Allogeneic human umbilical cord-derived mesenchymal stem/stromal cells for chronic obstructive pulmonary disease (COPD): study protocol for a matched case-control, phase I/II trial.

INTRODUCTION: The global prevalence of chronic obstructive pulmonary disease (COPD) is increasing, and it has become a major public health burden worldwide, including in Vietnam. A large body of preclinical and clinical studies supports the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of lung injury, including COPD. The aim of this trial is to investigate the safety and potential therapeutic efficacy of allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) as a supplementary intervention in combination with standard COPD medication treatments in patients with moderate-to-severe COPD based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2019 and Vietnam Ministry of Health's guidelines. METHODS AND ANALYSIS: This matched case-control phase I/II trial is conducted at Vinmec Times City International Hospital, Hanoi, Vietnam between June 2020 and December 2021. In this study, 40 patients will be enrolled and assigned into two age-matched, gender-matched and COPD condition-matched groups, including a UC-MSC group and a control group. Both groups will receive standard COPD medication treatment based on the GOLD 2019 guidelines and the Vietnam Ministry of Health protocol. The UC-MSC group will receive two doses of thawed UC-MSC product with an intervention interval of 3 months. The primary outcome measures will include the incidence of prespecified administration-associated adverse events and serious adverse events. The efficacy will be evaluated based on the absolute changes in the number of admissions, arterial blood gas analysis, lung function and lung fibrosis via CT scan and chest X-ray. The clinical evaluation will be conducted at baseline and 3, 6 and 12 months postintervention. ETHICS AND DISSEMINATION: Ethical approval was secured from the Ethical Committee of Vinmec International Hospital (number:166/2019/QD-VMEC) and Vietnam Ministry of Health (number:2002/QD-BYT). The results will be reported to trial collaborators, publication in peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: NCT04433104.

Persistent Detwinning of Iron-Pnictide EuFe_{2}As_{2} Crystals by Small External Magnetic Fields.

Our comprehensive study on EuFe_{2}As_{2} reveals a dramatic reduction of magnetic detwinning fields compared to other AFe_{2}As_{2} (A=Ba, Sr, Ca) iron pnictides by indirect magnetoelastic coupling of the Eu^{2+} ions. We find that only ∼0.1 T are sufficient for persistent detwinning below the local Eu^{2+} ordering; above T_{Eu}=19 K, higher fields are necessary. Even after the field is switched off, a significant imbalance of twin domains remains constant up to the structural and electronic phase transition (190 K). This persistent detwinning provides the unique possibility to study the low temperature electronic in-plane anisotropy of iron pnictides without applying any symmetry-breaking external force.

The effect of surgically assisted rapid maxillary expansion on sleep architecture: an exploratory risk study in healthy young adults.

Maxillary transverse deficiencies (MTD) cause malocclusions. Rapid maxillary expansion treatment is commonly used treatment for correcting such deficiencies and has been found to be effective in improving respiration and sleep architecture in children with obstructive sleep apnoea (OSA). However, thus far, the effect of surgically assisted rapid maxillary expansion (SARME) treatment on sleep architecture and breathing of normal subjects has not been assessed. We hypothesised that sleep quality will improve after maxillary expansion treatment. The objective of this study is to access the effect of maxillary expansion treatment on sleep structure and respiratory functions in healthy young adults with severe MTD. This is a prospective and exploratory clinical study. Twenty-eight consecutive young adult patients (15 males and 13 females, mean age 20·6 ± 5·8 years) presenting with severe MTD at the orthodontic examination were recruited into the study. All the participants underwent a standardised SARME procedure (mean expansion 6·5 ± 1·8 and 8·2 ± 1·8 mm, intercanine and intermolar distance, respectively) to correct malocclusion caused by MTD. An overnight in-laboratory polysomnography, before and after the treatment, was performed. The mean follow-up time was 9 months. The main outcome parameters were the changes in sleep architecture, including sleep stages, arousals, slow-wave activity (SWA) and respiratory variables. Before surgery, young adult patients with MTD presented no evidence of sleep breathing problems. At baseline sleep recording, 7 of 28 (25%) had apnoea-hypopnoea index (AHI) ≥ 5 events per hour. No negative effect of the SARME was observed in questionnaires or sleep laboratory parameters. In the patients with a higher baseline AHI (AHI ≥ 5 h of sleep), we observed a reduction in AHI after surgical treatment (P = 0·028). SARME did not have a negative effect on any sleep or respiration parameters in healthy young individuals with MTD. It normalised the breathing index in the patients with a mild AHI index.

