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Newly developed fused-ring electron acceptors (FREAs) have proven to be an effective class of materials for extending the absorption window and boosting the efficiency of organic photovoltaics (OPVs). While numerous acceptors have been developed, there is surprisingly little structural diversity among high performance FREAs in literature. Of the high efficiency electron acceptors reported, the vast majority utilize derivatives of 2-(3-oxo-2,3-dihydroinden-1-ylidene)malononitrile (INCN) as the acceptor moiety. It has been postulated that the high electron mobility exhibited by FREA molecules with INCN end groups is a result of close π-π stacking between the neighboring planar INCN groups, forming an effective charge transport pathway between molecules. To explore this as a design rationale for electron acceptors, we synthesized a new fused-ring electron acceptor, IDTCF, which has methyl substituents out of plane to the conjugated acceptor backbone. These methyl groups hinder packing and expand the π-π stacking distance by ∼1 Å, but have little impact on the optical or electrochemical properties of the individual FREA molecule. The extra steric hindrance from the out of plane methyl substituents restricts packing and results in large amounts of geminate recombination, thus degrading the device performance. Our results show that intermolecular interactions (especially π-π stacking between end groups) play a crucial role in performance of FREAs. We demonstrated that the planarity of the acceptor unit is of paramount importance as even minor deviations in end group distance are enough to disrupt crystallinity and cripple device performance.

Newly developed fused-ring electron acceptors (FREAs) have proven to be an effective class of materials for extending the absorption window and boosting the efficiency of organic photovoltaics (OPVs). While numerous FREA small molecules have been developed, there is surprisingly little structural diversity among high performance FREAs in literature. For example, of the high efficiency electron acceptors reported, the vast majority utilize derivatives of 2-(3-oxo-2,3-dihydroinden-1-ylidene)malononitrile (INCN) as the acceptor moiety. It has been postulated that the high electron mobility exhibited by FREA molecules with INCN end groups is a result of close π-π stacking between the neighboring planar INCN groups, forming an effective charge transport pathway between molecules. To explore this as a design rationale for electron acceptors, we synthesized a new fused-ring electron acceptor, IDTCF, which has methyl substituents out of plane to the conjugated acceptor backbone. These methyl groups hinder packing and expand the π-π stacking distance by ~ 1 A, but this change doesn’t affect the optical or electrochemical properties of the individual acceptor molecule. Overall, our results show that intermolecular interactions (especially π-π stacking between end groups) play a crucial role in performance of FREAs. We demonstrated that the planarity of the acceptor unit is of paramount importance as even minor deviations in end group distance are enough to disrupt crystallinity and cripple device performance.

In this study we have assessed zinc status and zinc-dependent cell-mediated immune functions (interleukin-2 production by mononuclear cells, natural killer cell lytic activity, and interleukin-1β production by mononuclear cells) in adult patients with squamous cell carcinoma of the upper aerodigestive tract at diagnosis and before any therapy was instituted. Inasmuch as significant interactions between zinc, copper, and iron exist, we also assayed the plasma copper level, serum iron level, and total iron-binding capacity in our patients. We recruited 30 cancer subjects and 21 control subjects. On the basis of cellular zinc criteria, we diagnosed a mild deficiency of zinc in 53% of cancer subjects. The plasma zinc level was not decreased in our subjects. A univariate analysis was applied by use of one-way analysis of variance comparing study variables among the three study groups (controls and zinc-deficient and zinc-sufficient cancer patients) and Tukey's multiple comparison test, and we showed that interleukin-2 production and natural killer lytic activity were decreased in zinc-deficient cancer patients. Interleukin-1β production (ELISA assay) was increased in both zinc-deficient and zinc-sufficient groups. Plasma copper level was not different, but the iron utilization was decreased in both groups of cancer subjects. We conclude that zinc deficiency and zinc-dependent immunologic dysfunctions are present in more than half of the patients with head and neck cancer in the Detroit area.

A 60-year-old woman was referred to the pulmonary clinic for evaluation of lung nodules. Her medical history was notable for hypothyroidism, anxiety, and a ruptured breast implant for which incomplete surgical resection and evacuation had been performed 10 years previously. She was a lifelong nonsmoker and worked as a gym instructor. The patient denied occupational exposures and had not traveled recently. Medications included levothyroxine and alprazolam. Except for a 1-month history of occasional dry cough, the review of systems was negative. The patient's physician queried whether the previously ruptured silicone breast implant may have played a role in the genesis of the nodules and referred the patient to our institution for further management. The lack of systemic symptoms relative to the degree of lung involvement provided an early diagnostic clue.

Introduction The prevalence of restless legs syndrome (RLS) varies from 5% to 24% in the general population and is associated with a variety of medical disorders. However, the association between RLS and pulmonary hypertension (PH) is unknown. Objectives To determine the prevalence of RLS in PH patients. Methods A cross-sectional questionnaire was given to patients with PH who attended the Pulmonary Hypertension Association conference. We used the RLS Diagnostic Index questionnaire. Demographic data included age, gender, height, weight, body mass index (BMI), medication list, PH World Health Organization (WHO) diagnosis group and current WHO functional class. Results The study included 128 PH patients. Most were females (86.8%) with a mean age of 49.68 years [standard deviation (SD) 14.24]. The mean BMI was 31.3 (SD 20.46). One hundred and twenty-one patients (93.75%) were classified as WHO group 1 (pulmonary arterial hypertension). Three patients were identified in WHO group 3 (hypoxemic states), four patients in group 4 (chronic thromboemboli) and one patient in group 5 (2.3%, 3.1% and 0.8%, respectively). Definite RLS was found in 16 of 128 patients with PH resulting in a prevalence of 12.5%, possible RLS in 39 of 128 patients (30.46%) and no RLS in 73 (57.03%) patients. Conclusion The prevalence of RLS is not increased in PH. There is a high prevalence of possible RLS in our study. The overall prevalence of combined definite and possible RLS is significant. Future research is needed to assess more patients with PH and the association or correlation with RLS.

