynamics typically rely on the sum of the longest diameters (SLD) of target lesions, and ignore heterogeneity in individual lesion dynamics located in different organs. Patients and methods Here we evaluated the benefit of analyzing lesion dynamics in different organs to predict survival in 900 patients with metastatic urothelial carcinoma treated with atezolizumab or chemotherapy (IMvigor211 trial). Results Lesion dynamics varied largely across organs, with lymph nodes and lung lesions showing on average a better response to both treatments than those located in the liver and locoregionally. A benefit of atezolizumab was observed on lung and liver lesion dynamics that was attributed to a longer duration of treatment effect as compared to chemotherapy (P value = 0.043 and 0.001, respectively). The impact of lesion dynamics on survival, assessed by a joint model, varied greatly across organs, irrespective of treatment. Liver and locoregional lesion dynamics had a large impact on survival, with an increase of 10 mm of the lesion size increasing the instantaneous risk of death by 12% and 10%, respectively. In comparison, lymph nodes and lung lesions had a lower impact, with a 10-mm increase in the lesion size increasing the instantaneous risk of death by 7% and 5%, respectively. Using our model, we could anticipate the benefit of atezolizumab over chemotherapy as early as 6 months before the end of the study, which is 3 months earlier than a similar model only relying on SLD. Conclusion We showed the interest of organ-level tumor follow-up to better understand and anticipate the treatment effect on survival., Highlights • Nine hundred metastatic urothelial carcinoma patients from the IMvigor211 phase III trial were treated with atezolizumab versus chemotherapy. • A total of 4489 organ-specific measurements were made: 1544 measurements in the lymph, 999 in the lung, 691 in the liver, and 559 locoregionally. • Longer treatment effect was observed in the lung (P value = 0.043) and liver (P = 0.001) lesions under atezolizumab compared to chemotherapy. • Those with a 10-mm growth of liver lesion had their instantaneous risk of death increased by 12%, compared to 5% in the lung. • Treatment effect on overall survival could be predicted based on early organ-specific tumor data 6 months after last patient inclusion.

© 2019 American Society for Clinical Investigation. Conjugated bile acids (CBAs), such as tauroursodeoxycholic acid (TUDCA), are known to resolve the inflammatory and unfolded protein response (UPR) in inflammatory diseases, such as asthma. Whether CBAs exert their beneficial effects on allergic airway responses via 1 arm or several arms of the UPR, or alternatively through the signaling pathways for conserved bile acid receptor, remains largely unknown. We used a house dust mite-induced (HDM-induced) murine model of asthma to evaluate and compare the effects of 5 CBAs and 1 unconjugated bile acid in attenuating allergen-induced UPR and airway responses. Expression of UPRassociated transcripts was assessed in airway brushings from human patients with asthma and healthy subjects. Here we show that CBAs, such as alanyl β-muricholic acid (AβM) and TUDCA, significantly decreased inflammatory, immune, and cytokine responses; mucus metaplasia; and airway hyperresponsiveness, as compared with other CBAs in a model of allergic airway disease. CBAs predominantly bind to activating transcription factor 6α (ATF6α) compared with the other canonical transducers of the UPR, subsequently decreasing allergen-induced UPR activation and resolving allergic airway disease, without significant activation of the bile acid receptors. TUDCA and AβM also attenuated other HDM-induced ER stress markers in the lungs of allergic mice. Quantitative mRNA analysis of airway epithelial brushings from human subjects demonstrated that several ATF6α-related transcripts were significantly upregulated in patients with asthma compared with healthy subjects. Collectively, these results demonstrate that CBA-based therapy potently inhibits the allergen-induced UPR and allergic airway disease in mice via preferential binding of the canonical transducer of the UPR, ATF6α. These results potentially suggest a novel avenue to treat allergic asthma using select CBAs.

Background Arterial hypertension is very common in chronic kidney disease (CKD) patients and its prevalence increases with lowering estimated glomerular filtration rate (eGFR). Blood pressure (BP) control is a cornerstone in the treatment of CKD patients but still most treatment decisions are based on office BP measurement (OBPM). The aim of this cross-sectional, retrospective study is to investigate the prevalence of hypertension phenotypes in CKD patients and whether different home (HBPM) or OBPM are associated with a different CKD stage and cardiovascular comorbidities. Methods We analyzed 560 consecutive patients (359 men, age 70±13 years), affected by stage 3-5 CKD, who performed HBPM recording; OBPM during a single visit was also assessed. Uncontrolled hypertension was defined as OBPM values ≥140/90 mmHg and HBPM values ≥135/85 mmHg, respectively. Results Systolic and diastolic HBPM values were lower than OBPM values. A white coat effect (systolic BP +18±12 mmHg) was detected in 62.5%, while a masked effect (systolic BP -14±10 mmHg) was detected in 22.7%. No relationship was found between BP differences and body weight, CKD stage, eGFR or presence of diabetes. Based on OBPM, 18.6% of patients showed controlled systolic and diastolic BP, whereas 37.8% had sustained hypertension. White-coat hypertension was detected in 23.4% and Masked hypertension in 12.1%. The multiple logistic regression model showed that masked uncontrolled hypertensive patients showed a higher probability of having ischemic heart disease (OR=2.54 [1.02-6.36]), while sustained hypertension was associated with an increased prevalence of stroke in comparison to normotensive or true control BP group (OR=4.72 [1.30-17.07]). Age, gender, diabetes or CKD stage, were not different among the four hypertension phenotypes. Conclusions We observed a quite high rate of masked uncontrolled hypertension and of white coat hypertension in stage 3-5ND CKD patients. Office BP measurement, as a single tool, is an inadequate diagnostic procedure in the clinical management of CKD patients. HBPM should be routinely implemented for identifying hypertensive phenotypes and then for avoiding misdiagnosis and mistreatment of pre-dialysis CKD patients in a tertiary care setting.

Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety.

Background Group A rotaviruses (RVA) are the leading cause of acute gastroenteritis (AGE) in young (aged

The arrival of potent directly acting antivirals (DAAs) for the treatment of chronic Hepatitis C virus (HCV) infection was a challenge for the regional health system of the Lombardia Region. Lombardia represents roughly 8% of the Italian territory but includes nearly 16% of the Italian population. In 2014, nearly 37,600 HCV patients were routinely followed-up in liver centers across the region; nearly 16,000 were classified as having advanced fibrosis or cirrhosis (Metavir F3-F4). The creation of a regional network was necessary to ensure uniformity in treatment access and treatment management. The first database analysis of the Lombardia Hepatitis Network was conducted in January 2016, and included data on 2432 patients who had received treatment from December 2014 to December 2015. The most prevalent HCV genotypes were HCV-1 found in 63% and HCV-3 found in 17%. Overall 90.4% patients achieved an SVR, SVR rates were 92.9% in HCV-1, 89.3% in HCV-2, 81.1% in HCV-3 and 88.9% in HCV-4.

The interaction between living beings, including men, animals and pathogens, sharing the same environment, should be considered as a unique dynamic system, in which the health of each component is inextricably interconnected and dependent with the others. Nowadays, a new integrated One Health approach is reflecting this interdependence with a holistic view to the ecological system. The One Health approach can be defined as a collaborative and a multidisciplinary effort at local, national and global level to guarantee an optimal healthy status for humans, animals and environment. Strictly related to the One Health concept is to be considered the control of infectious diseases, which have influenced the course of human history. Four different components might be identified as key elements within the 'One World - One Health' (OWOH) approach: the geographical component, the ecological one, the human activities and the food-agricultural ones.

West Nile virus (WNV) and Rift Valley fever virus (RVFV) represent an important group of viral agents responsible for vector-borne zoonotic diseases constituting an emerging sanitary threat for the Mediterranean Basin and the neighbouring countries. WNV infection is present in several Mediterranean countries, whereas RVF has never been introduced into Europe, but it is considered a major threat for North African countries. Being vector-borne diseases, they cannot be prevented only through an animal trade control policy. Several approaches are used for the surveillance of WNV and RVFV. With the aim of assessing the surveillance systems in place in Mediterranean countries, two disease-specific questionnaires (WNV, RVFV) have been prepared and submitted to Public Health and Veterinary Authorities of six EU countries. This study presents the information gathered through the questionnaires and describes some critical points in the prevention and surveillance of these diseases as emerged by the answers received.

Aim: The T-type calcium channel is expressed in vascular endothelial cells, but its role in endothelial cell function is yet to be elucidated. We analysed the endothelial functional role of T-type calcium channel-dependent calcium under angiotensin II (Ang II) stimulation. Methods: Human umbilical vein endothelial cells were co-incubated with hormone at 10 -7 M and either Efonidipine 10 -5 M or Verapamil 10 -5 M or Mibefradil 10- 5 M or Wortmannin 10- 6 M. The contribution of Ang II receptors was evaluated using PD123319 10 -7 M and ZD 7155 10 -7 M. The calcium ion concentration was observed using Fluo-3 acetossimetil ester. The cells were observed after 3, 6, 9 and 12 h. Results: The microfluorescence method points out that Ang II induces intracellular calcium modulation in time by distinct mechanisms. AT2 receptor blockade is necessary to observe significant increase in [Ca 2+ ] i levels. Pre-treatment with Mibefradil abolishes Ang II -induced cell migration. Conclusions: Our data show that Ang II, via AT1 receptor, modulates calcium concentration involving T-type calcium channel and L-type calcium channel but only the calcium influx via T-type calcium channels regulates endothelial cell migration which is essential for angiogenesis.

