A novel arginine substitution mutation in 1A domain and a novel 27 bp insertion mutation in 2B domain of keratin 12 gene associated with Meesmann's corneal dystrophy.

AIM: To determine the disease causing gene defects in two patients with Meesmann's corneal dystrophy. METHODS: Mutational analysis of domains 1A and 2B of the keratin 3 (K3) and keratin 12 (K12) genes from two patients with Meesmann's corneal dystrophy was performed by polymerase chain reaction amplification and direct sequencing. RESULTS: Novel mutations of the K12 gene were identified in both patients. In one patient a heterozygous point mutation (429A-->C = Arg135Ser) was found in the 1A domain of the K12 gene. This mutation was confirmed by restriction digestion. In the second patient a heterozygous 27 bp duplication was found inserted in the 2B domain at nucleotide position 1222 (1222ins27) of the K12 gene. This mutation was confirmed by gel electrophoresis. The mutations were not present in unaffected controls. CONCLUSION: Novel K12 mutations were linked to Meesmann's corneal dystrophy in two different patients. A missense mutation replacing a highly conserved arginine residue in the beginning of the helix initiation motif was found in one patient, and an insertion mutation, consisting of a duplication of 27 nucleotides, was found before the helix termination motif in the other.

Congenital unilateral pulmonary venous atresia: definitive diagnosis and treatment.

Three cases of unilateral right-sided pulmonary venous atresia were evaluated over an 18-year period. These bring the total number of cases to 25 in the literature. The clinical presentation of all these patients was similar and consisted of recurrent pulmonary infections, asthma-like symptoms, and exercise intolerance. The patients presented in 1982 (patient 1, a 12-year-old boy), 1994 (patient 2, a 9-year-old girl), and 1999 (patient 3, a 13-year-old boy). All patients were evaluated with a chest roentgenogram, and patients 1 and 2 had a ventilation and perfusion scan. Patients 1 and 3 also had cardiac catheterization and pulmonary angiography. Patient 2 had a magnetic resonance imaging study of the chest. Only patient 3 had wedge pulmonary angiography. Although a rare congenital defect, this diagnosis should be strongly suspected based on the typical clinical presentation and the preliminary studies, such as the chest roentgenogram and ventilation and perfusion scan. However, for definitive diagnosis, cardiac catheterization with wedge pulmonary angiography is necessary. Anastomosis of the atretic pulmonary veins to the left atrium is a theoretical consideration. However, this may not be feasible due to pulmonary venous anatomy or significant pulmonary dysfunction with pulmonary vascular changes. In these circumstances, we recommend performing pneumonectomy to remove the nidus for repeated bouts of pulmonary infections, to eliminate the left-to-right shunt, and to eliminate the dead space contributing to exercise intolerance.

Energy expenditure and substrate utilization in adults with cystic fibrosis and diabetes mellitus.

BACKGROUND: The onset of cystic fibrosis-related diabetes mellitus (CFDM) is often associated with a decline in clinical and nutritional status. OBJECTIVE: The purpose of this study was to characterize energy expenditure (EE) and substrate utilization during rest, exercise, and recovery from exercise in patients with CF diagnosed with diabetes mellitus. DESIGN: EE, substrate utilization, minute ventilation, tidal volume, and respiratory rate were calculated by indirect calorimetry durng rest; a 30-min, low-to-medium-intensity exercise bout on a treadmill; and a 45-min postexercise recovery period (in reclining position) in 10 CF, 7 CFDM, and 10 control subjects between 18 and 45 y of age. RESULTS: In all 3 periods, minute ventilation was higher in the CF and CFDM groups than in the control subjects (P < 0.01). During rest and exercise, the CF and CFDM groups maintained EE values at the high end of the normal range of the control subjects. However, during recovery, EE was higher in the CF and CFDM groups than in the control group (P < 0.01). CONCLUSIONS: EE may be higher than usual for the patients with CF and CFDM during periods of recovery from mild exercise or activity because of increased work of breathing consistent with higher ventilatory requirements. This information may be useful for patients receiving nutritional counseling who may choose to exercise regularly, but are concerned about possible weight loss.

