Carpal tunnel syndrome and gynaecomastia during growth hormone treatment of elderly men with low circulating IGF-I concentrations

OBJECTIVE We studied the relationship between plasma level of insulin-like growth hormone I (IGF-I), changes in lean body mass and in adipose mass, and adverse side-effects during human growth hormone (hGH) treatment of elderly men who had low IGF-I levels. DESIGN The first six months was a period of baseline observation. The subjects were then randomized into two groups so that during months 7–18, men in group I received hGH, and men in group II served as untreated controls. SUBJECTS Eighty-three overtly healthy elderly men, who were selected because their plasma IGF-I level was less than 0.35 units/ml. The men were randomly assigned in a ratio of three to one into group I (n= 62) or into group II (n= 21). MEASUREMENTS Plasma IGF-I level was measured monthly. Lean body mass and adipose mass were measured every six months. RESULTS Fifteen men left the study during the baseline period because of personal reasons or intercurrent medical events. In those who received drug (group I), there were a number of adverse reactions which could have been related to the hGH therapy: carpal tunnel syndrome 10, gynaecomastia 4, and hyperglycaemia 3. In total there were 27 dropouts from group I and two dropouts from group II after the six-month point, for a variety of medical and non-medical reasons, the majority probably not related to hGH therapy. During the hGH treatment of group I, plasma IGF-I increased from the range 0.10–0.35 units/ml into the range 0.5–2.2 units/ml. Among the 18 men who completed 12 months of hGH treatment without experiencing one of the three above-noted presumed hGH side-effects, mean and peak plasma IGF-I during treatment were significantly lower than among the 13 men who experienced carpal tunnel syndrome or gynaecomastia (one subject had both) while on hGH. With one exception, neither carpal tunnel syndrome nor gynaecomastia occurred in any individual with a mean IGF-I level less than 10 units/ml during hGH treatment. Twelve months of hGH treatment (group I) caused an increase in lean body mass to 106% of the initial baseline (month one of the protocol), and a reduction in adipose mass to 84% of the baseline. Meanwhile, the lean body mass of the untreated men in group II declined to 97% of the initial baseline. The body composition responses after 12 months of treatment in group I were larger in the men whose mean intra-treatment IGF-I level was 0.5–1.0 units/ ml, than in the men whose mean intra-treatment IGF-I level was 1.0–1.5 units/ml. CONCLUSIONS These observations show that when elderly men with low circulating IGF-I concentrations are treated continuously with hGH, elevation of plasma IGF-I above 10 units/ml is associated with a substantial frequency of carpal tunnel syndrome or gynaecomastia. It may be that the effects of the hormone in expanding lean body mass and reducing adipose mass can be achieved, and the side-effects avoided, by maintaining the mean IGF-I level in the range 0.5–1.0 units/ml.     

Role of endothelin in the exercise intolerance of chronic heart failure

In conclusion, plasma levels of the endothelialderived vasoconstrictor endothelin-1 (but not those of other neurohormonal vasoconstrictor factors), measured during exercise correlated closely with objective variables of exercise capacity in patients with heart failure. These findings suggest that endothelin-1 may contribute to exercise intolerance in patients with heart failure, perhaps by limiting the ability of the peripheral vasculature to dilate during exercise.     

Aspiration cytology of clear-cell lesions of the parotid gland: Morphologic features and differential diagnosis

Clear-cell lesions of the parotid gland are uncommon but when studied by fine-needle aspiration may result in a clinically important but cytologically difficult differential diagnosis. Clear-cell lesions involving the parotid include acinic cell neoplasm, clear cell oncocytoma, mucoepidermoid carcinoma, primary clear-cell carcinoma, epithelial-myoepithelial carcinoma, and metastatic renal cell carcinoma. Accurate diagnosis is achieved by assessment of nuclear features, other cell populations present, and clinical data including radiographic studies.     

Trisomy X in a female member of a family with X linked severe combined immunodeficiency: implications for carrier diagnosis.

We describe a family affected by X linked severe combined immunodeficiency (SCIDX1) in which genetic prediction of carrier status was made using X chromosome inactivation studies together with limited genetic linkage analysis. Linkage studies in this family showed a confusing pattern of inheritance for the X chromosome. A female with a random pattern of X chromosome inactivation in her T cells appeared to have inherited an X chromosome with four recombinations within 10 cM. The odds of this happening in a single meiotic event make this an unlikely explanation. Data obtained from studying the X chromosomes of her two unaffected sons showed that this could be explained simply on the basis of her having inherited three alleles each of the relevant polymorphic DNA loci. We used fluorescent in situ hybridisation (FISH) to confirm that this person had inherited three complete X chromosomes. Thus, although the results from X chromosome inactivation analysis indicated that this subject was not a carrier of the affected chromosome, FISH and genetic linkage analysis showed clearly that the affected chromosome had been inherited. The implications of this finding for diagnosis of carrier status in this family and for other families with X linked inherited immunodeficiencies is discussed.     