Background Despite significant clinical advances in orthognathic surgery, a perceived decrease in recent years in the number of orthognathic cases was noted at the authors' institution. Word of mouth suggested that this phenomenon was region-wide. To explore this possible dichotomy, a one-page questionnaire was designed and sent to all plastic surgeons in the American Society of Maxillofacial Surgeons and to all active practicing oral surgeons and orthodontists in the state of Ohio. Methods The questionnaire was designed to estimate both the surgeons' and the orthodontists' perception of whether the number of orthognathic cases was increasing, decreasing, or remaining the same over a 5-year period (from 1996 to 2000). A second questionnaire was then sent only to plastic surgeons and oral surgeons to further evaluate reasons for this possible increase or decrease. Results The overall response to the first survey was 39 percent (236 of 601 surveys sent); 87 responses (32 percent) were from plastic and oral surgeons, and 132 (40 percent) were from orthodontists. Seventy-five percent of responders perceived a decrease in the number of orthognathic operations. Of those, more than 80 percent claimed that reimbursement was the major reason for the reduction in the number of surgical procedures. The degree of reduction in reimbursement over this 5-year period was documented at the authors' institution, and the perceived reduction over this 5-year period was estimated by the respondents. Finally, reimbursement per hour was calculated for orthognathic cases and compared with three other standard plastic surgery procedures. Conclusion Implications of this reduction in orthognathic surgery in Ohio are discussed, and suggestions for better documentation of this health care issue are suggested.

West Nile virus (WNV) transmission has been confirmed in the last four years in Europe and in the Mediterranean Basin. An increasing concern towards West Nile disease (WND) has been observed due to the high number of human and animal cases reported in these areas confirming the importance of this zoonosis. A new epidemiological scenario is currently emerging: although new introductions of the virus from abroad are always possible, confirming the epidemiological role played by migratory birds, the infection endemisation in some European territories today is a reality supported by the constant reoccurrence of the same strains across years in the same geographical areas. Despite the WND reoccurrence in the Old World, the overwintering mechanisms are not well known, and the role of local resident birds or mosquitoes in this context is poorly understood. A recent new epidemiological scenario is the spread of lineage 2 strain across European and Mediterranean countries in regions where lineage 1 strain is still circulating creating favourable conditions for genetic reassortments and emergence of new strains. This paper summarizes the main epidemiological findings on WNV occurrence in Europe and in the Mediterranean Basin from 2009 to 2013, considering potential future spread patterns.

We present the previously unreported hazard of creating pressure ulceration in a susceptible host by the improper use of a silicone prosthetic liner. An 80-yr-old man sustained a recent transtibial amputation for peripheral vascular disease. His comorbidities included vascular cognitive impairment, type 2 diabetes mellitus, coronary artery disease, anemia of chronic disease, postherpetic neuralgia, and pruritus of uncertain origin. When not using his transtibial prosthesis, he found his 1.5-mm thick silicone liner (ICEROSS) more comfortable to wear than his stump shrinker and thermoplastic protector. Moreover, he repeatedly wore his liner rolled partway down his stump to allow him to scratch pruritic skin. A horizontal, linear, stage 2 ulcer developed on the residual limb under the upper edge of the rolled liner. The ulcer required >3 mos to heal. This case illustrates the importance of candidate selection for roll-on liners, proper patient and professional training, and optimal management of patient comorbidities.

The host immune response, including innate and adaptive immunity, plays a critical role in determining the outcome of viral infection. Nevertheless, little is known about the exact reasons for the failure of the host immune system in controlling hepatitis C virus (HCV) infection. Impairment of dendritic cells (DCs) function is probably one of the mechanisms responsible for immune evasion of HCV. In this study, the frequency and phenotype of DCs subsets were analyzed in three groups: HCV-infected individuals who developed viral persistence (1), HCV-infected individuals who spontaneously cleared the virus (2) and HCV-seronegative uninfected subjects (3). The results showed that the frequency of DCs subsets was not statistically significant between groups. Plasmacytoid DCs circulating exhibited an immature phenotype characterized by low expression of CD86. On the other hand, CD86 expression in myeloid DCs was significantly higher in chronic infected individuals compared to healthy controls (P=0.037). A positive correlation was observed between CD86(+) myeloid DC (mDC) and HCV viral load (r=0.4121, P=0.0263). These results suggest that HCV did not have an inhibitory effect on mDC maturation and the HCV viremia drives the increase of CD86 expression in mDC. The regulation of DCs maturation and migration lies at the level of intracellular signaling. HCV can activate or block intracellular signaling pathways and alter DC function. In conclusion, the present study suggests that imbalance of DC maturation by the virus represents a mechanism of evasion of the immune system despite the fact that HCV viremia appears to exert a "stimulatory" effect on cell-surface immune phenotype.