Breast abnormalities in patients with cystic fibrosis: previously unrecognized changes.

We reviewed breast tissue from 19 female postpubertal and three prepubertal patients with cystic fibrosis to determine the histopathologic changes present. Autopsy material was available from 19 patients who died from complications of cystic fibrosis. Two patients had lumpectomies for breast carcinoma and an additional patient had a breast biopsy and bilateral prophylactic mastectomies for breast carcinoma. The postpubertal patients ranged in age from 18 to 50 years (median age, 32 years). The histologic changes in the breast of female patients with cystic fibrosis have not been fully studied, and the only case reported suggests that these patients suffered from complete lobular agenesis. This study shows that postpubertal breasts had normal development and varying degrees of fibrosis affecting lobular units and ducts, and that proliferative lesions and carcinoma could be encountered.

Chronic varicella-zoster virus epithelial keratitis in patients with acquired immunodeficiency syndrome.

OBJECTIVE: To characterize further a chronic epithelial keratitis caused by varicella-zoster virus infection in patients with acquired immunodeficiency syndrome (AIDS). METHODS: Patients with AIDS and chronic epithelial keratitis associated with varicella-zoster virus from 3 institutions were identified. Patient records were reviewed retrospectively for the following data: medical and demographic characteristics, techniques of diagnosis, physical findings, course, response to treatment, and outcome. RESULTS: Sixteen patients were studied. CD4+ T-lymphocyte cell counts were available in 11 patients, with a median of 0.034 x 10(9)/L (range, 0-0.094 x 10(9)/L). Two patients had no history of a zosteriform rash. In the remaining patients, the interval between rash and keratitis ranged from 0 days to 6 years. In all cases, the keratitis was chronic and characterized by gray, elevated, dendriform epithelial lesions that stained variably with fluorescein and rose bengal. The peripheral and midperipheral cornea was most commonly affected, and, in 13 of the 16 patients, the lesions crossed the limbus. Pain was a prominent feature, occurring in 12 of 16 patients. In 9 of 12 patients tested, varicella-zoster virus was identified by culture, direct fluorescent antibody testing, polymerase chain reaction testing, or a combination of these studies, with direct fluorescent antibody testing (6 of 8 positive results) and polymerase chain reaction testing (3 of 3 positive results) appearing to be the most sensitive. Response to antiviral medication was variable. CONCLUSIONS: In patients with AIDS, varicella-zoster virus may cause a chronic infection of the corneal epithelium. The keratitis is characterized by dendriform lesions, prolonged course, and frequently by extreme pain. It can occur without an associated dermatitis.

Delusions of ocular parasitosis.

PURPOSE: To describe four cases of delusions of parasitosis in which self-inflicted ocular trauma occurred. Delusions of parasitosis is a somatic delusional disorder in which patients have the irrational belief that their bodies are infested by parasites or other infectious organisms. Self-inflicted trauma can result from attempts to eliminate the supposed infestation. METHODS: We reviewed the case histories of four patients (one male, three females, 35 to 45 years of age) who presented with complaints of ocular infestation but had no evidence of infectious ocular disease. The characteristics of these cases were compared with the features of delusions of parasitosis. RESULTS: All patients maintained their beliefs regarding infestation, despite extensive clinical and laboratory investigations that found no evidence of infectious diseases. Self-inflicted eye injury, associated with attempts to eliminate the infestation, occurred in each case. CONCLUSIONS: The cases presented in this report are consistent with a diagnosis of delusions of parasitosis. The eye can be a principal focus of attention in this disorder, which may lead to vision loss caused by self-inflicted injury.

Ocular cicatricial pemphigoid.

