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There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

Metaplastic breast cancers (MBC) are aggressive, chemoresistant tumors characterized by lineage plasticity. To advance understanding of their pathogenesis and relatedness to other breast cancer subtypes, 28 MBCs were compared with common breast cancers using comparative genomic hybridization, transcriptional profiling, and reverse-phase protein arrays and by sequencing for common breast cancer mutations. MBCs showed unique DNA copy number aberrations compared with common breast cancers. PIK3CA mutations were detected in 9 of 19 MBCs (47.4%) versus 80 of 232 hormone receptor-positive cancers (34.5%; P = 0.32), 17 of 75 HER-2-positive samples (22.7%; P = 0.04), 20 of 240 basal-like cancers (8.3%; P < 0.0001), and 0 of 14 claudin-low tumors (P = 0.004). Of 7 phosphatidylinositol 3-kinase/AKT pathway phosphorylation sites, 6 were more highly phosphorylated in MBCs than in other breast tumor subtypes. The majority of MBCs displayed mRNA profiles different from those of the most common, including basal-like cancers. By transcriptional profiling, MBCs and the recently identified claudin-low breast cancer subset constitute related receptor-negative subgroups characterized by low expression of GATA3-regulated genes and of genes responsible for cell-cell adhesion with enrichment for markers linked to stem cell function and epithelial-to-mesenchymal transition (EMT). In contrast to other breast cancers, claudin-low tumors and most MBCs showed a significant similarity to a "tumorigenic" signature defined using CD44(+)/CD24(-) breast tumor-initiating stem cell-like cells. MBCs and claudin-low tumors are thus enriched in EMT and stem cell-like features, and may arise from an earlier, more chemoresistant breast epithelial precursor than basal-like or luminal cancers. PIK3CA mutations, EMT, and stem cell-like characteristics likely contribute to the poor outcomes of MBC and suggest novel therapeutic targets.

Establishing a clinical diagnosis of infection in residents of long-term-care facilities (LTCFs) is difficult. As a result, deciding when to initiate antibiotics can be particularly challenging. This article describes the establishment of minimum criteria for the initiation of antibiotics in residents of LTCFs. Experts in this area were invited to participate in a consensus conference. Using a modified delphi approach, a questionnaire and selected relevant articles were sent to participants who were asked to rank individual signs and symptoms with respect to their relative importance. Using the results of the weighting by participants, a modification of the nominal group process was used to achieve consensus. Criteria for initiating antibiotics for skin and soft-tissue infections, respiratory infections, urinary infections, and fever where the focus of infection is unknown were developed.

The parenteral multivitamin preparations that are commercially available in the United States (U.S.) meet the requirements for most patients who receive parenteral nutrition (PN). However, a separate parenteral vitamin D preparation (cholecalciferol or ergocalciferol) should be made available for treatment of patients with vitamin D deficiency unresponsive to oral vitamin D supplementation. Carnitine is commercially available and should be routinely added to neonatal PN formulations. Choline should also be routinely added to adult and pediatric PN formulations; however, a commercially available parenteral product needs to be developed. The parenteral multi-trace element (TE) preparations that are commercially available in the U.S. require significant modifications. Single-entity trace element products can be used to meet individual patient needs when the multiple-element products are inappropriate (see Summary/A.S.P.E.N. Recommendations section for details of these proposed modifications).

The role of N-acetylcysteine (NAC) in the treatment of chronic bronchitis is unclear. Since a number of studies have been published on this topic, a systematic review of published studies seems justified. A systematic search (Medline, Embase, Cochrane Library, bibliographies, no language restriction) for published randomized trials comparing oral NAC with placebo in patients with chronic bronchitis was performed. Dichotomous data on prevention of exacerbation, improvement of symptoms and adverse effects were extracted from original reports. The relative benefit and number-needed-to-treat were calculated for both individual trials and combined data. Thirty-nine trials were retrieved; eleven (2,011 analysed patients), published 1976-1994, were regarded as relevant and valid according to preset criteria. In nine studies, 351 of 723 (48.5%) patients receiving NAC had no exacerbation compared with 229 of 733 (31.2%) patients receiving placebo (relative benefit 1.56 (95% confidence interval (CI) 1.37-1.77), number-needed-to-treat 5.8 (95% CI 4.5-8.1). There was no evidence of any effect of study period (12-24 weeks) or cumulative dose of NAC on efficacy. In five trials, 286 of 466 (61.4%) patients receiving NAC reported improvement of their symptoms compared with 160 of 462 (34.6%) patients receiving placebo (relative benefit 1.78 (95% CI 1.54-2.05), number-needed-to-treat 3.7 (95% CI 3.0-4.9)). With NAC, 68 of 666 (10.2%) patients reported gastrointestinal adverse effects compared with 73 of 671 (10.9%) taking placebo. With NAC, 79 of 1,207 (6.5%) patients withdrew from the study due to adverse effects, compared with 87 of 1,234 (7.1%) receiving placebo. In conclusion, with treatment periods of approximately 12-24 weeks, oral N-acetylcysteine reduces the risk of exacerbations and improves symptoms in patients with chronic bronchitis compared with placebo, without increasing the risk of adverse effects. Whether this benefit is sufficient to justify the routine and long-term use of N-acetylcysteine in all patients with chronic bronchitis should be addressed in further studies and cost-effectiveness analyses.