Sleep disturbances are frequently seen in neurodegenerative conditions. They are common in tauopathies,1–3 synucleinopathies,4–8 and prion disorders.9,10 The sleep disorders in Alzheimer disease,3 Parkinson disease (PD),5,6,8,11 and fatal familial insomnia (FFI)9,10 have been well characterized. Less is known about the sleep dysfunction in progressive supranuclear palsy,12,13 Pick disease, corticobasal degeneration,14,15 and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).16 Pallido-ponto-nigral degeneration (PPND) is a familial neurodegenerative disorder pathologically characterized by the presence of 4 repeat tau deposits in neurons and glia due to an N279K mutation in the gene for the microtubule associated protein tau (MAPT).17,18 PPND belongs to a cluster of disorders collectively labeled as FTDP-17. Clinical, pathological, and neuropsychometric findings in PPND were previously published.16,18,19 Despite recent progress in the understanding of motor and cognitive symptoms, pathology, and genetics of FTDP-17, little is known about sleep disturbances in this disorder. A previous study determined that the PPND kindred demonstrated progressive, generalized slowing on electroencephalography (EEG) as the clinical severity of the disorder increased.16 Daytime recordings captured no sleep, although patients were encouraged to fall asleep. The sleep difficulties observed during the baseline EEG study prompted further polysomnographic investigation.20 Initial polysomnographic data revealed that members of this kindred did not have clinical or electrophysiological features of rapid eye movement (REM) sleep behavior disorder.21 The prevailing theory of sleep generation is a flip-flop switch that governs sleep versus arousal.22 The ascending arousal system is composed of multiple anatomically distinct groups of neurons, including the tuberomammillary nucleus (TMN), the locus ceruleus (LC), the nucleus basalis of Meynert (nbM), and the pedunculopontine tegmentum/laterodorsal tegmentum (PPN/LDT). Meanwhile, the preoptic area of the hypothalamus has been demonstrated to be responsible for generating and maintaining non-REM (NREM) sleep via efferent connections from the median preoptic nucleus (MnPN) and the ventrolateral preoptic nucleus (VLPO), respectively.23,24 These γ-aminobutyric acidergic neurons are inhibitory for the PPN/LDT and LC, thus promoting sleep. Orexin nuclei in the hypothalamus are understood to stabilize the switch via efferent connections to the LC and nbM.25,26 Pathology in the anteroventral and dorso-medial thalamus has also been implicated in sleep disorders, specifically FFI.9 Positron emission tomography (PET) studies of the PPND kindred showed decreased acetylcholinesterase activity in the thalamus,27 which may parallel underlying behavioral similarities between PPND and FFI. The goal of this study was to examine NREM and REM sleep in both affected family members and those genealogically at risk for the disease. We sought to specifically characterize the nature of the sleep disturbance in PPND and compare these findings to those in other progressive neurological illnesses. Based on the inability to sleep noted in the initial study,16 we hypothesized that the PPND patients would have impaired sleep initiation and reduced sleep efficiency. Polysomnographic findings of 6 affected and 5 at-risk individuals from the PPND family are reported. The polysomnographic results prompted further investigation by retrospective, postmortem pathological analysis of available sleep-related areas of the brain.

Iron deficiency anemia has been linked to restless legs syndrome (RLS) and regular blood donation may lead to iron deficiency. It has been reported that blood donations may be associated with RLS. A recent study from Sweden found that 25% of the women donors were affected by RLS. However, this type of study has not been replicated in the United States. We conducted a study in our blood donation unit between September and October 2008. To identify those with RLS, we used the RLS diagnostic index questionnaire by Benes et al. The proportion of blood donors with RLS was estimated and the number of blood donations and hemoglobin levels were compared according to RLS status. One hundred and fifty one patients were interviewed; 7 patients who donated only platelets were excluded, leaving 144 patients for analysis. There were 13 (9.0%, 95% confidence interval [CI]: 4.9-14.9%) patients with RLS. Of these, 7 (4.9%, 95% CI: 2.0-9.8%) had possible RLS and 6 (4.2%, 95% CI: 1.5-8.9%) had major or clinically relevant RLS. There was no dramatic association between RLS and number of blood donations or hemoglobin level (all P >or= 0.21). In our sample of blood donors in the United States, the prevalence of major RLS was 4%. We could not demonstrate an association between RLS and the frequency of blood donation or hemoglobin level in our relatively small sample; a larger sample is needed to better identify any associations.

Restriction in pulmonary function is characterized by reduction in absolute lung volumes. The prototypical restrictive diseases include disorders of the chest wall and lung parenchyma and are characterized by significant respiratory abnormalities during sleep. Sleep may be disturbed by frequent respiratory-related arousals and hypoxemia may be profound, especially during rapid eye movement sleep. Patients with sleep-associated hypoventilation often suffer significant daytime functional sequelae and lowered survival rates. Although supplemental oxygen therapy may alleviate the nocturnal hypoxemia, nocturnal intermittent positive pressure ventilation with or without oxygen seems to improve daytime function and offers a survival advantage in severe disease.

During the past decade, associations between sleep disorders and certain ophthalmologic disorders have been increasingly recognized. To review the literature on these important associations, we conducted a PubMed search using combinations of the following terms: sleep disorders, sleep apnea, circadian rhythm disorder, continuous positive airway pressure, eye disease, floppy eyelid syndrome, glaucoma, ischemic optic neuropathy, papilledema, nocturnal lagophthalmos, and vision loss. We limited our search to articles published in English that involved human participants. All available dates were included. One of the most common sleep disorders, obstructive sleep apnea, has been associated with a variety of eye diseases, including glaucoma, nonarteritic anterior ischemic optic neuropathy, floppy eyelid syndrome, papilledema, and continuous positive airway pressure-associated eye complications. Nocturnal lagophthalmos manifests during sleep and is defined as the failure to fully close the eyelids at night. Finally, blindness is associated with increased risk of circadian rhythm disorders. On the basis of the existing published literature, we discuss these rarely recognized associations, potential pathophysiologic mechanisms, and the effect these associations have on the clinical management of patients. The knowledge of these associations is important for the primary care physician, ophthalmologist, and sleep physician so that underlying sleep disorders or ophthalmologic disorders can be detected.