CP is a systemic disease of presumed autoimmune etiology that may involve the skin, conjunctiva, or any mucosal surface. As many patients present with ocular symptoms, ophthalmologists must inquire about signs of potential life-threatening esophageal and laryngeal involvement. Ocular involvement is a bilateral chronic cicatricial conjunctivitis that may result in fornix foreshortening, symblepharon formation, trichiasis, and entropion and keratinization of the eyelids and conjunctiva. These mechanical factors are responsible for progressive scarring and vascularization of the ocular surface. Successful systemic treatment of the autoimmune disease is now available; however, the condition often is not diagnosed until significant structural damage to the ocular adnexa has occurred. Our ability to rehabilitate visually patients with advanced disease by penetrating keratoplasty and associated techniques remains extremely limited. Hence, the focus of treatment in OCP should be on early detection of the disease, including conjunctival biopsy, prompt systemic treatment to prevent disease progression, and early aggressive treatment of secondary eyelid and conjunctival abnormalities to avoid the blinding keratopathy so prevalent in this disease.

Ocular and sinus microsporidial infection cured with systemic albendazole.

PURPOSE: To report treatment of a patient with acquired immunodeficiency syndrome (AIDS) and ocular and paranasal sinus microsporidial infection. METHOD: Case report. RESULTS: A patient with AIDS and ocular microsporidial infection experienced resolution of ocular symptoms with topical fumagillin, but symptoms recurred upon cessation of therapy. Paranasal sinus microsporidial infection was diagnosed. The patient received sequential systemic treatment with itraconazole followed by albendazole. Sinus symptoms resolved with albendazole. He remained symptom-free with a normal examination 17 months after concluding therapy. CONCLUSIONS: Although fumagillin and itraconazole may have played a role, systemic albendazole appears to be responsible for clinical resolution of microsporidial infection.

Supratarsal injection of corticosteroid in the treatment of refractory vernal keratoconjunctivitis.

PURPOSE: We studied supratarsal injection of corticosteroid as a new therapeutic modality for treating severe vernal keratoconjunctivitis to determine its efficacy in treating patients refractory to all conventional therapy. METHODS: Twelve patients with vernal keratoconjunctivitis resistant to all established therapy were prospectively studied by randomly assigning them to receive supratarsal injection of either short- or intermediate-acting corticosteroid. Relief of symptoms and resolution of clinical signs were evaluated. Patients were followed up to four years to identify side effects. RESULTS: All patients experienced dramatic symptomatic relief within one to five days, regardless of the type of corticosteroid injected. Marked decrease in cobblestone papillae was noted in 14.9 days (mean) after short-acting corticosteroid injection and 12.8 days after intermediate-acting corticosteroid injection (P = .65). Shield ulcers and limbal involvement resolved in one to three weeks, independent of the corticosteroid used (P = .90). No complications were observed with supratarsal injection of short-acting corticosteroid. One patient developed persistent increase of intraocular pressure after injection of intermediate-acting corticosteroid. CONCLUSIONS: The dramatic symptomatic and clinical improvement suggests that supratarsal injection of corticosteroid may be a valuable therapeutic approach to treating refractory vernal keratoconjunctivitis. Short-acting and intermediate-acting corticosteroids were equally efficacious. Because of the lack of intraocular pressure increase observed with short-acting corticosteroid, we favor its use in supratarsal injection.

Cystic fibrosis-related diabetes is associated with HLA DQB1 alleles encoding Asp-57- molecules.

The incidence of insulin-dependent diabetes in individuals with cystic fibrosis is nearly 100 times greater than in the general population. In the latter group, strong associations with specific HLA DQA1 and DQB1 alleles have been observed. To determine if a similar distribution of alleles occurs in cystic fibrosis patients with diabetes, a cohort of these individuals was typed for DQA1 and DQB1 alleles. HLA DQB1*0201 (Asp57-) was more frequent in diabetics compared to controls (40.4 vs 28%), while the frequency of alleles encoding Asp57+ molecules was lower in diabetics relative to both the cystic fibrosis-only controls (P = 0.025) and the general population (P = 0.008). The presence of at least one protective DQA1-DQB1 heterodimer (i.e., Arg52- and Asp57+, respectively) in cis or trans was significantly lower in the diabetics than in either of the control groups. Thus, the HLA alleles known to be associated with insulin-dependent diabetes mellitus in the general population are also found in diabetics with cystic fibrosis.

