Malan syndrome: Sotos-like overgrowth with de novo NFIX sequence variants and deletions in six new patients and a review of the literature

De novo monoallelic variants in NFIX cause two distinct syndromes. Whole gene deletions, nonsense variants and missense variants affecting the DNA-binding domain have been seen in association with a Sotos-like phenotype that we propose is referred to as Malan syndrome. Frameshift and splice-site variants thought to avoid nonsense-mediated RNA decay have been seen in Marshall–Smith syndrome. We report six additional patients with Malan syndrome and de novo NFIX deletions or sequence variants and review the 20 patients now reported. The phenotype is characterised by moderate postnatal overgrowth and macrocephaly. Median height and head circumference in childhood are 2.0 and 2.3 standard deviations (SD) above the mean, respectively. There is overlap of the facial phenotype with NSD1-positive Sotos syndrome in some cases including a prominent forehead, high anterior hairline, downslanting palpebral fissures and prominent chin. Neonatal feeding difficulties and/or hypotonia have been reported in 30% of patients. Developmental delay/learning disability have been reported in all cases and are typically moderate. Ocular phenotypes are common, including strabismus (65%), nystagmus (25% ) and optic disc pallor/hypoplasia (25%). Other recurrent features include pectus excavatum (40%) and scoliosis (25%). Eight reported patients have a deletion also encompassing CACNA1A, haploinsufficiency of which causes episodic ataxia type 2 or familial hemiplegic migraine. One previous case had episodic ataxia and one case we report has had cyclical vomiting responsive to pizotifen. In individuals with this contiguous gene deletion syndrome, awareness of possible later neurological manifestations is important, although their penetrance is not yet clear.     

Membrane-associated sickle hemoglobin: a major determinant of sickle erythrocyte rigidity

Micropipette aspiration tests on single erythrocytes have previously shown that the static rigidity (membrane shear modulus) of oxygenated sickle cells increased with increasing hemoglobin concentration, whereas the rigidity of normal cells was independent of hemoglobin concentration. Moreover, it was observed that after mechanical extension, sickle cells exhibited persistent deformation more frequently and to a greater extent than normal cells. To ascertain if differences in association of normal and sickle hemoglobin with the membrane could account for these observations, we measured rheologic properties of normal membranes reconstituted with sickle hemoglobin and sickle membranes reconstituted with normal hemoglobin. The static rigidity of normal ghosts reloaded with sickle hemoglobin was higher than those of either normal ghosts reloaded with normal hemoglobin or native normal cells. On the other hand, the increased rigidity of native sickle cells decreased to near-normal values following reconstitution with normal hemoglobin. Furthermore, we observed that normal ghosts reconstituted with sickle hemoglobin exhibited persistent bumps after mechanical extension, but no bumps formed on normal ghosts reconstituted with normal hemoglobin. Moreover residual bumps were not produced on sickle cells reloaded with normal hemoglobin. Since mechanical characteristics peculiar to sickle cells could be induced in normal cells by incorporation of sickle hemoglobin, and since normal characteristics could be restored to sickle cells by incorporation of normal hemoglobin, we suggest that the interaction of sickle hemoglobin with the cell membrane is responsible for augmented static rigidity of oxygenated sickle erythrocytes.     