The optimal schedule of post-chemotherapy granulocyte colony-stimulating factor (G-CSF) administration has not been determined. G-CSF is customarily started 24 hours after chemotherapy; however, clinical data demonstrated that delaying G-CSF until 5 days after completion of chemotherapy has not resulted in a longer duration of neutropenia. Here, we examined the optimal timing of post-chemotherapy G-CSF administration in a mouse model, to show that delayed administration does not postpone the appearance of mature granulocytes in the peripheral blood. We also investigated the mechanism of decreased efficacy of the early G-CSF application after chemotherapy by characterizing the changes in bone marrow cellular composition. To our knowledge, we demonstrate for the first time, that early after chemotherapy, the bone marrow is predominantly composed of mature residual granulocytes and very few progenitors and precursors, on which G-CSF would act to generate granulocytes. The point when immature progenitors reappear does not occur in murine bone marrow until 48 hours after a single dose of cyclophosphamide. Our results indicate that the bone marrow cellular composition early after discontinuation of chemotherapy is not optimal for G-CSF action on acceleration of myeloid recovery. Given the high cost of G-CSF prophylaxis, its delayed administration may potentially result in substantial economic benefits.

Evans' syndrome (ES) is characterized by autoimmune hemolytic anemia and thrombocytopenia and has been associated with immune deficiency and lymphoproliferation in some cases. Abnormalities of Fas-mediated apoptosis have been reported in various immune dysregulation disorders associated with autoimmunity and lymphoproliferation. We measured lymphocyte Fas expression and Fas-mediated T lymphocyte apoptosis in 7 children with ES, 7 with acute idiopathic thrombocytopenic purpura (ITP) and 9 with non-immune-mediated disorders. Patients with ES had higher Fas expression on peripheral blood T and B lymphocytes (P

To determine the prevalence of glaucoma in patients with obstructive sleep apnoea. Cross-sectional case series. One hundred patients with moderate to severe obstructive sleep apnoea. Within 48 h of the polysomnographic diagnosis of obstructive sleep apnoea, patients underwent the following tests: intraocular pressure, gonioscopy, automated perimetry, stereoscopic biomicroscopy, and fundascopic assessment for the presence of glaucomatous optic nerve changes. The prevalence of glaucoma in patients with obstructive sleep apnoea and the associations between patient characteristics and both glaucoma and intraocular pressure. Glaucoma was diagnosed in 27 of 100 patients yielding an estimated prevalence of 27% (95% CI 19–37%). The presence of glaucoma did not correlate with sex, body mass index (BMI), or AHI, but did appear to be associated with age (P=0.014). There was no evidence of a relationship between intraocular pressure and either the apnoea plus hypopnoea index or age. The prevalence of glaucoma in patients with obstructive sleep apnoea is an estimated 27%. Sex, age, body mass index or apnoea plus hypopnoea index are not factors influencing the presence of glaucoma in this population of patients.

Pergolide is an ergot derivative dopamine agonist used in the treatment of Parkinson's disease and restless legs syndrome. Ergot derivatives are known to be associated with fibrotic conditions, including a carcinoid-like, fibrotic, valvular heart disease (VHD). Recently, pergolide was identified in association with the development of VHD. This article includes a summary of the literature published on pergolide-associated VHD, a description of the potential mechanisms of drug-induced VHD, and the clinical implications for the management of patients taking pergolide.

The occurrence of chronic sleep deprivation in the population is commonplace. Both duration and quality of sleep are important to assess when evaluating a patient who has sleep complaints. Excessive sleepiness and decreased psychomotor performance have been demonstrated after sleep deprivation. Sleep loss may impact mood, autonomic function, and the immune system. Sleep-deprived adults may have impaired job performance and are prone to motor vehicle accidents. Simple interventions to ensure adequate sleep can help avoid these hazards.

Natural killer (NK) cells play a part in tumor resistance, host immunity to viral and other microbial infections, and the regulation of lymphoid and other haemopoietic cell populations(1). Yet the lineage to which NK cells belong, and the nature of their target cell specificity remain uncertain. The phenotypic heterogeneity of cells with spontaneous cytotoxicity has led to the suggestion that NK activity is not restricted to a single cell type but is a property of cells of several different lineages at particular stages of maturation or activation. Do NK cells, like T and B lymphocytes, recognize their targets via clonally distributed receptors for distinct cell-surface antigens, or do they, like macrophages, bind to target cells via non-specific structures such as Fc receptors, complement receptors, or lectin-like receptors for ubiquitous cell-surface carbohydrates? Joseph Kaplan has previously proposed(2) that both the nature and specificity of NK cells can be accounted for in terms of a single unifying concept - that NK cells are pre-thymic T cells which, as originally proposed by Jerne(3), express germ line V gene-encoded receptors for either self or non-self histocompatibility antigens. Here he discusses how this hypothesis fits with current evidence concerning NK cell lineage and target specificity.

We cloned a novel murine gene, designated Hemogen (hemopoietic gene), which was sequentially expressed in active hematopoietic sites and downregulated in the process of blood cell differentiation. Hemogen transcripts were specifically detected in blood islands, primitive blood cells and fetal liver during embryogenesis, and then remained in bone marrow and spleen in adult mice. Immunostaining demonstrated that Hemogen was a nuclear protein. We also identified a human homologue of Hemogen, named EDAG, which was mapped to chromosome 9q22, a leukemia breakpoint. Like Hemogen, EDAG exhibited specific expression in hematopoietic tissues and cells. Taken together, these data are consistent with Hemogen and EDAG playing an important role in hematopoietic development and neoplasms.