Effect of combined supplementation with vitamin E and alpha-lipoic acid on myocardial performance during in vivo ischaemia-reperfusion

Reactive oxygen species (ROS) contribute significantly to myocardial ischaemia-reperfusion (I-R) injury. Recently the combination of the antioxidants vitamin E (VE) and alpha-lipoic acid (alpha-LA) has been reported to improve cardiac performance and reduce myocardial lipid peroxidation during in vitro I-R. The purpose of these experiments was to investigate the effects of VE and alpha-LA supplementation on cardiac performance, incidence of dysrhythmias and biochemical alterations during an in vivo myocardial I-R insult. Female Sprague-Dawley rats (4-months old) were assigned to one of the two dietary treatments: (1) control diet (CON) or (2) VE and alpha-LA supplementation (ANTIOXID). The CON diet was prepared to meet AIN-93M standards, which contains 75 IU VE kg-1 diet. The ANTIOXID diet contained 10 000 IU VE kg(-1) diet and 1.65 g alpha-LA kg(-1) diet. After the 14-week feeding period, significant differences (P<0.05) existed in mean myocardial VE levels between dietary groups. Animals in each experimental group were subjected to an in vivo I-R protocol which included 25 min of left anterior coronary artery occlusion followed by 10 min of reperfusion. No group differences (P>0.05) existed in cardiac performance (e.g. peak arterial pressure or ventricular work) or the incidence of ventricular dysrhythmias during the I-R protocol. Following I-R, two markers of lipid peroxidation were lower (P<0.05) in the ANTIOXID animals compared with CON. These data indicate that dietary supplementation of the antioxidants, VE and alpha-LA do not influence cardiac performance or the incidence of dysrhythmias but do decrease lipid peroxidation during in vivo I-R in young adult rats.     

ROMK1 (Kir1.1) causes apoptosis and chronic silencing of hippocampal neurons

Lentiviral vectors were constructed to express the weakly rectifying kidney K(+) channel ROMK1 (Kir1.1), either fused to enhanced green fluorescent protein (EGFP) or as a bicistronic message (ROMK1-CITE-EGFP). The channel was stably expressed in cultured rat hippocampal neurons. Infected cells were maintained for 2-4 wk without decrease in expression level or evidence of viral toxicity, although 15.4 mM external KCl was required to prevent apoptosis of neurons expressing functional ROMK1. No other trophic agents tested could prevent cell death, which was probably caused by K(+) loss. This cell death did not occur in glia, which were able to support ROMK1 expression indefinitely. Functional ROMK1, quantified as the nonnative inward current at -144 mV in 5.4 mM external K(+) blockable by 500 microM Ba(2+), ranged from 1 to 40 pA/pF. Infected neurons exhibited a Ba(2+)-induced depolarization of 7 +/- 2 mV relative to matched EGFP-infected controls, as well as a 30% decrease in input resistance and a shift in action potential threshold of 2.6 +/- 0.5 mV. This led to a shift in the relation between injected current and firing frequency, without changes in spike shape, size, or timing. This shift, which quantifies silencing as a function of ROMK1 expression, was predicted from Hodgkin-Huxley models. No cellular compensatory mechanisms in response to expression of ROMK1 were identified, making ROMK1 potentially useful for transgenic studies of silencing and neurodegeneration, although its lethality in normal K(+) has implications for the use of K(+) channels in gene therapy.     

Primitive Neuroectodermal Tumors of the Central Nervous System

Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists.
Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum.
The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses.
Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.     

Cystic lesions of the salivary glands: cytologic features in fine-needle aspiration biopsies

A variety of neoplastic and nonneoplastic lesions of the salivary glands have a predominantly cystic architecture. Fine-needle aspirates of these lesions yield watery or mucoid material, frequently of low cellularity. Such aspirates may be obtained from mucus retention cysts, lymphoepithelial cysts, cystadenomas, Warthin's tumors, cystic pleomorphic adenomas, low-grade mucoepidermoid carcinomas, cystadenocarcinomas, and examples of polycystic disease of the parotid gland. The cellular component within the fluid obtained from these lesions may be exceedingly scant or absent, making cytologic diagnosis difficult and, at times, impossible. We studied a series of 56 cystic lesions of the salivary glands, including 38 Warthin's tumors, 6 benign cysts, 2 lymphoepithelial cysts, 5 low-grade mucoepidermoid carcinomas, 1 cystic pleomorphic adenoma, 2 cystadenomas, and 2 cystadenocarcinomas. Careful attention to the cellular elements present often allowed definitive cytologic diagnosis, with an overall accuracy rate of 84%. The presence of atypical squamous metaplasia in oncocytic lesions was a significant cause of false-positive diagnoses of carcinoma (4 cases, 7%). Aspirates of low-grade mucoepidermoid carcinoma may contain no epithelial cells and result in false-negative diagnoses (1 case, 2%).     

Hydrogen peroxide induces DNA single strand breaks in respiratory epithelial cells

The respiratory epithelium is often exposed to oxidant gases, including ozone from photochemical smog and toxic oxygen metabolites released from neutrophils recruited in conditions of airway inflammation. We evaluated DNA single strand break formation by alkaline elution as a measure of oxidant-induced DNA damage to bronchial epithelial cells. Human AdenoSV-40-transformed bronchial epithelial cells (BEAS), subclone R1.4 or nonhuman primate bronchial epithelial cells were cultured in growth factor supplemented Ham's F12 medium on polycarbonate filters. DNA was labeled by incubation with [³H]thymidine. Cells were incubated for 1 h in HBSS or HBSS and increasing concentrations of hydrogen peroxide (H₂O₂). Cells incubated in H₂O₂ demonstrated dose-dependent increases in strand break formation, and BEAS cells were more sensitive to H₂O₂-induced injury than primary bronchial epithelial cells. The addition of catalase or preincubation of cells with the iron chelator desferoxamine prevented H₂O₂-induced strand breakage. DNA strand break formation may be an important mechanism of oxidant injury in respiratory epithelial cells.This work was supported by NIEHS grant ES-00628 and California Primate Research Center Base grant. Portions of this work were presented at the American Thoracic Society annual meeting, May 1992, Miami, Florida.