Background One of the best ways to control the transmission of malaria is by breaking the vector-human link, either by reducing the effective population size of mosquitoes or avoiding infective bites. Reducing house entry rates in endophagic vectors by obstructing openings is one simple way of achieving this. Mosquito netting has previously been shown to have this effect. More recently different materials that could also be used have come onto the market. Therefore, a pilot study was conducted to investigate the protective effect of three types of material against Anopheles funestus and Anopheles gambiae s.l entry into village houses in Mozambique when applied over the large opening at the gables and both gables and eaves. Methods A two-step intervention was implemented in which the gable ends of houses (the largest opening) were covered with one of three materials (four year old mosquito bed nets; locally purchased untreated shade cloth or deltamethrin-impregnated shade cloth) followed by covering both gable ends and eaves with material. Four experimental rounds (each of three weeks duration), from four houses randomly assigned to be a control or to receive one of the three intervention materials, were undertaken from March to August 2010 in the village of Furvela in southern Mozambique. Mosquito entry rates were assessed by light-trap collection and the efficacy of the different materials was determined in terms of incidence rate ratio (IRR), obtained through a Generalized Estimating Equations (GEE), of mosquito entry in a treated house compared to the untreated (control) house. Results Altogether 9,692 An. funestus and 1,670 An. gambiae s.l. were collected. Houses treated with mosquito netting or the untreated shade cloth had 61.3% [IRR = 0.39 (0.32-0.46); P

HTLV-1 infection is associated with several inflammatory disorders, including the neurodegenerative condition HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is unclear why a minority of infected subjects develops HAM/TSP. CD4+ T cells are the main target of infection and play a pivotal role in regulating immunity to HTLV and are hypothesized to participate in the pathogenesis of HAM/TSP. The CD39 ectonucleotidase receptor is expressed on CD4+ T cells and based on co-expression with CD25, marks T cells with distinct regulatory (CD39+CD25+) and effector (CD39+CD25−) function. Here, we investigated the expression of CD39 on CD4+ T cells from a cohort of HAM/TSP patients, HTLV-1 asymptomatic carriers (AC), and matched uninfected controls. The frequency of CD39+ CD4+ T cells was increased in HTLV-1 infected patients, regardless of clinical status. More importantly, the proportion of the immunostimulatory CD39+CD25− CD4+ T-cell subset was significantly elevated in HAM/TSP patients as compared to AC and phenotypically had lower levels of the immunoinhibitory receptor, PD-1. We saw no difference in the frequency of CD39+CD25+ regulatory (Treg) cells between AC and HAM/TSP patients. However, these cells transition from being anergic to displaying a polyfunctional cytokine response following HTLV-1 infection. CD39−CD25+ T cell subsets predominantly secreted the inflammatory cytokine IL-17. We found that HAM/TSP patients had significantly fewer numbers of IL-17 secreting CD4+ T cells compared to uninfected controls. Taken together, we show that the expression of CD39 is upregulated on CD4+ T cells HAM/TSP patients. This upregulation may play a role in the development of the proinflammatory milieu through pathways both distinct and separate among the different CD39 T cell subsets. CD39 upregulation may therefore serve as a surrogate diagnostic marker of progression and could potentially be a target for interventions to reduce the development of HAM/TSP., Author Summary Human T-lymphotropic virus type 1 (HTLV-1) has been estimated to infect 10–20 million worldwide. The majority of infected individuals are asymptomatic, however, 2% to 3% develop a neurodegenerative disorder called HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The reasons why persons with HTLV-1 develop these complications appear to be multiple and complex. Cellular immune response has been implicated in the development of inflammatory alterations in these patients, however the pathogenic mechanisms for disease progression remain unclear. Regulatory CD4+ T cells (Treg) and Th17 cells derive from a common progenitor and conflicting results regarding frequency and function are found in the development of HAM/TSP. The expression of the CD39 ectoenzyme, a molecule that can mediate immunostimulatory and inhibitory effects, is useful to define IL-17 secreting cell populations, suppressive CD4+ T cells and CD4+ T cells with immunostimulatory properties. The interplay of these T-cell subsets may reveal important aspects of HAM/TSP pathogenesis. In this study, we performed an evaluation of the immunoregulatory CD4+ T-cell subsets defined by CD39 expression including Th17 cells. Our results present phenotypic and functional alterations in the CD4+ T cell profile that could account for the transition from asymptomatic status to HAM/TSP, predicting clinical disease risk and tracking disease progression.

Natural killer T (NKT) cells are a heterogeneous population of lymphocytes that recognize antigens presented by CD1d and have attracted attention because of their potential role linking innate and adaptive immune responses. Peripheral NKT cells display a memory-activated phenotype and can rapidly secrete large amounts of pro-inflammatory cytokines upon antigenic activation. In this study, we evaluated NKT cells in the context of patients co-infected with HIV-1 and Mycobacterium leprae. The volunteers were enrolled into four groups: 22 healthy controls, 23 HIV-1-infected patients, 20 patients with leprosy and 17 patients with leprosy and HIV-1-infection. Flow cytometry and ELISPOT assays were performed on peripheral blood mononuclear cells. We demonstrated that patients co-infected with HIV-1 and M. leprae have significantly lower NKT cell frequencies [median 0.022%, interquartile range (IQR): 0.007–0.051] in the peripheral blood when compared with healthy subjects (median 0.077%, IQR: 0.032–0.405, P < 0.01) or HIV-1 mono-infected patients (median 0.072%, IQR: 0.030–0.160, P < 0.05). Also, more NKT cells from co-infected patients secreted interferon-γ after stimulation with DimerX, when compared with leprosy mono-infected patients (P = 0.05). These results suggest that NKT cells are decreased in frequency in HIV-1 and M. leprae co-infected patients compared with HIV-1 mono-infected patients alone, but are at a more activated state. Innate immunity in human subjects is strongly influenced by their spectrum of chronic infections, and in HIV-1-infected subjects, a concurrent mycobacterial infection probably hyper-activates and lowers circulating NKT cell numbers.