Phemx (Pan hematopoietic expression) is a novel murine gene expressed in developmentally regulated sites of hematopoiesis from early in embryogenesis through adulthood. Phemx is expressed in hematopoietic progenitors and mature cells of the three main hematopoietic lineages. Conceptual translation of the murine Phemx cDNA predicts a 25-kDa polypeptide with four hydrophobic regions and several potential phosphorylation sites, suggestive of a transmembrane protein involved in cell signaling. The PHEMX protein is structurally similar to tetraspanin CD81 (TAPA-1), a transmembrane protein involved in leukocyte activation, adhesion, and proliferation. Phemx maps to the distal region of chromosome 7, a segment of the mouse genome that contains a cluster of genes that exhibit genomic imprinting. However, imprinting analysis of Phemx at the whole organ level shows that it is biallelically expressed, suggesting that mechanisms leading to monoallelic expression are not imposed at this locus. The human PHEMX ortholog is specifically expressed in hematopoietic organs and tissues and, in contrast to murine Phemx, undergoes alternative splicing. The unique mode and range of Phemx expression suggest that it plays a role in hematopoietic cell function.

The “NK-triggering-antigen regulator” ( Nktar ) gene is a locus identified in the C57BL/6 genome which regulates the ability of unlabeled activated Con A blasts to compete for recognition of labeled syngeneic Con A blasts by BALB/c NK cells. Linkage analysis on Con A blasts from (BALB/c × CByB6F1) N2 backcross progeny for (1) relative level of competitive inhibition of BALB/c NK lysis of syngeneic Con A blasts and (2) genotypes at polymorphic microsatellite markers distributed throughout the mouse genome mapped the Nktar gene locus to a 5-cM region of chromosome 10 containing the interferon-γ receptor ( Ifngr ) gene locus. N2 Con A blasts exhibited an inverse relationship between (a) their cell surface density of IFN-γR molecules detected by FACS with monoclonal anti-CD119 and (b) their cold target inhibition of BALB/c NK self-reactivity. Con A blasts from Ifngr −/− knockout mice showed a relatively high level of inhibition of BALB/c NK self-lysis and a relatively low level of class I MHC, which were both reversed by transient transfection with the Ifngr gene. Sequencing studies showed that Balb/c Ifngr encodes a Gly 69 whereas C57BL/6 Ifngr encodes Glu 69 due to a difference at nucleotide 284. Sequencing studies of N2 progeny demonstrated 100% concordance between their Nktar inhibitory phenotype and their Ifngr genotype. These findings demonstrate that the Nktar and Ifngr loci are identical. They further indicate that polymorphisms related to the Ifngr locus and affecting expression of cell surface IFN-γR may underlie genetic differences in the availability of NK-triggering antigens (NKTAgs) to recognition by self-reactive BALB/c NK cells by differentially affecting the ability of IFN-γR molecules to mediate up-regulation of NKTAg-masking class I molecules.

Factor VIII inhibitory antibodies occur following treatment in more than 30% of subjects with severe factor VIII deficiency. Almost all inhibitor formation occurs in subjects with little if any circulating factor VIII. In the absence of in utero exposure to endogenous or maternal factor VIII, these subjects probably recognize factor VIII as a non-self antigen; in other words, their immune systems fail to become tolerant to factor VIII. This opens up the possibility of preventing inhibitor formation by neonatal induction of tolerance to factor VIII. The various possible approaches include prenatal or neonatal tolerance by the parenteral or oral administration of purified factor VIII protein or factor VIII-encoding DNA. The results of preliminary experiments in mice indicate that feeding newborns a series of low doses of factor VIII does not suppress induction of anti-factor VIII antibody. Whether tolerance can be achieved by feeding mice high doses of factor VIII or by intrauterine or neonatal administration of factor protein or DNA remains to be determined.

Zinc deficiency is a common nutritional problem in adult sickle-cell disease (SCD) patients. Hyperzincuria and increased requirement of zinc due to continued hemolysis in SCD are probable bases for zinc deficiency in these patients. Zinc deficiency affects adversely T-helper1 (TH1) functions and cell mediated immunity and interleukin (IL)-2 production is decreased in zinc deficient subjects. We hypothesized that zinc supplementation will improve T-helper1 function and decrease incidence of infections in patients with SCD. We tested this hypothesis in 32 SCD subjects who were divided in three groups (Grs A, B, and C). Grs A (n = 11) and B (n = 10) were zinc deficient based on cellular zinc criteria and Gr C (n = 11) were zinc sufficient. Gr A subjects were observed for 1 year (baseline), following which they received zinc acetate (50 to 75 mg of elemental zinc orally daily) for 3 years. Gr B subjects were observed for 1 year (baseline), following which they received placebo for 1 year and then switched to zinc supplementation (50 to 75 mg of elemental zinc orally daily) for 2 years. Gr C subjects did not receive any intervention inasmuch as they were zinc sufficient. Prolonged zinc supplementation resulted in an increase in lymphocyte and granulocyte zinc (P = 0.0001), and an increase in interleukin-2 production (P = 0.0001), decreased incidence of documented bacteriologically positive infections (P = 0.0026), decreased number of hospitalizations and decreased number of vaso-occlusive pain crisis (P = 0.0001). The predominant pathogens isolated were staphylococci and streptococci involving the respiratory tract and aerobic gram-negative bacteria, particularly Escherichia coli, involving the urinary tract. Further confirmation of our observations will require prospective studies of zinc supplementation in a larger number of SCD patients.