[Two uncommon extrapulmonary forms of Mycoplasma pneumoniae infection]. / Infections extrapulmonaires àMycoplasma pneumoniae : atteintes neurologique et rénale.

Mycoplasma pneumonia is the second most frequent bacterium in pneumonia and the leading intracellular type. M. pneumoniae pulmonary infection is characterized by a slower onset profile and a lower biological inflammatory picture than pneumococcal infection. Both upper and lower respiratory tracts are often affected and sometimes a Kawasaki-like syndrome can be associated, with conjunctivitis or cheilitis. Extrapulmonary forms of the disease can occur, whether or not it is associated with pulmonary infection. We report two cases: in the first case, a renal form of M. pneumoniae disease developed in a 6-year-old girl, with membranous proliferative glomerulonephritis expressed as a picture of impure nephritic syndrome with decreased serum complement concentration, following an upper respiratory infection. Diagnosis was obtained by means of a kidney biopsy. The second case occurred in an 8-year-old girl who expressed, after a respiratory tract infection, neurological symptoms such as ocular flutter, perception disorder, and ataxia. This onset is typical of post-infectious rhombencephalitis. Biological investigations and imaging were normal. In both cases, M. pneumoniae infection was diagnosed on the basis of immunoglobulin M-positive serology. Direct exploration of the bacterium was negative, due to its fragility and delayed diagnostic hypothesis. Several forms of M. pneumoniae infection are either the direct effect of the bacterium or are secondary to a cross-immunological reaction. As its frequency is increasing, M. pneumoniae infection should be raised as a cause of atypical, less well-known extrapulmonary forms of the disease.

Natural history of small duct primary sclerosing cholangitis: a case series with review of the literature.

BACKGROUND AND AIMS: Information about the natural history of small duct primary sclerosing cholangitis (SDPSC) remains scant despite literature suggesting that it constitutes 6-16% of all cases of primary sclerosing cholangitis (PSC). We combined clinical data on SDPSC cases from two tertiary care institutions with liver transplantation programs with the aim of studying the natural history of SDPSC. METHODS: Medical records of 25 individuals with SDPSC were reviewed. Diagnosis of SDPSC was based on liver biopsy findings consistent with PSC, a normal cholangiogram, and elimination of known causes of secondary sclerosing cholangitis. Demographic information, symptoms, past medical history, laboratory values, and histologic data were evaluated. Our primary outcome measure was liver transplantation or death. Secondary outcome measures included evidence of end-stage liver disease, development of cholangiocarcinoma, and/or the development of classic PSC on a repeat cholangiogram. RESULTS: Data on 25 individuals (13 males, 12 females; mean age 40 ± 15 years) diagnosed with SDPSC were analyzed. Upon presentation, 11 patients had symptoms including abdominal pain, fatigue, and pruritus. Inflammatory bowel disease was present in 14 patients (56%) at diagnosis. On initial liver biopsy, 60% had early-stage disease (I or II) and none had cirrhosis. On follow-up (1-168 months, median 17 months), malignancy or progression to classic large duct PSC was not noted. Two (8%) patients had evidence of varices and one of the two also developed ascites; one of these patients underwent liver transplantation and the other one died due to sepsis. CONCLUSIONS: SDPSC, a mild disease at presentation typically runs a benign course and likely is not an early stage of classic PSC. Further studies with a control group of classic PSC and longer follow-up are needed to study the natural history of SDPSC.

[Acral circumscribed hypokeratosis of plantar and dorsum of the finger localization: two cases]. / Hypokératose acrale circonscrite : forme plantaire et forme du dos du doigt (deux cas).

