Variable expression of autosomal recessive polycystic kidney disease and congenital hepatic fibrosis within a family

Blyth and Ockenden [1971] assigned patients with autosomal recessive polycystic kidney disease (ARPCKD) to 4 discrete groups (perinatal, neonatal, infantile, juvenile) on the basis of the age of presentation. They and others speculated that at least 4 genes were responsible for what they considered to be closely related, but different conditions. These views have gained wide but not universal acceptance. Some workers have insisted that the perinatal and neonatal "forms" of ARPCKD differ fundamentally from the juvenile "form." However, others have proposed that ARPCKD-CHF (congenital hepatic fibrosis) and CHF-ARPCKD are manifestations of the same disease with variation of expression in a kindred. We report on a patient who presented at birth (1979) with ARPCKD and respiratory distress. He died at 18 hr. An older sib presented at 16 yr in 1984. She had no symptoms, but her mother wanted reassurance that the daughter did not have a condition similar to that of the deceased sib. Blood pressure was 120/80 mm Hg and there was hepatosplenomegaly. A diagnosis of renal tubular ectasia and CHF was made by ultrasonography, radiologic studies, and a liver biopsy. The evidence from families such as this favors the concept that ARPCKD and CHF presenting as Blyth and Ockenden's perinatal form, and CHF and renal tubular ectasia as their juvenile form, are manifestations of the same genetic disorder, and that the different manifestations are more likely variations in expression than the results of different mutant genes. The manifestations in this family add weight to the growing body of evidence that intrafamilial variability may occur, not only in autosomal dominant conditions, but also in autosomal recessive disorders.     

A model of corrective gene transfer in X-linked ichthyosis

Single gene recessive genetic skin disorders offer attractive prototypes for the development of therapeutic cutaneous gene delivery. We have utilized X-linked ichthyosis (XLI), characterized by loss of function of the steroid sulfatase arylsulfatase C (STS), to develop a model of corrective gene delivery to human skin in vivo. A new retroviral expression vector was produced and utilized to effect STS gene transfer to primary keratinocytes from XLI patients. Transduction was associated with restoration of full-length STS protein expression as well as steroid sulfatase enzymatic activity in proportion to the number of proviral integrations in XLI cells. Transduced and uncorrected XLI keratinocytes, along with normal controls, were then grafted onto immunodeficient mice to regenerate full thickness human epidermis. Unmodified XLI keratinocytes regenerated a hyperkeratotic epidermis lacking STS expression with defective skin barrier function, effectively recapitulating the human disease in vivo. Transduced XLI keratinocytes from the same patients, however, regenerated epidermis histologically indistinguishable from that formed by keratinocytes from patients with normal skin. Transduced XLI epidermis demonstrated STS expression in vivo by immunostaining as well as a normalization of histologic appearance at 5 weeks post-grafting. In addition, transduced XLI epidermis demonstrated a return of barrier function parameters to normal. These findings demonstrate corrective gene delivery in human XLI patient skin tissue at both molecular and functional levels and provide a model of human cutaneous gene therapy.      

Bacterial clearance and cytokine profiles in a murine model of postsurgical nosocomial pneumonia

The development of a nosocomial pneumonia is facilitated by alterations in host innate pulmonary antibacterial defenses following surgical trauma, which can result in decreased pulmonary bacterial clearance and increased morbidity and mortality. In a murine model of postoperative nosocomial infection, surgical stress (laparotomy) decreased Escherichia coli clearance from the lungs of animals that underwent surgery. Consistent with previous studies, (i) pulmonary levels of tumor necrosis factor alpha at 6 h and of interleukin-1beta (IL-1beta), IL-6, and gamma interferon (IFN-gamma) at 24 h post-bacterial infection (PBI) were decreased in animals that underwent laparotomy 24 h prior to E. coli infection (LAP/E. coli) compared to animals that received E. coli only; (ii) KC and macrophage inhibitory protein 2 were elevated at 6 h PBI in LAP/E. coli animals compared to E. coli-only animals; however, at 24 h PBI, levels were higher in the E. coli-only group; (iii) at 24 h PBI, monocyte chemoattractant protein 1 was lower in the LAP/E. coli group compared to the E. coli-only group; (iv) IL-10 levels were unaffected at all time points evaluated; and (v) the total number of neutrophils present in the lungs of LAP/E. coli animals at 6 h PBI was decreased in comparison to that in E. coli-only animals, resulting in decreased bacterial clearance and increased mortality in LAP/E. coli animals by 24 h PBI. Similar changes in cytokine profiles, pulmonary bacterial clearance, and mortality were consistent with reported findings in patients following surgical trauma. This model, therefore, provides a clinically relevant system in which the molecular and cellular mechanisms that lead to the development of nosocomial pneumonia can be further explored.     

The distribution of neuropeptide Y-immunoreactive neurons and nerve fibers in the forebrain of the carp Cyprinus carpio L

The present study reports the distribution of Neuropeptide Y (NPY)-immunoreactive neurons and fibers in the forebrain of the adult carp Cyprinus carpio L. Serial Nissl-stained sections were used for cytoarchitecture and identification of anatomical structures. Immunostaining of NPY-containing neurons and fibers was used as neurochemical marker and tool for comparison with other species, including the goldfish.The general outline of the cytoarchitecture of the carp forebrain is similar to that of other Cypriniformes. However, using NPY immunohistochemistry, we found several specific differences with the goldfish, especially in the diencephalon. In the hypothalamus of the carp NPY-immunoreactive (NPYir) neurons were identified in the n. dorsolateralis thalami, and in the n. ventralis lateralis thalami. In the same location, we observed the n. anterior hypothalami and the n. preglomerulosus pars lateralis, described in the goldfish, as parts of n. prerotundus. However, in the carp we were not able to identify a n. preglomerulosus pars medialis, a n. preglomerulosus pars medialis commissuralis and a n. glomerulosus. We describe a n. rotundus, in which we did not find substructures typical of the goldfish.Further differences with the goldfish, trout and salmon were also noted.     