In this review, we provide evidence based on our studies, for zinc deficiency and cell mediated immune disorders, and the effects of protein and zinc status on clinical morbidities in patients with head and neck cancer. We investigated subjects with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx. Patients with metastatic disease and with severe co-morbidity were excluded. Nutritional assessment included dietary history, body composition, and prognostic nutritional index (PNI) determination. Zinc status was determined by zinc assay in plasma, lymphocytes, and granulocytes. Pretreatment zinc status and nutritional status were correlated with clinical outcomes in 47 patients. Assessment of immune functions included production of TH1 and TH2 cytokines, T cell subpopulations and cutaneous delayed hypersensitivity reaction to common antigens. At baseline approximately 50% of our subjects were zinc-deficient based on cellular zinc criteria and had decreased production of TH1 cytokines but not TH2 cytokines, decreased NK cell lytic activity and decreased proportion of CD4+ CD45RA+ cells in the peripheral blood. The tumor size and overall stage of the disease correlated with baseline zinc status but not with PNI, alcohol intake, or smoking. Zinc deficiency was associated with increased unplanned hospitalizations. The disease-free interval was highest for the group which had both zinc sufficient and nutrition sufficient status. Zinc deficiency and cell mediated immune dysfunctions were frequently present in patients with head and neck cancer when seen initially. Zinc deficiency resulted in an imbalance of TH1 and TH2 functions. Zinc deficiency was associated with increased tumor size, overall stage of the cancer and increased unplanned hospitalizations. These observations have broad implications in the management of patients with head and neck cancer.

Objective: Leptin, the product of the ob gene, plays a key role in a feedback loop that maintains energy balance by signaling the state of energy stores to the brain and by influencing the regulation of appetite and energy metabolism. Zinc also plays an important role in appetite regulation. Thus, we evaluated the relationship between zinc status and the leptin system in humans.Methods: We studied nine healthy men with marginal zinc deficiency, induced by dietary means, before and after zinc supplementation.Results: Zinc restriction decreased leptin levels while zinc supplementation of zinc-depleted subjects increased circulating leptin levels. In addition, zinc supplementation increased IL-2 and TNF-α production that could be responsible for the observed increase in leptin concentrations.Conclusions: Zinc may influence serum leptin levels, possibly by increasing the production of IL-2 and TNF-α.

To explore the modulatory effects of IL-2-activated NK cells on hematopoietic stem cell (HSC) engraftment further, we used fresh newborn liver cells (NLC) and IL-2-activated newborn liver cells (ANLC) as combined sources, respectively, of transplanted HSC and IL-2-activated NK cells free of contaminating CD3+ T cells. As previously found with adult IL-2-activated spleen cells, NLC cultured with IL-2 for 7 days exhibited lymphokine-activated killer (LAK) activity, veto activity, and natural suppressor activity, and enhanced both short-term and long-term stem cell engraftment by intact co-injected syngeneic and allogeneic NLC in totally MHC-mismatched lethally irradiated recipients. However, unlike adult IL-2-stimulated adult spleen cells, IL-2-activated NLC lacked CD3+ T cells and failed to induce lethal GVHD. FACS analysis and cell sorting experiments showed that the cells in ANLC which enhanced short-term HSC engraftment belonged to the relatively immature CD3-NK1.1-2B4+ NK cell subset. By contrast, cells belonging to the more mature CD3-NK1.1+2B4+ NK cell subset showed no HSC-enhancing effects. Identification and isolation in humans of similar NK cell enhancers of HSC could lead to a new approach to improving stem cell engraftment in MHC-mismatched recipients without increasing the risk of GVHD.

31-year-old man sought medical assistance because of a 4-day history of low-grade fever, worsening dyspnea, and lethargy. For more than 6 months, he had had a chronic cough that produced mucopurulent sputum, the color and consistency of which had remained unchanged. A diagnosis of human immunodeficiency virus (HIV)-I infection had been established 8 years previously, and antiretroviral therapy, consisting of two nucleoside ana­ logues, had been administered for I year. He had suffered numerous episodes of pneumonia of unknown cause but had no history of Pneumocystis carinii pneumonia (PCP). He had been vaccinated against pneumococcal disease. His history was positive for thrush more than 6 months before the current examination but no recent episodes. He had no history of sweats or weight loss. Three months before admission, the CD4+ lymphocyte count was 170 cells/ul., He had been noncompliant with inhaled pentamidine for PCP prophylaxis. He admitted to a sev­ eral-year history of abuse of orally administered narcotics, for which he was in a methadone program. He denied any current or past intravenous drug abuse. He reported an allergy to trimethoprim-sulfamethoxazole (TMP-SMX). Physical examination revealed an obese man who ap­ peared lethargic. He had a temperature of 37.9°C, pulse rate of 96 beats/min, blood pressure of 120/80 mm Hg, and respirations of 24/min. The oropharynx was normal. No lymphadenopathy was palpable. Faint crackles were de­ tected at both lung bases. Cardiac examination showed normal findings, as did examination of the abdomen and extremities. A chest roentgenogram revealed diffuse bilateral reticu­ lar and nodular densities with a basilar predominance (Fig. I). The room air arterial oxygen tension (Pao.) was 73.8 mm Hg. The serum lactate dehydrogenase (LDH) level was 212 U/L (normal, 91 to 196).

OBJECTIVE To determine the prevalence of restless legs syndrome (RLS) in native South Americans and identify the impact of geographic location. PARTICIPANTS AND METHODS An epidemiological telephone survey of RLS symptoms involving natives from coastal and mountainous areas was performed during July 2, 2004, through September 28, 2004. The process consisted of 2 phases: the creation of the epidemiological instrument and the telephone survey. RESULTS Five hundred adults, 250 from the mountainous regions and 250 from the coastal region (190 men and 310 women; age range, 25-85 years) were interviewed and subsequently divided on the basis of International Restless Legs Syndrome Study Group criteria into those who had RLS (RLS+ group) and those who did not (RLS-group). Ten (2.0%) had RLS. The overall rate of RLS in adults living in the mountainous region at 2816 m above sea level (3.2% [8/250]) was significantly higher than that for adults living in the coastal region at 4 m above sea level (0.80% [2/250]; P =.002). The mean age of the RLS+ group was 49.5 years (SD, 15.20 years; range, 25-85 years). CONCLUSION Native South American adults have a prevalence of RLS well below that reported in populations with European ancestry but similar to that in Asian and Turkish populations. Furthermore, in Ecuador, geographic differences were identified in areas of similar population density.