West Nile virus (WNV) is a mosquito-transmitted Flavivirus belonging to the Japanese encephalitis antigenic complex of the Flaviviridae family. Its spread in the Mediterranean basin and the Balkans poses a significant risk to human health and forces public health officials to constantly monitor the virus transmission to ensure prompt application of preventive measures. In this context, predictive tools indicating the areas and periods at major risk of WNV transmission are of paramount importance. Spatial analysis approaches, which use environmental and climatic variables to find suitable habitats for WNV spread, can enhance predictive techniques. Using the Mahalanobis Distance statistic, areas ecologically most suitable for sustaining WNV transmission were identified in the Mediterranean basin and Central Europe. About 270 human and equine clinical cases notified in Italy, Greece, Portugal, Morocco, and Tunisia, between 2008 and 2012, have been considered. The environmental variables included in the model were altitude, slope, night time Land Surface Temperature, Normalized Difference Vegetation Index, Enhanced Vegetation Index, and daily temperature range. Seasonality of mosquito population has been modelled and included in the analyses to produce monthly maps of suitable areas for West Nile Disease. Between May and July, the most suitable areas are located in Tunisia, Libya, Egypt, and North Cyprus. Summer/Autumn months, particularly between August and October, characterize the suitability in Italy, France, Spain, the Balkan countries, Morocco, North Tunisia, the Mediterranean coast of Africa, and the Middle East. The persistence of suitable conditions in December is confined to the coastal areas of Morocco, Tunisia, Libya, Egypt, and Israel.

Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma and the identification of the predictors of response to antiviral therapy is an important clinical issue.To determine the independent contribution of factors including IL28B polymorphisms, IFN-gamma inducible protein-10 (IP-10) levels and the homeostasis model assessment of insulin resistance (HOMA-IR) score in predicting response to therapy in chronic hepatitis C (CHC).Multivariate analysis of factors predicting rapid (RVR) and sustained (SVR) virological response in 280 consecutive, treatment-naive CHC patients treated with peginterferon alpha and ribavirin in a prospective multicentre study.Independent predictors of RVR were HCV RNA400 000 IU/mL (OR 11.37; 95% CI 3.03-42.6), rs12980275 AA (OR 7.09; 1.97-25.56) and IP-10 (OR 0.04; 0.003-0.56) in HCV genotype 1 patients and lower baseline γ-glutamyl-transferase levels (OR=0.02; 0.0009-0.31) in HCV genotype 3 patients. Independent predictors of SVR were rs12980275 AA (OR 9.68; 3.44-27.18), age40 years (OR=4.79; 1.50-15.34) and HCV RNA400 000 IU/mL (OR 2.74; 1.03-7.27) in HCV genotype 1 patients and rs12980275 AA (OR=6.26; 1.98-19.74) and age40 years (OR 5.37; 1.54-18.75) in the 88 HCV genotype 1 patients without a RVR. RVR was by itself predictive of SVR in HCV genotype 1 patients (OR 33.0; 4.06-268.32) and the only independent predictor of SVR in HCV genotype 2 (OR 9.0, 1.72-46.99) or genotype 3 patients (OR 7.8, 1.43-42.67).In HCV genotype 1 patients, IL28B polymorphisms, HCV RNA load and IP-10 independently predict RVR. The combination of IL28B polymorphisms, HCV RNA level and age may yield more accurate pre-treatment prediction of SVR. HOMA-IR score is not associated with viral response.

In line with the results of general surgeons, who revolutionised the surgical approach and the success rate of ventral hernia repair using synthetic mesh, urologists and gynaecologists recently moved towards the use of prosthesis to augment the native tissues. The rationale was based on the relatively high failure rates of the traditional anterior vaginal compartment repair and the recognition that the native tissue may no longer assume the position, strength or functionality by simple re-approximation. Actually the plethora of mesh or graft material, ranging from absorbable (synthetic and biological) to non-absorbable materials, indicates how uncertain we are about the best management. The surgical results are variable on the basis of 1) the material used (synthetic or biological, absorbable or not absorbable); 2) the position of the mesh (incorporated in the suture, overlay the suture, below or under the fascia); 3) the tension adopted. Major problems concern the complications related to the use of the meshes in urogynaecological surgery and the final message is that surgeons may want to consider adopting use of graft techniques to improve surgical results with care given to carefully monitor complications.