Expression of CD27 and its ligand, CD70, on chronic lymphocytic leukemia B cells

Crosslinking the CD27 antigen on T cells provides a costimulatory signal that, in concert with T-cell receptor crosslinking, can induce T- cell proliferation and cellular immune activation. We find that chronic lymphocytic leukemia (CLL) B cells from most patients coexpress both membrane-bound and soluble CD27, along with its newly identified ligand, CD70. The expression of soluble CD27 may preclude leukemic B cells from stimulating T cells via CD70, thereby potentially impairing their ability to function as effective antigen-presenting cells. We find that leukemic B-cell expression of soluble and membrane-bound CD27 can be downmodulated through a CD40-dependent signal. This signal also induces enhanced expression of CD70 on both normal and leukemic B cells. We find that tumor necrosis factor (TNF)-alpha, or the Th1 cytokine interferon (IFN)-gamma, also can induce downmodulation of CD27, whereas Th2-associated cytokines interleukin-4 (IL-4) or IL-10 can enhance leukemic B-cell expression of this accessory molecule. The modulation of CD27 induced by these conditions is accompanied by reciprocal changes in the expression levels of CD70, suggesting that these accessory molecules may be engaged in reciprocal receptor-ligand downmodulation. Consistent with this, we observe that co-culture of CLL B cells with transfected murine plasmacytoma cells that express human CD70 affects downmodulation of CD27 and enhanced expression of CD70 on leukemic B cells, but does not affect expression of CD27 mRNA. However, we find that CD40-crosslinking, in addition to reducing the level of CD27 protein, also reduces leukemic B-cell expression of CD27 mRNA. This argues that the changes in the expression levels of CD27 following CD40-signaling are not simply due to induced increases in the expression levels of CD70. Finally, we demonstrate that reciprocal changes in expression of CD27 and CD70 may contribute to the enhanced antigen-presenting capacity of CLL B cells after CD40-dependent leukemic B-cell activation. These findings expand the understanding of the regulation of costimulatory molecules important in antigen presentation and also have implications for the immunobiology of and therapy for CLL.     

Ruptured papillary muscle, a complication of myocardial infarction: clinical presentation, diagnosis, and treatment

Ruptured papillary muscle due to myocardial infarction was encountered in 14 patients during the period 1975-1983. Five of the 14 patients had a history of angina pectoris and two had a history of prior myocardial infarction. Eleven patients with myocardial infarction developed additional pain due to myocardial ischemia and/or a murmur of mitral regurgitation and pulmonary edema within a week, 3 others had a prolonged course with intermittent pain due to myocardial ischemia and breathlessness for longer periods and then deteriorated. Thirteen of our 14 patients developed a murmur and all but one had pulmonary edema on the chest x-ray. Five patients had infarction patterns on the electrocardiogram, the remainder of the patients had only ST- and T-wave changes. Echocardiograms showed fine flutter and notching of the anterior mitral leaflets and vigorous contractions of the left ventricle. Only one patient was demonstrated to have a papillary muscle tip prolapsing into the left atrium on two-dimensional echocardiography. Twelve patients underwent surgery and 8 survived. Seven patients had single-vessel coronary disease, 4 involving the circumflex system and 3 involving the right coronary system. Four of the 7 patients with single-vessel coronary disease survived surgery. Five patients went to surgery with the intra-aortic balloon pump in place and only 3 survived. Three others had the pump inserted intraoperatively and 2 of these survived. Six of 9 patients who had mitral valve replacement and coronary bypass survived. Ejection fraction ranged from 40 to 79%. Surgical survival did seem to be related to the extent of papillary muscle rupture, with the best results occurring in the group with a small portion of the tip ruptured. Seven patients had a stormy clinical course and required surgery within 10 days of rupture. Four of these 7 survived. It seems reasonable to believe that these patients who often have small infarction and limited coronary disease have good potential for survival. Our approach has been to move toward surgery once the diagnosis is made to avoid the sudden deterioration that frequently occurs. The surgical mortality in this group remains in the 30 to 40% range.     

Helicobacter pylori and risk of gastroenteritis

BACKGROUND: Helicobacter pylori infection is thought to modify susceptibility to gastroenteritis. METHODS: Members of northern California households with an index case of gastroenteritis were interviewed regarding recent episodes and tested for H. pylori. Conditional logistic regression was used to evaluate the risk of secondary gastroenteritis within households matched for members with secondary gastroenteritis (cases) and those without symptoms (control subjects). Case and control subjects were also tested for hepatitis A virus (HAV). RESULTS: Of 801 households, 205 (26%) had at least 1 member with secondary gastroenteritis, of which 116 (56%) also included at least 1 member without symptoms (158 case and 285 control subjects). Compared with uninfected members and adjusting for age, those with antibodies to only 1 infection were at a decreased risk of secondary gastroenteritis (odds ratio [OR] for H. pylori infection, 0.25 [95% confidence interval [CI], 0.08-0.82]; OR for HAV, 0.45 [95% CI, 0.23-0.87]). Having antibodies to both H. pylori and HAV did not add to this negative effect (adjusted OR, 0.39 [95% CI, 0.18-0.84]). CONCLUSIONS: H. pylori did not increase the risk of gastroenteritis in these households. A strong negative association between H. pylori infection and gastroenteritis is likely explained by prior exposure and immunity to other enteric pathogens.     