The prevalence of restless legs syndrome (RLS) varies from 5% to 24% in the general population and is associated with a variety of medical disorders. However, the association between RLS and pulmonary hypertension (PH) is unknown.To determine the prevalence of RLS in PH patients.A cross-sectional questionnaire was given to patients with PH who attended the Pulmonary Hypertension Association conference. We used the RLS Diagnostic Index questionnaire. Demographic data included age, gender, height, weight, body mass index (BMI), medication list, PH World Health Organization (WHO) diagnosis group and current WHO functional class.The study included 128 PH patients. Most were females (86.8%) with a mean age of 49.68 years [standard deviation (SD) 14.24]. The mean BMI was 31.3 (SD 20.46). One hundred and twenty-one patients (93.75%) were classified as WHO group 1 (pulmonary arterial hypertension). Three patients were identified in WHO group 3 (hypoxemic states), four patients in group 4 (chronic thromboemboli) and one patient in group 5 (2.3%, 3.1% and 0.8%, respectively). Definite RLS was found in 16 of 128 patients with PH resulting in a prevalence of 12.5%, possible RLS in 39 of 128 patients (30.46%) and no RLS in 73 (57.03%) patients.The prevalence of RLS is not increased in PH. There is a high prevalence of possible RLS in our study. The overall prevalence of combined definite and possible RLS is significant. Future research is needed to assess more patients with PH and the association or correlation with RLS.

Methods for monitoring cell line identification and authentication include species-specific immunofluorescence, isoenzyme phenotyping, chromosome analysis, and DNA fingerprinting. Most previous studies of DNA fingerprinting of cell lines have used restriction fragment length polymorphism analysis. In this study, we examined the utility of an alternative and simpler method of cell line DNA fingerprinting—polymerase chain reaction (PCR) amplification of fragment length polymorphisms. Fourteen human cell lines previously found by other methods to be either related or disparate were subjected to DNA fingerprinting by PCR amplification of selected fragment length polymorphism loci. Cell identification patterns by this method were concordant with those obtained by isoenzyme phenotyping and restriction fragment length polymorphism-DNA fingerprinting, and were reproducible within and between assays on different DNA extracts of the same cell line. High precision was achieved with electrophoretic separation of amplified DNA products on high resolution agarose or polyacrylamide gels, and with fragment length polymorphism (FLP) loci-specific “allelic ladders” to identify individual FLP alleles. Determination of the composite fingerprint of a cell line at six appropriately chosen fragment length polymorphism loci should achieve a minimum discrimination power of 0.999. The ability of PCR-based fragment length polymorphism DNA fingerprinting to precisely and accurately identify the alleles of different human cell lines at multiple polymorphic fragment length polymorphism loci demonstrates the feasibility of developing a cell line DNA fingerprint reference database as a powerful additional tool for future cell line identification and authentication.

NK cell specificity for normal lymphoblasts was tested in mice by direct cytotoxicity and competitive inhibition assays. IL-2-activated NK cells lysed Hh-1 incompatible but not Hh-1 compatible or Hh-1[null] allogeneic and semisyngeneic lymphoblasts. NK cells also lysed some syngeneic blasts. NK alloreactivity was inhibited by unlabeled targets which shared at least one Hh-1 determinant with the labeled target. NK self-reactivity was inhibited by syngeneic cells as well as by some allogeneic cells. Class I molecule-deficient beta2m-/- blasts universally inhibited NK lysis of all normal blasts. Cold targets appeared to specifically inhibit NK lysis by competing for recognition by NK activatory receptors rather than by competing for NK lysis by sharing with hot targets the absence of MHC class I inhibitory molecules recognized by NK cell Ly49 molecules. Backcross analysis revealed that a single non-MHC-linked gene locus regulates the accessibility of some normal lymphoblast target antigens to recognition by triggering receptors on self-reactive BALB/c NK cells. The results suggest that target lymphoblast class I molecules may differentially control the accessibility of universally expressed polymorphic NK triggering antigens to positive recognition by distinct sets of alloreactive and self-reactive NK cells.

Objective : To determine whether trauma induces an increase in the concentration of circulating transforming growth factor-β (TGF-β), and whether there is a temporal correlation between plasma TGF-β concentration and the development of posttrauma cellular immunosuppression. Materials and Methods : Male Sprague-Dawley rats were anesthetized, subjected to bilateral femur fractures or sham injury, and killed 1, 3, or 5 days later. Plasma TGF-β levels, splenocyte phenotypes, mitogen-induced proliferation, interleukin-2 (IL-2) production, and IL-2 receptor (IL-2R) expression were determined at each time point. Measurements and Main Results : Splenocyte proliferation increased on day 1 postinjury without corresponding change in IL-2 or plasma TGF-β levels. Splenocyte proliferation and IL-2 production were suppressed on day 3 postinjury, while plasma TGF-β levels peaked. No differences were observed between trauma and control groups on day 5. Splenocyte phenotypes and IL-2R expression were similar in injured and control rats at all times. Conclusions : Suppression of lymphocyte proliferation and IL-2 production after trauma occurs concomitantly with a rise in plasma TGF-β. The immune response is restored with normalization of TGF-β concentration. These observations suggest that TGF-β may contribute to posttrauma immunosuppression.

Objective To describe three cases of obstructive sleep apnea that resembled coronary artery disease and to suggest features that might distinguish these two syndromes. Design We present three detailed case reports of patients with severe obstructive sleep apnea and discuss similar cases from the literature. Material and Methods Two obese women and one obese man with previously undiagnosed obstructive sleep apnea had chest discomfort, episodic dyspnea, and palpitations, most prominent at night. All three patients had multiple cardiac risk factors and had previously undergone cardiac evaluations, including at least two prior cardiac catheterizations each. Repeated cardiac catheterization revealed less coronary occlusive disease than expected on the basis of the symptoms in all three patients and a small atrial septal defect in one patient. When reassessed, the medical histories suggested obstructive sleep apnea. Results Overnight polysomnography documented the presence of severe sleep apnea; the three patients had mean values of 56 disordered breathing events per hour and 44% minimal oxygen saturation. Although bilevel or continuous positive airway pressure yielded initial improvement, all patients had difficulty with routine use of this therapy after 1½ years of follow-up. Conclusion The initial manifestations of severe obstructive sleep apnea may simulate angina, suggest arrhythmia, or mimic heart failure. Failure to inquire about snoring and daytime somnolence in patients with chest pain may prevent the identification of clinically significant disordered breathing during sleep.