Common variable immunodeficiency disorder (CVID) is the commonest cause of primary antibody failure in adults and children, and characterized clinically by recurrent bacterial infections and autoimmune manifestations. Several innate immune defects have been described in CVID, but no study has yet investigated the frequency, phenotype or function of the key regulatory cell population, natural killer T (NKT) cells. We measured the frequencies and subsets of NKT cells in patients with CVID and compared these to healthy controls. Our results show a skewing of NKT cell subsets, with CD4+ NKT cells at higher frequencies, and CD8+ NKT cells at lower frequencies. However, these cells were highly activated and expression CD161. The NKT cells had a higher expression of CCR5 and concomitantly expression of CCR5+CD69+CXCR6 suggesting a compensation of the remaining population of NKT cells for rapid effector action.

Summary Human T lymphotropic virus type 1 (HTLV-1) infects 10–20 million people worldwide. The majority of infected individuals are asymptomatic; however, approximately 3% develop the debilitating neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is also currently no cure, vaccine or effective therapy for HTLV-1 infection, and the mechanisms for progression to HAM/TSP remain unclear. NK T cells are an immunoregulatory T cell subset whose frequencies and effector functions are associated critically with immunity against infectious diseases. We hypothesized that NK T cells are associated with HAM/TSP progression. We measured NK T cell frequencies and absolute numbers in individuals with HAM/TSP infection from two cohorts on two continents: São Paulo, Brazil and San Francisco, CA, USA, and found significantly lower levels when compared with healthy subjects and/or asymptomatic carriers. Also, the circulating NK T cell compartment in HAM/TSP subjects is comprised of significantly more CD4+ and fewer CD8+ cells than healthy controls. These findings suggest that lower numbers of circulating NK T cells and enrichment of the CD4+ NK T subset are associated with HTLV-1 disease progression.

To better understand and, therefore, treat Vietnam combat veterans with a diagnosis of posttraumatic stress disorder (PTSD), the Rorschach was administered to 50 patients so diagnosed. The most important findings were that, on average: (a) These patients have a low level of stress tolerance and are, therefore, likely to respond impulsively to stressful situations; (b) this low stress tolerance appears to be a long-term adjustment problem; and (c) their perception of reality is unconventional and often distorted. A primary therapeutic indication from these data is that the use of structure would be important for successful therapy. Other findings and therapeutic recommendations are also discussed.

Cerebrospinal fluid (CSF) and serum levels of transforming growth factor (TGF)-beta and soluble intercellular adhesion molecule-1 (sICAM-1) were evaluated in ten patients with definite multiple sclerosis (MS) of the relapsing-remitting type. CSF TGF-beta levels of MS patients in remission were significantly (p < 0.01) higher than of MS patients in active phase, and there was a significant inverse correlation (p < 0.05) between TGF-beta and slCAM-1 levels in the CSF of patients in both remitting and relapsing type. This is consistent with a possible down-regulation of TGF-beta on ICAM-1 expression and suggests a possible synthesis in the central nervous system of TGF-beta.

Aesthetic nasal surgery has progressed in the last years, as concerning both surgical techniques and surgical instruments, which allowed the finding of new and more sophisticated surgical solutions. Clinical practice led to observe sometimes functional surgical failures, due rather than an inaccurate surgical technique, to an incomplete diagnostic approach to the patient. It has been observed that modifying the external conformation of nasal pyramidis inner-nose volumes and spaces will be subsequently reduced, giving as a result a condition which is only aesthetically but not functionally valid. 32 subjects, selected for a rhinoplasty and presenting nasal respiratory obstruction and anterior ethmoid abnormalities, confirmed by nasal endoscopy and nasal CT, were evaluated and subdivided into two groups: the first (A) group underwent only to an aesthetic rhinoplasty, the second group (B) was operated of a rhinoplasty combined with functional endoscopic sinus surgery (FESS) in order to correct the above mentioned anatomical abnormalities. The nasal airflow, and though the nasal cavities patency, was evaluated pre- and post-operatively in the two groups of patients, referring to rhinomanometric conductance values. Patients of group A reported decreased post-operative conductance values, patients of group B reported increased post-operative conductance values, showing though the functional involvement of anterior ethmoid in nasal obstruction and the necessity of correcting its anatomical abnormalities, in order to reach not only a new nasal profile, but also a better respiratory performance.

Peripheral distal neuropathy associated with hypoglycemia secondary to insulinoma is quite rare. So far, less than 40 cases have been reported in literature. In this report, we describe a 50-year-old patient with insulinoma-polineuropathy and neuropsychiatric symptoms, interpreted as temporal lobe epilepsy, over the preceding 7 years. Due to the variability of the clinical presentation, diagnostic mistakes are frequent, and diagnosis of insulinoma is often delayed. Thus, the hypoglycemic nature of neuropathy can be lately recognized.