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

Examining relationships between socio-demographics and self-efficacy among registered nurses in Australia

Background

Self-efficacy in nursing is the nurses’ perception of their abilities to show caring orientations, attitudes, and behaviours and to develop caring relationships with patients. Self-efficacy is associated with years of experience, higher levels of job satisfaction and changes to nursing practices that conform with best practice. There is currently a paucity of evidence and no Australian studies were found examining the relationships between socio-demographic variables and self-efficacy in Australian nurses.

Effects of intraoral prosthetics on swallowing in patients with oral cancer

The swallowing patterns of four patients with oral cancer with intraoral palate reshaping/lowering prostheses were studied with and without their prostheses 3 months postoperatively. The prostheses resulted in improved swallow efficiency, increased duration of tongue contact to the pharyngeal wall, and improved speed of movement of the bolus from the valleculae to the pyriform sinus. These results emphasize the effects of the tongue on the pharyngeal as well as oral stage of the swallow.     

Cervical spine surgery in patients with rheumatoid arthritis: an appraisal.

OBJECTIVES: To review the outcome of surgery undertaken to stabilise the neck in patients with rheumatoid arthritis performed over a five year period, to compare the results with those of previous reports, and to identify factors that may predict surgical outcome. METHODS: Outcome was assessed at time of discharge from hospital after surgery by review of patients' notes, and at follow up by patient interview, clinical examination, anonymous questionnaire, and cervical spine radiograph. The Ranawat classification of neurological impairment and Steinbrocker functional classification were used. RESULTS: Thirty nine patients underwent 44 procedures; 28 patients were available for review after a mean period of 29.8 months (range 12-65 months). Fourteen patients had preoperative neurological impairment and were available for follow up; 13 returned the questionnaire. Four (29%) had improved Ranawat class, nine were unchanged, and one had deteriorated. Nine (69%) reported a subjective improvement in neurological symptoms by questionnaire, even though the Ranawat class was unchanged in five. Twenty five of the patients reviewed had pain before operation; 21 returned the questionnaire. Pain relief was reported by direct questioning and questionnaire in 76% and 67% of patients, respectively. Overall, 67% felt that surgery had been successful. Surgery was more successful in producing symptomatic relief in patients with neck or radicular pain than in those with neurological deficit, but did prevent progression of neurological symptoms. CONCLUSIONS: Our results are similar to those from other centres. Overall patient satisfaction with surgery was good. Surgery was more likely to produce symptomatic relief in patients with neck or radicular pain before operation than in those with neurological deficit. The greater subjective improvement in neurological symptoms as judged by questionnaire probably reflects the relative insensitivity of the Ranawat classification in detecting change in neurological status; previous reports of poor outcome for patients with neurological symptoms who undergo surgery may in part be a reflection of the insensitivity of this method of assessment. No clear factors emerged which allowed prediction of those patients at greatest risk of operative mortality. In particular, an increased risk of neurological compromise appeared to confer no additional risk of immediate perioperative death. Our data support the suggestion that early surgery to correct symptomatic atlantoaxial subluxation may prevent progression of instability.     

Plasma Cortisol and Growth Hormone Responses to Intravenous Catheterization

Abstract

Plasma Cortisol and growth hormone (HGH) responses to venous catheterization were studied in 29 volunteer subjects. Repeat catheterizations were performed in 18 individuals. Mean plasma cortisol levels were significantly elevated during the first hour of the initial catheterization experience. Morning and afternoon levels of cortisol were not distinguishable during the first catheterization, but PM levels were significantly lower than AM levels during the second catheterization experience. Growth hormone responses were much more variable than cortisol and were distributed logarithmically. Growth hormone responses tended to parallel cortisol responses during the first catheterization experience. Individuals who listed more symptoms in response to venipuncture and catheterization after finishing their first catheterization had significantly higher cortisol and growth hormone levels during this experience. These data suggest a definite endocrine adaptation to catheterization by the second or third hour of the experience.