Objective. To investigate the association between CD5+ B cell expression and IgM rheumatoid factor (IgM-RF) in juvenile rheumatoid arthritis (JRA). Methods. CD5+ B cell levels analyzed by flow cytometry and IgM-RF expression determined by enzymelinked immunosorbent assay were compared in children with JRA, children with other collagen vascular diseases, and healthy controls. Results. Children with polyarticular JRA had expanded populations of CDS+ B cells, and expansion of CDS+ B cells and IgM-RF both correlated with disease activity. Conclusion. The results indicate that an expanded CD5+ B cell population leads to IgM-RF production in patients with polyarticular JRA, as well as patients with RA.

We have found that murine lymphokine activated killer (LAK) cells have veto and natural suppressor activities in vitro, and prevent graft- versus-host disease (GVHD) in vivo. To determine whether human LAK cells mediate veto and natural suppression we measured their ability to inhibit generation of allospecific cytotoxic T cells (CTL) in mixed lymphocyte culture (MLC). When added to MLCs at low concentrations LAK cells caused veto-type inhibition: stimulator-type LAK cells inhibited generation of CTL but responder or third-party LAK cells did not. At higher concentrations LAK cells caused nonspecific inhibition: all three LAK cell types inhibited generation of CTL. LAK cell veto and natural suppressor activities were largely eliminated by irradiation with 30 Gy and by depletion of CD56+ cells, but increased after depletion of CD3+ cells. LAK cell veto activity is not likely an artifact of cold-target inhibition by the LAK cells themselves or by proliferation of T cells contaminating LAK cell preparations: (1) veto only occurred when LAK cells were added to MLC on days 0 through 2, but not when added on day 5; (2) addition of saturating numbers of labeled targets to fixed numbers of allo-CTL effectors failed to overcome the inhibitory effects of adding stimulator-type LAK cells at the onset of MLC; and (3) CD3-depleted LAK cells showed greater veto activity than threefold greater numbers of control LAK cells. In light of our previous findings in mice, the current results imply that adoptive immunotherapy with LAK cells may be useful in preventing GVHD in human bone marrow transplant recipients.

BACKGROUND The Third National Health and Nutrition Examination Survey suggested some Mexican American children are at risk of zinc deficiency. OBJECTIVE We measured the effects of zinc and micronutrients or of micronutrients alone on indexes of cell-mediated immunity and antiinflammatory plasma proteins. DESIGN Subjects (n = 54) aged 6-7 y were randomly assigned and treated in double-blind fashion in equal numbers with 20 mg Zn (as sulfate) and micronutrients or with micronutrients alone 5 d/wk for 10 wk. RESULTS Before treatment the mean +/- SD plasma zinc was 14.9 +/- 1.7 micromol/dL and the range was within the reference; hair zinc was 1.78 +/- 0.52 micromol/g and 41.6% were < or =1.68 micromol/g; serum ferritin was 25.7 +/- 18.6 microg/L and 50.0% were < or =20 microg/L. The zinc and micronutrients treatment increased the lymphocyte ratios of CD4(+) to CD8(+) and of CD4(+)CD45RA(+) to CD4(+)CD45RO(+), increased the ex vivo generation of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), decreased the generation of interleukin-10 (IL-10), and increased plasma interleukin-1 receptor antagonist (sIL-1ra) and soluble tumor necrosis factor receptor 1 (sTNF-R1). Micronutrients alone increased the ratio of CD4(+) to CD8(+) but not of CD4(+)CD45RA(+) to CD4(+)CD45RO(+), increased IFN-gamma but had no effect on IL-2 or IL-10, and increased sIL-1ra but not sTNF-R1. Efficacy of zinc and micronutrients was greater than micronutrients alone for all indexes except the ratio of CD4(+) to CD8(+), which was affected similarly. CONCLUSIONS Before treatment, concentrations of hair zinc in 41.6% of subjects and serum ferritin in 50% were consistent with the presence of zinc deficiency. The greater efficacy of the zinc and micronutrients treatment compared with micronutrients alone supports this interpretation.

Obstructive sleep apnea syndrome is the most common cause of hypersomnolence in patients referred to sleep disorders centers. This type of sleep apnea is characterized by loud snoring, nocturnal oxyhemoglobin desaturation, and disrupted sleep that leads to daytime hypersomnolence. The anatomic configuration of the pharynx and the physiologic responses to occlusion of the upper airway play a major role in the pathogenesis of this disorder. Polysomnography can accurately identify obstructive sleep apnea, and the multiple sleep latency test allows an objective measurement of daytime alertness. Weight loss and training the patient to sleep in a lateral position are frequently used to alleviate mild cases. Nasally applied continuous positive airway pressure is an extremely effective modality for treating moderate and severe obstructive sleep apnea. Surgical correction of obvious anatomic defects has a role in diminishing obstructive sleep apnea, but the exact role of surgical intervention in patients without obvious anatomic defects remains unknown. The choice of therapy should be tailored to the individual patient with sleep apnea, and careful follow-up is essential to ensure a positive response to therapy.