INTRODUCTION: Palmar or plantar circumscribed hypokeratosis is a remarkable clinicopathologic entity described in 2002. It consists in a well demarcated decrease in thickness of the stratum corneum, that can be clinically mistaken for Bowen's disease or porokeratosis. We present a classical plantar localisation and a more original case on the dorsum of the finger, together with a microscopic and immunohistochemical study. CASE REPORTS: Case 1. A 65-year-old man was seen 15 years after a first consultation for a well demarcated 1.5cm erythematous lesion localised on the border of his left foot. The biopsy, then misinterepreted as keratosis sulcata, was reviewed. It showed a sudden and well demarcated decrease in thickness of the stratum corneum, overlying a slightly acanthotic epidermis, associated with dilated capillaries in the papillary dermis. HPV immunostaining was negative. Case 2. A 75-year-old woman had a well demarcaated erythematous lesion of the dorsum of her right index finger, lasting for months without significant evolution. A first biopsy showed pale and haloed keratinocytes that could be interpreted as koilocytes. She was therefore treated by cryotherapy, 5-fluro-uracile and imiquimod, that proved unsuccessful. A second biopsy showed a sudden and major decrease in thickness of the stratum corneum, overlying an area containing a few pale keratinocytes with perinuclear halo. HPV immunostaing was negative and Ki67 positive cells were slightly decreased in number when compared to lateral normal skin. DISCUSSION: Our first case is typical of plantar hypokeratosis characterised by its long evolution, typical semiology and well demarcated anomaly of the stratum corneum. Our second case is original as it shows that the disease can also affect the dorsum of the fingers. Acral circumscribed hypokeratosis is therefore a better name for this condition. We did not find any arguments in favor of a viral cause or an increased proliferation of keratinocytes. As often described in other cases, the lesion can remain unchanged for decades, which confirm its benign evolution. Topical treatments are generally ineffective. The pathogenesis of this localised hypokeratosis remains mysterious.

[Virology: the contribution of molecular biology in the microbiologic diagnosis of pediatric respiratory diseases]. / Virologie : l'apport de la biologie moléculaire dans le diagnostic microbiologique en pneumopédiatrie.

The conventionnal tools used for virological diagnosis include direct antigen detection by immunofluorescence (IFA) or an immunoenzymatic test (EIA), and viral isolation technique (VIT). In most cases, IFA and EIA have a slightly lower sensitivity than VIT but are also able to detect some VIT-negative samples. Results of several teams using RT-PCR technologies show that the molecular methods detect more positive cases than the conventional tools. Work is under way to expand the number of viruses detected by multiplex RT-PCR and to determine wether newly discovered viruses, such as human metapneumovirus, contribute to burden of paediatric lower respiratory infections. In conclusion, according to requirements of speed, low cost of the methods, and to achieve the highest rate of detection of respiratory viruses, the combined use of IFA and multiplex RT-PCR is today likely to be the best way to improve diagnosis of respiratory illnesses in children.

[Acute respiratory tract infections due to a human metapneumovirus in children: descriptive study and comparison with respiratory syncytial virus infections]. / Infections respiratoires aiguës à métapneumovirus humain chez l'enfant: études descriptive et comparative avec le virus respiratoire syncytial.

BACKGROUND: A new paramyxovirus, the human metapneumovirus was recently isolated. We report the first French cases collected between 2000 and 2002. MATERIAL AND METHODS: Samples were obtained from nasopharyngeal aspirates from children hospitalised for acute respiratory tract infection in hospitals of Caen and Flers in Basse-Normandie. Human metapneumovirus was studied by polymerase chain reaction on negative samples for respiratory syncytial virus, influenza A and B virus, parainfluenza (1, 2 and 3) virus, adenovirus, coronavirus and rhinovirus. Comparison between metapneumovirus virus and respiratory syncytial virus infections was done after matching sex, age and infection month. RESULTS: Twenty-six human metapneumovirus infections were identified. A comparative study of a matched group of children infected by respiratory syncytial virus found no significative difference for hospitalisation motive, clinical criteria and treatment. CONCLUSION: The human metapneumovirus is responsible for typical acute bronchiolitis in children.

[Adenoviral respiratory diseases in healthy children: a study of 116 hospital cases]. / Prise en charge des pathologies respiratoires à adénovirus chez l'enfant immunocompétent: À propos d'une étude rétrospective de 116 enfants hospitalisés.

Adenoviruses most commonly cause respiratory illness; however, depending on the infecting serotype, they may also cause various other diseases. Diagnosis may be difficult to achieve.The clinical findings for 116 children hospitalised with adenoviral infection were studied retrospectively. In 71 children, the diagnosis was based on detection of adenovirus antigen in the nasopharyngeal specimens and in 71 children on viral culture. The clinical picture of adenoviral infection was characterised by high-grade (mean 39°1C) and prolonged fever (mean duration 4,3 days). Upper respiratory and lower respiratory symptoms were the most common infections. Twelve had been admitted to the hospital due to febrile convulsions, 6 had meningitis. Laboratory findings varied from normal values to values seen in bacterial infections. Thus it was difficult to distinguish adenoviral disease from a bacterial disease. Fifty-nine children were referred to the hospital due to infection unresponsive to antimicrobial therapy.Symptoms of respiratory infection caused by adenovirus may range from the common cold syndrome to pneumonia, croup and bronchiolitis. Adenoviruses can be responsible for severe consequences, even in previously healthy children. Studies of the molecular mechanisms of viral infections of the airways could provide important insights into the nature of the inflammatory process involved in asthma and chronic obstructive pulmonary disease. Most infections are mild and require no therapy or only symptomatic treatment. There are at present time no recognised antiviral agents that are effective in treating serious adenovirus disease. The rapid detection of adenovirus antigen in nasopharygeal specimens proved to have a great clinical value in the diagnosis.