17q21-qter trisomy is an indicator of poor prognosis in acute myelogenous leukemia

A reciprocal translocation (9;11) is often found in acute myeloid leukemia (AML), mostly of the M5a type. We report a case of a child with AML, in whom t(9;11) was observed at diagnosis as the sole structural abnormality, together with trisomies 19 and 21. The diagnosis was AML evolving from a myelodysplastic syndrome (MDS), and the blast morphology was undifferentiated. Chemotherapy failed to induce morphological remission and the patient's condition soon worsened. A subclone appeared and expanded during the course of the disease, with an additional unbalanced translocation (1;17) leading to trisomy of the long arm of chromosome 17 (17q). The data available from the literature on acquired anomalies involving 17q and our observation led us to postulate a specific link between the gain of 17q and complete chemoresistance.     

An ultrastructural study of normal human mammary epithelial cells in culture

The ultrastructure of normal human mammary cells cultured from post-weaning breast fluids is described. Cells from confluent monolayers in two week old cultures were studied. The epithelial nature of these cells was established by the demonstration of a well developed system of cell-to-cell interdigitation and numerous desmosomes. These cells also share with breast epithelial cells in vivo, polarity, with blunt short microvilli on the apical surface and an oriented arrangement of organelles in the basal and apical portions of the cells. The Golgi apparatus, which is the most highly developed organelle, is localized in the apical pole and contains substantial quantities of secretory material in the cisternae and vesicles. A variegated palisade of finely granular material mixed with tonofilaments is seen in the basal portion of the cells; many of these tonofilaments end in the terminal web of the desmosomes. The regular occurrence of these cells in breast fluids during the terminal phases of lactation suggests that their separation is a part of normal breast involution.     

Altered major histocompatibility complex-restricted antigen recognition by T cells from elderly humans.

Positive selection of T cells within the thymus gland leads to major histocompatibility complex (MHC)-restricted recognition of antigen by T lymphocytes. As the thymus gland involutes with age, altered MHC-restricted antigen recognition by T cells from elderly humans would be expected. We have tested this hypothesis by comparing the proliferative response of T cells and T cell clones from aged and young subjects to influenza determinants presented by autologous or allogeneic antigen-presenting cells (APC). Under conditions in which the allogeneic mixed lymphocyte reaction was minimal, T cells from six of seven aged donors but only one of seven young donors were stimulated by influenza vaccine presented by allogeneic APC. More importantly, one-half of the influenza-specific T cell clones derived from aged donors, but none of the clones derived from young donors, were activated by influenza vaccine presented by allogeneic APC. While 80% of the MHC-nonrestricted influenza-specific T cell clones expressed the gamma/delta T cell receptor, 20% of these clones expressed the alpha/beta T cell receptor. Thus, changes in MHC-restricted antigen recognition by T cells and in altered distribution of alpha/beta versus the gamma/delta T cell receptor bearing antigen-specific T cell clones occur with aging.     

Hypogammaglobulinemia with hyper-IgM, severe T-cell defect, and abnormal recirculation of OKT4 lymphocytes in a girl with chronic lymphadenopathy

We describe here one 8-year-old girl with an unusual form of immunodeficiency, characterized by hypogammaglobulinemia with hyper-IgM, severe T-cell defect, and chronic lymphadenopathy. Patient's B cells failed to produce IgG or IgA in vitro following stimulation with either pokeweed mitogen or Epstein-Barr virus, suggesting an intrinsic B-cell defect. Abnormal T-cell function was demonstrated by impaired in vivo delayed type hypersensitivity, reduction of mitogen-induced proliferation and interleukin 2 production, reduction of interferon-gamma production, and marked decrease of circulating OKT4+ cells. The latter cells were found in normal proportion in the patient's lymph node tissue. This finding suggests that the decrease of OKT4+ cells in peripheral blood was due to the abnormal recirculation of these cells. The identity of this syndrome with the infantile form of the acquired immunodeficiency syndrome was apparently ruled out by the failure to demonstrate HTLV-III-related sequences in patient's lymphocytes or virus-specific serum antibodies.     

Coping in chest pain patients with and without psychiatric disorders

We first examined relations between psychiatric disorder and coronary heart disease (CHD) in 77 patients presenting with chest pain. The coping profiles of chest pain patients with and without psychiatric disorder and CHD were then compared. Psychiatric patients with no medical illness (n = 129) were also studied. On the basis of previous research we hypothesized specific coping differences across the groups. As expected, chest pain patients without psychiatric disorder scored significantly higher on a problem-focused coping scale than chest pain patients with psychiatric disorder, who in scored higher on this scale than psychiatric patients with no medical illness. The opposite pattern occurred for a measure of wishful thinking. Scores of chest pain patients with psychiatric disorder were higher on a measure of avoidance and lower on a measure of seeking of social supports than those without psychiatric disorder. Scores on a self-blame measure were not different across the groups. The results are discussed in the context of illness behavior and somatization.