Nonunion is a complication in mandibular fractures. The causative factors include delay in treatment, infection, inadequate immobilization, and improper internal fixation; concomitant infection may be present. Pain, mobility of the fracture segments, and radiographic evidence of radiolucency did in diagnosis.Three clinical cases are used to present the methods of treatment to manage nonunion following a gunshot wound, assault with a blunt object, and a fall. Treatment included antimicrobial therapy, fracture site debridement, segment immobilization, and bone grafting. Maxillomandibular fixation, debridement, and placement of a reconstruction plate were used in the first case; reconstruction plate, autogenous bone graft in a polyglactin resorbable mesh, and screw buttons in the second; and custom reconstruction plate and iliac crest bone graft in the third.All cases healed uneventfully. Due to rapid revascularization, use of autogenous cancellous bone grafts is preferred to cortical bone. Custom-molded polyglactin mesh provides control of the loose cancellous bone graft.

Interferon-alpha plus ribavirin therapy for chronic hepatitis C is associated with adverse effects that lead to therapy discontinuation in up to 27% of patients in randomized controlled trials.To examine the causes and predictive factors for therapy discontinuation in patients treated in current clinical practice.We retrospectively enrolled 441 consecutive patients, scheduled to receive interferon-alpha + ribavirin for chronic hepatitis C, in five centres. Patients had been treated with 3 or 6 MU interferon-alpha three times a week plus ribavirin, 800-1200 mg daily, for 6 or 12 months.One hundred and eight [24.5%; confidence interval (CI), 20.5-28.8%] patients failed to finish combination therapy because of adverse events. The discontinuation rate was higher during the first 6 months of treatment; anaemia was an important cause (36.1% of discontinuations); unexplained lipothymia resulted in discontinuation in 11 patients. Female gender [hazard ratio (HR) = 1.85; CI, 1.17-2.92], an interferon-alpha dose15 MU/week (HR = 1.79; CI, 1.12-2.86) and no previous interferon-alpha treatment (HR = 1.63; CI, 1.04-2.57) were independent factors associated with discontinuation. The simultaneous presence of these factors identified patients at high risk for discontinuation [odds ratio (OR) = 10; CI, 3.98-25.13].The study identified some predictive factors for adverse event-related discontinuation, which may improve the safety profile and effectiveness of interferon-alpha + ribavirin combination therapy in chronic hepatitis C.

The gestational age of 302 neonates whose obstetric gestational age was known was assessed at birth using the Dubowitz method; it was obtained from Dubowitz score both graphically from a nomogram and by calculation from the corresponding equation. The values obtained graphically differed to a lesser extent from the obstetric gestational age than did the gestation derived algebraically. With infants small for gestational age (SGA) the difference between the methods was smaller and not significant. It is concluded that the concurrent knowledge of obstetric gestational age introduced a bias in the graphic step; this did not happen in SGA infants probably because in these cases the available information is sometimes less certain. These data demonstrate that even simple procedures are influenced by concurrent information; as a philosophical point about the interpretation of data in general, this study provides an empirical example of the 'theory-ladenness of facts' in medicine.

SUMMARYWe studied the relationship between the HLA specificities associated with multiple sclerosis (MS) susceptibility in southern Italy and the reactivity of the human myelin basic protein (hMBP) immunogenic peptides 84–98 and 143–168, using short-term T-cell lines established from 9 MS patients and from 8 healthy individuals. In our population, DR15 was significantly associated with MS (34·9% in MS versus 13·7% in healthy controls, P < 0·05). This result is in agreement with the association found in northern Europe, but not with data obtained in a population from the island of Sardinia (Italy). In MS patients the frequency of reactive T-cell lines (TCL), tested for fine specificity against the immunodominant hMBP peptides 84–98 and 143–168, was increased for the hMBP 143–168 peptide (P < 0·05) but not for the 84–98 peptide. Although this reactivity was higher in DR15+ MS patients than in DR 15− MS patients, it seemed not to be associated with DR15 specificity in the MS population. Furthermore, there were no significant differences in frequency of reactive TCL to hMBP peptide 84–98 in DR15-positive or DR15-negative MS patients. Consequently, it appears that peptide 84–98, considered as a relevant autoantigen, is not implicated in the pathogenesis of MS in our population from southern Italy.

In a health care environment dominated by the growth of managed care organizations, generic competition, therapeutic substitution and drug utilization review, drug development is an extremely risky proposition. Consequently, it is imperative to incorporate a mechanistic approach to drug development that combines a thorough understanding of a drug at the molecular/cellular level with a rigorous preclinical, and clinical pharmacology program. This should enable the sponsor to evaluate multiple hypotheses during the early "learning" phases of clinical development (Phases I and IIA) and to eliminate nonpromising candidates early on while drug development costs are low. Clinical research done properly in the early stages of drug development will also set the stage for designing and conducting optimal "confirming" registrational Phase IIB/III studies for promising drug candidates. Pharmacokinetics (PK) and pharmacodynamics (PD) modeling and simulation are crucial components of a mechanistic approach to optimal drug development and their application has significant impact in both early and late development efforts. This communication describes several applications of pharmacokinetics and pharmacodynamics modeling and simulation that were important in guiding, optimizing and ensuring the success of development efforts for drug candidates in the therapeutic areas of cardiology and oncology. These examples are used to illustrate and discuss the use of the current state-of-the-art in pharmacokinetics and pharmacodynamics modeling and simulation at numerous stages in the development cycle and to postulate on future directions in this area.