Modulating radiation cataractogenesis by hormonally manipulating lenticular growth kinetics.

There is considerable evidence that the lens epithelium is the primary site of injury leading to the development of cataracts following radiation exposure. That the damaged cells of the epithelium are the progenitors of the aberrantly differentiating fibers associated with the cataract is indisputable. So too is the observation that post-radiation proliferative activity in the lens epithelium is required for cataracts to develop. The natural hormonal regulation of lens epithelial mitotic activity in the frog offers the opportunity to alter the cell cycle of the lens epithelium in vivo, thus enabling the direct examination of the role of lenticular mitosis in the cytopathomechanism of radiation-induced cataracts. The cell cycle of the lens epithelium of northern leopard frogs was manipulated by hypophysectomy (to halt mitotic activity) and pituitary hormone administration (to stimulate baseline mitosis and reverse hypophysectomy-induced mitotic suppression). Animals were hypophysectomized, irradiated and injected with pituitary hormone replacement. Irradiated animals, irradiated animals + hormone replacement and irradiated hypophysectomized animals served as controls. Cataract development was evaluated by slit-lamp biomicroscopy and correlated with histologic determinations of mitotic index and meridional row disorganization on lens epithelial whole mounts. In another study, hypophysectomized-irradiated animals received varying concentrations of replacement hormone in an attempt to quantitatively modulate lens epithelial mitotic activity and determine the effect on cataractogenesis. It was found that irradiated-hypophysectomized (mitosis halted) frogs failed to develop opacities, while those with hormonal replacement (mitosis reinstated) developed cataracts.(ABSTRACT TRUNCATED AT 250 WORDS)

Inapparent transmission of Pseudomonas (Burkholderia) cepacia among patients with cystic fibrosis.

Pseudomonas cepacia is a significant pathogen in children and young adults with cystic fibrosis, and prevention of its acquisition has become an important goal in patient management. Although it is now clear that this bacterium can be transmitted from person to person, the frequency of this mode of acquisition and the measures required to prevent it are controversial. In this report we describe the use of a novel genotyping method to extend our previous investigation of person to person transmission of P. cepacia among patients with cystic fibrosis attending an educational program. Three (20%) of 15 individuals acquired P. cepacia after contact with a chronically colonized patient. Analysis revealed that the isolates recovered from the three newly colonized patients were the same as that from the index patient. We also demonstrated that pulmonary colonization with P. cepacia may not be detected by currently recommended culture methods for as long as 2 years after acquisition. These data indicate a need to develop more sensitive means of detecting P. cepacia colonization in order better to understand host-pathogen interaction and to optimize preventive strategies.

Enzyme therapy for pancreatic insufficiency: present status and future needs.

Pancreatic enzyme extracts have been used for several decades to decrease maldigestion of macro- and micronutrients due to pancreatic insufficiency and to alleviate various abdominal symptoms, including the pain of alcohol-induced chronic pancreatitis and distal intestinal obstruction. Decreasing nutrient maldigestion and malabsorption in pancreatic insufficiency is of additional critical importance because improvement in nutritional status reduces morbidity and mortality. For example, pancreatic sufficient patients with cystic fibrosis (CF) demonstrate a slower decline in pulmonary function. In spite of the recognized importance of pancreatic enzymes, several problems exist with current preparations, and as newer enzyme preparations are marketed, proper evaluation becomes critical. There is a clear need to optimize the constituents of enzyme preparations, improve manufacturing processes, and find better sources of enzymes. Other issues that need addressing include standardization of the ratios of enzymes (lipase, amylase, protease) in these products; the stability of the enzymes at room temperature; the shelf life of the finished product; whether there are significant batch-to-batch differences; and the need for a USP reference standard.