The histologic effects of low-dose methotrexate therapy for primary biliary cirrhosis.

OBJECTIVE: Primary biliary cirrhosis is a progressive liver disease that is believed to be autoimmune in nature. Treatment, at best, may slow the progression of the disease, although no therapy has been able to halt its progression. Preliminary data suggest a beneficial effect of methotrexate in the treatment of primary biliary cirrhosis. We evaluated the histologic effect of 2 years of treatment with methotrexate. DESIGN: Liver biopsies were obtained before methotrexate was started and after 2 years of therapy. Ninety-six paired biopsies from 48 patients with primary biliary cirrhosis were reviewed by a pathologist who was blinded to all clinical history and sequence of the biopsies. Variables examined included stage of the disease, degree of portal fibrosis, portal inflammation and piecemeal necrosis, bile duct injury or loss, bile ductular proliferation, lobular inflammation and necrosis, steatosis, granulomas, cholestasis, and nuclear pleomorphism of hepatocytes. RESULTS: In most categories, pretreatment and posttreatment biopsies did not reflect a change over the 2-year period of treatment. There was a trend toward progression of the stage of the disease, portal fibrosis, bile duct loss, fat, and pleomorphism over the 2 years and toward regression in piecemeal necrosis, bile duct injury, ductular proliferation, granulomas, and lobular inflammation and necrosis. CONCLUSION: After 2 years of treatment with methotrexate, the stage of disease and fibrosis of primary biliary cirrhosis continue to progress, although overall, inflammation and bile duct injury decrease with methotrexate treatment.

Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway.

We have explored the role of an activation-induced T cell molecule, 4-1BB (CDw137), in the amplification of tumor immunity by retrovirus-mediated transduction of the 4-1BB ligand (4-1BBL) into tumor cells. Mice inoculated with P815 tumor cells expressing 4-1BBL developed a strong cytotoxic T lymphocyte (CTL) response and long-term immunity against wild-type tumor. The optimal effect of 4-1BBL in CTL stimulation required B7-CD28 interaction since blockade of this interaction by antibodies down-regulated the expression of 4-1BB on T cells and decreased CTL activity. Furthermore, co-expression of 4-1BBL and B7-1 in the poorly immunogenic AG104A sarcoma enhanced the induction of effector CTL and the rejection of the wild-type tumor while neither 4-1BBL nor B7-1 single transfectants were effective, suggesting a synergistic effect between the 4-1BB and the CD28 co-stimulatory pathways. Our results underscore the importance of the 4-1BB T cell stimulation pathway in the amplification of an antitumor immune response.

Costimulation, tolerance and ignorance of cytolytic T lymphocytes in immune responses to tumor antigens.

Despite the fact that many tumors express MHC class I molecules presenting "foreign" peptide antigens, a vigorous tumor-destructing immune response is seldom detected. A possible explanation is that tumors cannot provide adequate costimulatory signals as provided by professional antigen presenting cells. CD28, upon interacting with B7, triggers costimulatory signals critical for the T-cell response. Transfection of tumor cells with B7 augments the immunogenicity of the tumor so that an anti-tumor immune response can be amplified. When B7-CD28 costimulation is provided CTL specific for otherwise silent epitopes can be activated. Therefore, unresponsiveness of T cells to many tumor antigens should be considered as ignorance rather than tolerance. Immunological ignorance may thus contribute to the failure of the immune system to respond against the tumor antigens.

Functional expression in mast cells of chimeric receptors with antibody specificity.

Chimeric genes composed of a single-chain Fv domain (scFv) of an antibody linked with receptor chains normally present in cells of hematopoietic origin were constructed. Such genes could be expressed as functional surface receptors in the RBL-2H3 (rat basophilic leukemia) mast cell line. The chimeric receptors exhibited binding properties of an antibody molecule and triggered degranulation of transfected mast cells on stimulation with antigen. Genetically engineered designer cells (e.g., T-lymphocytes, mast cells, or natural killer cells), equipped with built-in antibody-type recognition, can be now exploited for immunotherapy.