Diabetic mastopathy, an uncommon form of lymphocytic mastitis and stromal fibrosis, typically occurs in longstanding type 1 diabetes. Nineteen cases meeting predetermined histopathologic criteria for diabetic mastopathy were correlated as to clinical history and disease recurrence. Physical examination revealed palpable discrete masses or diffuse nodularity, both predominantly in the subareolar region. One nonpalpable lesion was detected incidentally during reduction mammoplasty. All cases contained lymphocytic ductitis and lobulitis with varying degrees of keloidal fibrosis, vasculitis, epithelioid fibroblasts, and lymphoid nodule formation. Single mammary lesions were found in 11 patients with type 1 diabetes, 1 with type 2 diabetes, and 3 without diabetes. Four cases were bilateral (3 patients with type 1 and 1 patient with type 2 diabetes). Six of 19 cases recurred (3 ipsilateral, 2 contralateral, and 1 bilateral). We confirm the histopathologic constellation for diabetic mastopathy. However, we question the specificity of these features because of identical findings in patients with type 2 diabetes and nondiabetic patients. We found diabetic mastopathy in men and women, as a solitary mass or bilateral disease, and recurrence in either breast, sometimes multiple. Recognition of potential recurrence is important because it might spare patients with documented diabetic mastopathy from repeated breast biopsies.

Journal Article The Susceptibility of Bacteroides fragilis to 24 Antibiotics Get access Jay Ward Kislak Jay Ward Kislak From the Infectious Disease and Immunology Division, Department of Medicine, New York University School of Medicine; the Medical Service, Goldwater Memorial Hospital; and the Infectious Disease Research Laboratory, French Hospital Division of the French and Polyclinic Medical School and Health Center, New York, New York Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 125, Issue 3, March 1972, Pages 295–299, https://doi.org/10.1093/infdis/125.3.295 Published: 01 March 1972 Article history Received: 26 January 1971 Revision received: 30 September 1971 Published: 01 March 1972

The incidence of Rh immunization of Rh‐negative volunteers given approximately 500 ml of Rh‐positive blood is 18 out of 22. Complete Rh immune suppression was achieved in a treated group given a precalculated dose of Rh immune globulin. Rh immune prophylaxis is safe, effective and practical after transfusion accidents or massive fetomaternal hemorrhages where large volumes of Rh‐positive blood enter the circulation of Rh‐negative individuals. The dose of RhoGAM,* Rho(D) Immune Globulin (Human) found to be effective in suppressing an immune response to the Rh factor was 20 μg/ml of red blood cells (not whole blood). Since each vial contains no less than 300 μg of anti‐Rho(D), the potency for RhoGAM is 15 ml of red blood cells/vial.

BACKGROUND: Little is known about the clinical and virologic manifestations of human herpesvirus (HHV)-8 infection in immunocompetent persons in the absence of malignancy. METHODS: A total of 46 human immunodeficiency virus-negative, HHV-8-seropositive men collected saliva daily, and 25 recorded 15 common symptoms daily (gastrointestinal, constitutional, and oropharyngeal) and absences from work or school. Quantitative polymerase chain reaction measured HHV-8 DNA in saliva. RESULTS: Some 44 (96%) of 46 men reported having sex with men (MSM). Of the 44 MSM, 27 (61%) had HHV-8 detected in saliva on > or = 1 day; heterosexual men also shed HHV-8. In analyses restricted to MSM, HHV-8 DNA was detected on 636 (22%) of 2897 days. Among MSM with HHV-8 detected in saliva, the median rate was 20% (range, 1%-100%), with 30% shedding on > 50% of days, and the median quantity was 4.5 log10 copies/mL (range, 2.0-7.3 log10 copies/mL). The quantity of HHV-8 shed was lower in nonwhites (P<.001) and younger participants (P=.03). The frequency of HHV-8 detection and quantity were correlated (r=0.62; P<.001). Symptoms were reported on 10 (9%) of 114 days when HHV-8 was present, compared with 78 (9%) of 830 days without (odds ratio, 0.93 [95% confidence interval, 0.30-2.88]; P=.9). CONCLUSIONS: HHV-8 is detected frequently and intermittently in the saliva of chronically infected immunocompetent MSM, but this infection is asymptomatic.