Background Cephalic tetanus is a rare form of the tetanus caused primarily by wounds or other infectious processes involving the head and neck. This condition frequently progresses to the generalized form of tetanus with the attendant risks and complications. Methods A case report of a young female who developed an unusual form of tetanus after a tongue piercing is presented here. We discuss this disorder as it applies to the contemporary caregiver with a focus on its presentation and recognition. Results A delay in diagnosis of 13 days from presentation occurred. The patient had a slow, uneventful but incomplete recovery course. She never developed significant airway compromise, nor did she demonstrate any evidence of hemodynamic instability but continued to have right facial weakness up to 6 months after discharge. Conclusions A few factors were identified that contributed to the significant delay in diagnosis. The unusual nature of the disease and a lowered index of suspicion on the part of the initial caregivers were probably the major causes. Fortunately, no major adverse sequelae resulted from the delay. However, if this case heralds the onset of a rise in the incidence of tetanus, early recognition and diagnosis would seem essential to avoid much of the morbidity and mortality associated with the disease. © 2000 John Wiley & Sons, Inc. Head Neck 22: 728–732, 2000.

Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.

In spite of recent progress, treatment for liver echinococcal cysts is still far from satisfying. In recent years, percutaneous drainage has been increasingly used for this purpose and it has been shown to be an effective alternative to surgery and chemotherapy alone. This technique is known as PAIR, from Puncture, Aspiration, Injection (of a scolecidal agent), Reaspiration: here we present our experience and the state of the art of PAIR. Patients from Italy and Turkana (Kenya), harbouring 233 Gharbi type I, II and III echinococcal cysts were successfully treated with PAIR: it was performed according to protocols established at the Division of Infectious and Tropical Diseases, IRCCS--Policlinico S. Matteo, University of Pavia. In Italy, one relapse was recorded, four years after the procedure; the patient was treated again with PAIR; no cases of anaphylactic shock or peritoneal dissemination were observed in a follow-up of 10 years; only 10 minor complications (biliary fistula, urticarioid reaction, abscessualization of the cyst, anaphylactoid reactions) were reported. Long-term results indicate that in Gharbi type I, II and III echinococcal cysts, and in developing countries, in particular, PAIR is a first choice method for the treatment of abdominal localizations of this disease.

Docetaxel activity has been documented in many solid tumors, including metastatic breast cancer and non-small cell lung cancer. However, as clinical studies in other tumor types are now being conducted, the validation of an optimal sampling strategy would allow the performance of pharmacokinetics/pharmacodynamics studies with minimum inconvenience for the patient. Six optimal sampling strategies with one to six sampling times were computed, based on the D-optimality theory, using population pharmacokinetic parameters estimated from a large pharmacokinetic database of 547 patients treated in previous Phase II studies. Validation of these sampling strategies was performed on a set of 35 patients, from two Phase I studies, who received docetaxel as a 1-h infusion at doses ranging from 50 to 100 mg/m2. Validation consisted of comparing clearance assessed by maximum likelihood estimation obtained using complete plasma concentration-time data (considered as the reference) and clearance determined by Bayesian estimation with an optimal design. For all of the optimal sampling strategies tested, clearance was found to be well estimated when at least two samples were taken. Bayesian estimation with two measured levels (at the end of infusion and at 6 h after the start of infusion) can be selected, because it allows adequate estimation of clearance with a nonsignificant bias of +1.37% and a precision of 12.3%.

Synovial chondromatosis is a rare benign intraarticular metaplasia of synovium. This process may result in the production of detached particles of highly cellular cartilage in the involved joint spaces. It is most often reported in the larger joints of the body including the knee, hip, elbow, and ankle. Since Axhausen in 1933 reported the first case affecting the temporomandibular joint, several articles have been listed in the literature regarding the presentation, diagnosis, and management of this form of an arthropathy. This is a case of a recurrent synovial chondromatosis that was approached with a meniscectomy and a complete synovectomy.

We report hyperamylasemia due to macroamylasemia in a 33-year-old-woman with gluten enteropathy. Macroamylasemia was demonstrated by precipitation of 97% of amylase activity with PEG 6000. It was associated with increased serum IgA, with elevated values of specific IgA antibodies against alpha-gliadin and with a high titre of IgA anti-endomysium antibodies. Macroamylasemia disappeared after 2 months of a strict gluten-free diet. These data suggest that the increased IgA concentration in adult gluten enteropathy led to increased macroamylase formation.