HLA-DR expression in bile duct damage in hepatitis C.

Several investigations have demonstrated aberrant expression of HLA-DR on damaged bile duct epithelium of patients with primary biliary cirrhosis, liver allograft rejection, graft versus host disease, and AIDS. Since bile duct damage is a prominent feature of chronic hepatitis C, it may also be associated with HLA-DR induction. Therefore, we examined the expression of HLA-DR antigen in formalin-fixed, paraffin-embedded liver biopsy sections of 30 patients with chronic hepatitis C by the avidin-biotin peroxidase complex method using a monoclonal antibody to HLA-DR. HLA-DR was not detected on bile duct epithelium in any of the cases, although bile duct damage of varying degree was observed in 90% of the cases. HLA-DR was expressed by Kupffer cells; inflammatory infiltrates in portal tracts, and in areas of piecemeal necrosis and lobular necrosis; dendritic cells in portal and periportal areas; and occasionally hepatocytes. These observations suggest that the mechanism of bile duct injury in chronic hepatitis C may be different from that of other conditions such as primary biliary cirrhosis, liver allograft rejection, and graft versus host disease.

Hepatic histopathology in the acquired immunodeficiency syndrome.

Involvement of the liver with the same opportunistic organisms and neoplasms affecting other organs has been recognized since the beginning of the AIDS epidemic. In this overview of hepatic histopathologic features in AIDS, we review the range of opportunistic infections and neoplasms accompanying HIV infection. Hepatic disease may result from viral, bacterial, protozoal, or fungal infection, or secondary to drugs and neoplasms. Liver involvement in AIDS usually reflects disseminated rather than primary disease. CMV and mycobacteria are the most common organisms in liver identified in biopsy and autopsy studies. A variety of nonspecific features, including steatosis, granulomas, and sinusoidal abnormalities may also be seen. HIV-1 itself was recently identified in the liver. Speculation regarding the significance of this finding has been discussed in this review. Hepatitis B, C, and D may also complicate the course of disease in patients with AIDS. Hepatitis B behaves differently in the population with AIDS than in immunocompetent patients. We concluded our review with a discussion of the present recommendations regarding the use of liver biopsies in these patients. This topic continues to be widely debated in the literature.

The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis.

Before the availability of serological markers for hepatitis C, the morphological features of this diagnosis, which represents most non-A, non-B hepatitis, could not be confirmed. We examined biopsy specimens from 50 patients with chronic hepatitis C and 21 patients with autoimmune chronic hepatitis. Each biopsy specimen was graded on 19 different histological features. The results indicated that at the time of biopsy, the average age of patients with chronic hepatitis C was 46 yr vs. 36 yr for autoimmune chronic hepatitis. Cirrhosis was seen more frequently in autoimmune chronic hepatitis (90%) than in hepatitis C (58%). Features more commonly observed in chronic hepatitis C were bile duct damage (91% vs. 40%), bile duct loss (91% vs. 20%), steatosis (72% vs. 19%) and lymphoid cell aggregation (follicles) within portal tracts (49% vs. 10%). Severe lobular necrosis and inflammation (76% vs. 38%), piecemeal necrosis (81% vs. 10%), multinucleated hepatocytes (29% vs. 6%) and broad areas of parenchymal collapse (76% vs. 6%) were seen more often in autoimmune chronic hepatitis. Exclusion of five patients with autoimmune chronic hepatitis who received immunosuppression before biopsy accentuated these differences. In conclusion, morphological criteria, in addition to serological data, may be useful for differentiating chronic hepatitis C from autoimmune chronic hepatitis, which histologically is a more aggressive disease.

Hepatocellular carcinoma in a long-term survivor of intrahepatic biliary duct hypoplasia.

We describe the development of hepatocellular carcinoma (HCC) in a 46-yr-old woman with intrahepatic biliary duct hypoplasia. Her underlying liver disease was quiescent for many years until a dramatic rise in serum bilirubin was seen. Orthotopic liver transplantation was performed, and a large tumor was found during surgery. A bile-producing HCC was identified, infiltrating about 50% of an otherwise noncirrhotic liver which had a paucity of intrahepatic ducts. The findings of HCC in this long-term survivor of intrahepatic biliary duct hypoplasia indicates HCC may occur in patients with long-standing disease.