Pneumococcus vaccine, injected alone or mixed with diphtheria-tetanus toxoid-pertussis, did not elicit significant concentrations of pneumococcus type 6 antibodies in 2- to 5-year-old sickle cell anemia patients (n = 22). Reinjection 5 months later failed to elicit a booster response to pneumococcus type 6. We then injected conjugates of pneumococcus type 6B and of Haemophilus influenzae type b (Hib), each bound to tetanus toxoid (TT), alternatively at monthly intervals into sickle cell anemia patients of the same age group (n = 25); most received 3 injections of each vaccine. Pneumococcus vaccine was administered to 19 patients and Hib to 1 at approximately 1 year of age. Blood samples were taken before each and approximately 6 months after the last injection. Infrequent and minimal local reactions and only 6 episodes of fever (3%) occurred after injection of the conjugates. Pneumococcus type 6B-TT elicited a rise in the geometric mean concentration of pneumococcus type 6 antibodies (Ab) from 104 ng of antibody nitrogen (AbN)/ml in preimmunization sera to 385 ng of AbN/ml after the first injection (P less than 0.01). There were further increases after the 2 subsequent injections; 6 months after the third injection, the mean concentration was 940 ng of AbN/ml and 15 of 16 (94%) had greater than 300 ng of AbN/ml. Hib-TT elicited a 160-fold increase of Hib antibodies to a geometric mean concentration of 39.0 micrograms of Ab/ml after the first injection. These levels rose approximately 2-fold following 2 additional injections to 71.7 micrograms/ml and declined to 10.7 micrograms/ml at the 6-month sampling.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies from numerous institutions have shown that the pulsed-dye laser lithotripter is a safe and effective tool for the treatment of urinary calculi. In most of these series, only one or two well-trained operators perform the procedure. We report a series of 53 patients with a 96% successful stone ablation rate in which 19 urologists were involved. There was no morbidity or mortality related to laser use. These results compare favorably with series from experienced single operators and that with standard urologic and endoscopic experience, laser training, and appropriate case selection, laser lithotripsy is a safe and effective modality for the treatment of urinary calculi even when performed by occasional users.

Background House dust mite allergen has previously been detected in the cord blood of some newborns but not others. The factors that affect the presence and levels in cord blood of this and possibly other allergens are unknown. Objective To test the hypothesis that the levels of maternal allergen and allergen specific IgG affect the presence and levels of newborn allergen. Methods Enzyme-linked immunosorbent assays were used to measure the levels of house dust mite allergen Der p 1 and Der p 1 specific IgG and IgE in paired blood samples from 98 mothers and full-term newborns. Results Der p 1 was detected in 27 mothers and 12 newborns. None of the 71 mothers who lacked Der p 1 had Der p 1–positive newborns. When present, cord blood Der p 1 levels correlated with and were approximately one third of Der p 1 levels in maternal blood. Cord blood Der p 1 levels also tended to correlate with maternal blood levels of Der p 1 specific IgG but showed little, if any, correlation with maternal blood levels of Der p 1 specific IgE. Conclusions When detectable, the levels of an allergen in the blood of newborns correlate with the levels of that allergen in the blood of their mothers and tend to be related to maternal levels of allergen specific IgG.

OBJECTIVE To investigate the frequency of valvular heart disease in patients taking pergolide. PATIENTS AND METHODS The medical records of patients seen at the Mayo Clinic in Jacksonville, Fla, between 1998 and 2003 were searched electronically for the word pergolide and the presence of a 2-dimensional echocardiogram. Patients who had not taken pergolide before undergoing echocardiography served as the control group. Echocardiograms were reviewed for the presence of valvular regurgitation. The frequency of valvular disease in patients taking pergolide was calculated and compared with controls. Associations with dosage and years of treatment also were examined. RESULTS Fifty-five patients made up the pergolide group, and 63 served as controls. When looking at aortic regurgitation (AR) of any degree, 45% of patients in the pergolide group had AR, compared with 21% of controls ( P =.006). The frequency of moderate to severe valvular regurgitation in the pergolide group was 11% (95% confidence interval [CI], 4%-22%), 13% (95% CI, 5%-24%), and 13% (95% CI, 5%-24%) for the tricuspid, mitral, and aortic valves, respectively. No statistical difference was identified in the frequency of moderate to severe valvular regurgitation (mitral, tricuspid, or aortic) when compared with controls. There was marginal evidence of an association between a higher daily dosage of pergolide and moderate to severe AR ( P =.05). CONCLUSION The frequency of AR appears to be increased in patients taking pergolide. Our study suggests that if a causeeffect relationship exists between pergolide and valvular heart disease, it likely occurs at a low but clinically important incidence and may be associated with dosage.

Programmed cell death, or apoptosis, is a physiological means of eliminating unwanted cells and maintaining immune homeostasis. One of the primary mechanisms is the Fas (CD95)/Fas ligand system. Its inactivation in normal cells and malignant cells may be involved in malignant trans-formation and refractory clinical course, respectively. We established a Fas resistant clone and evaluated the molecular basis for its mechanism of resistance. The Fas-sensitive leukemia cell line, MML-1, was established from a child with B-precursor acute lymphoblastic leukemia. A Fas resistant clone, MML-1R, was obtained by co-culture selection with anti-Fas antibody CH-11. Flow cytometry analysis showed both cell lines had equivalent expression of cell surface CD13, 15, 19, 22 and Fas receptor. Western blot analysis revealed equal expression of FADD (Fas-associated death domain protein), caspase-3 and -8. MML-1 was quite sensitive to both CH-11 and etoposide-induced apoptotis. By contrast, MML-1R had similar sensitivity to etoposide but no response to CH-11. Fas receptor mutation analysis showed a heterozygous death domain A --> G point mutation at 1009 bp, causing a switch from glutamine to glycine at amino acid 256. Immunoprecipitation assay showed decreased binding of Fas to FADD. We also found that etoposide bypassed Fas-FADD interaction in MML-1R by activating caspase-8 and caspase-3. These results indicate that Fas resistance can result from mutations of the gene encoding the Fas receptor which result in decreased FADD binding, thereby blocking formation of the death inducing signaling complex. Screening for similar Fas mutations in therapy resistant malignancies would lead to a better understanding of tumorigenesis and recurrence.