ABSTRACT NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor‐associated NK cells (TANKs; peripheral blood) and tumor‐infiltrating NK cells (TINKs) show proangiogenic, decidual NK‐like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual‐like NK polarization toward the CD56 bright CD16 dim/− CD9 + CD49 + subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary‐like structures in vitro. dNK cells release specific proangiogenic factors; among which, angiogenin and invasion‐associated enzymes related to the MMP9‐TIMP1/2 axis. Here, we describe, for the first time, to our knowledge, the expression of angiogenin, MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC‐NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC‐TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary‐like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion‐associated molecules. Combination of Stat5 or MMP inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti‐ tumor antimetastatic ones.—Bruno, A., Bassani, B., D'Urso, D. G., Pitaku, I., Cassinotti, E., Pelosi, G., Boni, L., Dominioni, L., Noonan, D. M., Mortara, L., Albini, A. Angiogenin and the MMP9‐TIMP2 axis are up‐regulated in proangiogenic, decidual NK‐like cells from patients with colorectal cancer. FASEB J. 32, 5365–5377 (2018). www.fasebj.org

OBJECTIVE: The aim of the study was to perform a third cognitive assessment in our pediatric-onset multiple sclerosis (MS) patient cohort and determine predictors of the individual cognitive outcome. METHODS: After 4.7 ± 0.7 years from baseline evaluation, 48 of 63 patients in the original cohort were reassessed on an extensive neuropsychological battery and compared with 46 healthy controls. Two alternate versions of the tests were used at different assessment points. Cognitive impairment was defined as the failure of ≥3 tests; individual change in the cognitive impairment index was measured. RESULTS: At year 5, 38% of the subjects with MS fulfilled our criterion for impairment. Between years 2 and 5, regarding individual cognitive impairment index change, 66.7% of the patients improved. However, comparing baseline and 5-year testing (when the same versions of the tests were used), cognitive impairment index deterioration was observed in 56% of the patients, improvement in 25%, and stability in 18.8%. A deteriorating performance was related to male sex, younger age and age at MS onset, and lower education. None of these variables, however, was retained in the multivariate analysis. CONCLUSIONS: Cognitive outcome in pediatric-onset MS can be heterogeneous. Progression of cognitive problems in a few subjects and potential for compensation and improvement in others call for systematic cognitive screening in this population and development of effective treatment strategies.

Some studies have suggested that drinking in moderation may be beneficial for health, but many of these studies do not address body weight. Evidence suggests that consuming moderate amounts of alcohol is a risk factor for obesity, which is a risk factor for several adverse health outcomes. Recommendations regarding alcohol intake thus should take into account a variety of factors, including baseline body weight, location of body fat, and overall diet.

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. The 5T allele in intron 8 (IVS8) causes abnormal splicing in the CFTR gene, and is associated with lung disease when it occurs in cis with a missense mutation in the CFTR gene, R117H. However, the 5T variant alone has not been reported to cause lung disease. We describe two adult female patients with CF-like lung disease associated with the 5T allele. One patient's genotype is 5T-TG12-M470V/5T-TG12-M470V, and the other is DeltaF508/5T-TG12-M470V; full sequencing of the CFTR gene revealed no other mutation on the same allele as the 5T variant. The levels of full-length CFTR mRNA in respiratory epithelia were very low in these patients (11 and 6%, respectively, of total CFTR mRNA expression). Both patients had defective CFTR-mediated chloride conductance in the sweat ductal and/or acinar epithelia (sweat chloride, mmol/L, mean +/- SEM: 40.0 +/- 5.0 [n = 8 samples] and 80. 0 +/- 3.5 [n = 6 samples]) and airway epithelia (mV, mean +/- SEM CFTR-mediated Cl(-) conductance of 1.2 +/- 2.2 [n = 5 studies] and -6.75 +/- 8.1 [n = 4 studies]). These data suggest that the 5T polythymidine tract sequence on specific haplotype backgrounds (TG12 and M470V) may cause a low level of full-length functional CFTR protein and CF-like lung disease.

1. Transplantation of the intact semitendious for repair or replacement of the medial collateral ligament is a sound procedure on an anatomical, mechanical, and clinical basis. 2. When injury to a knee has been severe enough to lacerate or avulse a medial collateral ligament, other co-existing pathological changes are to be expected and may need definitive care at time of surgery. 3. Any type of late repair of such a badly damaged structure may be expected to leave cerain residual abnormalities. Each procedure submitted will have to be judged by the amount of relief provided to the greatest percentage of patients by the average surgeon later using such procedure. Therefore, in this, as in any new or variant procedure, final results are not now fully determinable