Cystic fibrosis and pulmonary involvement from multiple perspectives.

The pulmonary involvement in cystic fibrosis (CF) is discussed from several perspectives including historical, current treatment, and possible future therapies. The clinical realities that have limited and frustrated the successful control of the pulmonary progression are reviewed. A variety of pending new therapies are briefly presented including antiinflammatory agents, protease inhibitors, ion transport inhibitors, antiviscosity agents, chloride channel modifiers, and immunomodifiers. An appeal is made for more effective down-regulation of the overstimulated local and systemic immune responses to the chronic inflammatory processes. More attention needs to be paid to improvement of current methods of aerosol administration that will be of critical importance for living cell/viral/gene/liposome delivery. Other means of buying additional survival time are urgently needed such as improvements in lung transplantation and better treatment of cor pulmonale. The explosion of molecular genetics progress in CF basic research is an exciting and encouraging dynamic that may lead to a cure for patients with CF in spite of the more than 200 known genetic variations known to date. The survival of CF patients has increased 1 year for 1 year during the past 10 years and now is 29.4 years in 1991. If this progress can be maintained, the hope is that advances in molecular genetics and cell electrophysiology can soon be brought to clinical application in an effective fashion. A magnificent choice of new treatment directions is becoming available, leading to very realistic hope and optimism for the future for patients with CF.

Detection of three rare frameshift mutations in the cystic fibrosis gene in an African-American (CF444delA), an Italian (CF2522insC), and a Soviet (CF3821delT).

We have identified three new frameshift mutations in the CFTR gene in patients with cystic fibrosis (CF). The first one involves the deletion of an adenine nucleotide in exon 4 in an African-American patient (CF444delA), the second involves the insertion of a cytosine nucleotide in exon 13 in an Italian patient (CF2522insC), and the third results from the deletion of a thymidine nucleotide in exon 19 in a Soviet patient (CF3821delT). Each mutation is predicted to result in premature termination of the CFTR protein.

Enhancement of hypoxemia by atrial shunting in cystic fibrosis.

Patients with CF may develop hypoxemia which seems disproportionate to the degree of pulmonary disease. In a series of patients with CF and advanced pulmonary disease undergoing transesophageal echocardiography for the evaluation of cor pulmonale, eight of 15 patients were found to have atrial shunts through a stretched foramen ovale. To our knowledge, this is the first observation of intracardiac shunting in CF. This phenomenon may account for unexplained levels of cyanosis and worsening of hypoxemia with exercise, vasodilators, or PEEP and poses the threat of paradoxic emboli when central venous lines are used in these patients.

Analysis and HPLC fractionation of urine from patients with cystic fibrosis, chronic lung diseases and normal controls.

The amounts of creatinine, protein, carbohydrate and sialic acid in the urine of 19 patients with cystic fibrosis (CF), 12 normal controls and 11 pathological controls with chronic lung disease have been determined. The mean creatinine excretion levels of the total CF group as well as the CF subgroups are significantly decreased when compared to normal controls but comparable to pathological controls. Mean urinary protein levels appear to be increased in patients with CF compared to normal controls and pathological controls but the increased levels resulted from factors (e.g., presence of diabetes mellitus) other than CF. No significant differences were found in amounts of total carbohydrate and sialic acid in urine and fractionated urinary preparations for the total group of nondiabetic patients with CF when compared to both normal and pathological controls. HPLC fractionation of low Mr (less than 10,000 Daltons) urinary preparations indicated the presence of an unknown peak in all of the antibiotic-treated CF patients, 43% of CF patients on low or no medication, 17% of the normal controls and 9% of the pathological controls. The present results illustrate the importance of including appropriate pathological controls and dividing patients with CF into subgroups according to clinical factors and types of therapy employed.