The records of 92 patients with flail chest injury treated at a Level I trauma center were analyzed retrospectively. Associated intrathoracic injuries included pulmonary contusion (46 percent) and pneumothorax or hemothorax, or both (70 percent). The incidence of great vessel, tracheobronchial and diaphragmatic injuries was no different from that of a control population with simple rib fractures. Adult respiratory distress syndrome developed in 27 percent of patients with flail chest; 69 percent of all patients required ventilation (mean duration, 22 days). Mean length of hospital stay was 24 days. The mortality rate was 33 percent. We conclude that flail chest serves as a marker of significant intrathoracic injury, highly associated with pulmonary contusion, but even more so with pneumothorax or hemothorax. Flail chest does not seem to be a marker for great vessel, tracheobronchial, or diaphragmatic injuries. The majority of patients (more than two-thirds) will require mechanical ventilation for prolonged periods. Of paramount importance is the recognition of flail chest as a marker of high kinetic energy absorption, resulting in life-threatening thoracic as well as nonthoracic injuries.

Carbon monoxide is a product of haem degradation by haem oxygenase (HO), activated by inflammatory cytokines and oxidants. This study examined whether allergen challenge can increase exhaled CO levels, as a reflection of HO activation. Exhaled CO and nitric oxide, an expired gas also thought to reflect cytokine-induced airway inflammation, were measured in 15 atopic steroid-naive nonsmoking patients with asthma (13 males, aged 30+/-2 yrs) before and for up to 20 h after allergen challenge. Baseline CO (4.4+/-0.3 parts per million (ppm)) and NO (20.6+/-1.2 parts per billion (ppb)) levels were elevated in asthmatic as compared with nonsmoking normal volunteers (n = 37, 2.1+/-0.2 ppm and 7.0+/-0.1 ppb, respectively, p<0.05). In 10 patients with a dual response in the forced expiratory volume in one second (FEV1) there was a maximal increase in exhaled CO at 1 h (343+/-7.1%) and at 6 h (69+/-12%, p<0.01), followed by a maximal fall in FEV1 (28+/-9%, p<0.05) at 9 h, whereas the maximal NO increase was observed at 10 h (50.2+/-11.8%). The maximal increase in exhaled CO in single response patients (n = 5) was 30+/-2% during the early asthmatic reaction and 46.3+/-9.2% between 4 and 10 h, followed by a fall in FEV1 (9+/-3%, p>0.05) at 9 h, whereas exhaled NO was not significantly changed. In five patients exhaled CO was not attenuated by inhalation of increasing concentrations of histamine causing a 20% fall in FEV1 (PC20) or its subsequent relief by beta2-agonists. In conclusion, exhaled carbon monoxide is increased during the early and late asthmatic reactions independently of the change in airway calibre, while exhaled nitric oxide is increased only during the late reaction and follows the increase in carbon monoxide and fall in the forced expiratory volume in one second in time.

Systemic lupus erythematosus (SLE) is the paradigm of systemic autoimmune diseases characterised by a wide spectrum of clinical manifestations with an unpredictable relapsing-remitting course. The aim of the present work was to identify current available clinical practice guidelines (CPGs) for SLE, to provide their review and to identify physicians' and patients' unmet needs. Twenty-three original guidelines published between 2004 and 2017 were identified. Many aspects of disease management are covered, including global disease management, lupus nephritis and neuropsychiatric involvement, management of pregnancies, vaccinations and comorbidities monitoring. Unmet needs relate with disease management of some clinical manifestations and adherence to treatment. Many patient's unmet needs have been identified starting with faster diagnosis, need for more therapeutic options, guidelines on lifestyle issues, attention to quality of life and adequate education.

Recovery from COVID-19 is associated with production of anti-SARS-CoV-2 antibodies, but it is uncertain whether these confer immunity. We describe viral RNA shedding duration in hospitalized patients and identify patients with recurrent shedding. We sequenced viruses from two distinct episodes of symptomatic COVID-19 separated by 144 days in a single patient, to conclusively describe reinfection with a new strain harboring the spike variant D614G. With antibody and B cell analytics, we show correlates of adaptive immunity, including a differential response to D614G. Finally, we discuss implications for vaccine programs and begin to define benchmarks for protection against reinfection from SARS-CoV-2.

Lumbar hernia is an uncommon flank hernia and a rare complication of blunt trauma. We present a case of acute lumbar hernia as a direct result of blunt trauma. Traditionally, exploratory laparotomy with open repair is indicated, but we report a case of a traumatic lumbar hernia explored and repaired laparoscopically.

Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome assembly, why the anemia occurs is not known. We cultured marrow cells from DBA (n = 3) and del(5q) MDS (n = 6) patients and determined how heme (a toxic chemical) and globin (a protein) are coordinated. We show that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit-erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 μM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA and del(5q) MDS marrow cultures by 68 to 95% (P = 0.03 to 0.05), whereas the erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. Our studies demonstrate that erythropoiesis fails when heme exceeds globin. Our data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA, del(5q) MDS, and perhaps other macrocytic anemias.