X-linked juvenile retinoschisis: localization between (DXS1195, DXS418) and AFM291wf5 on a single YAC

We studied 17 pedigrees with 108 affected males with X-linked juvenile retinoschisis (RS; McKusick No. 31270) and have analyzed all of the known polymorphic markers in the RS region of Xp22.1-p22.2 between DXS987 and DXS41. By haplotype analyses we found 7 individuals who showed crossovers in this interval surrounding RS. We previously reported AFM291wf5 as the centromeric boundary, and this remains unchanged in the present study. A new recombination was identified on the telomeric side at (DXS1195, DXS418). Our data support the locus order Xpter--(DXS987, DXS207, DXS1053, DXS43)--(DXS1195, DXS418)--(RS, DXS257, DXS999)--(AFM291wf5, DXS443)--DXS1052--(DXS1226, DXS274, DXS41)--Xcen; loci grouped in parentheses could not be mutually ordered by our genetic data. Physical mapping has indicated a distance of at most 900-1,000 kb between (DXS1195, DXS418) and AFM291wf5. No recombination was observed between RS and DXS257 which lies in our new interval of interest, but one critical individual was not informative with this marker. Our data now define the smallest RS inclusion interval. This interval is contained on a single YAC from which we have identified expressed sequences as candidate genes for RS.     

Relationship between genotype of angiotensin converting enzyme gene and left ventricular hypertrophy in Chinese hypertensives

Incontinentia pigmenti is an uncommon neurocutaneous syndrome characterised by skin lesions, dental and ocular abnormalities and central nervous system involvement. We report the cranial MRI findings in two sisters with this condition. These include hypoplasia of the corpus callosum, enlargement of the lateral ventricles and periventricular white-matter lesions. One girl also had unilateral microphthalmia and rostral agenesis of the corpus callosum, a feature not previously described.     

Cerebral structural abnormalities in obsessive-compulsive disorder. A quantitative morphometric magnetic resonance imaging study

BACKGROUND: A previous pilot study of only posterior brain regions found lower white-matter volume in patients with obsessive-compulsive disorder than in normal control subjects. We used new cohorts of patients and matched normal control subjects to study whole-brain volume differences between these groups with magnetic resonance imaging-based morphometry. METHODS: Ten female patients with obsessive-compulsive disorder and 10 female control subjects, matched for handedness, age, weight, education, and verbal IQ, underwent magnetic resonance imaging with a 3-dimensional volumetric protocol. Scans were blindly normalized and segmented by means of well-characterized semiautomated intensity contour mapping and differential intensity contour algorithms. Brain structures investigated included the cerebral hemispheres, cerebral cortex, diencephalon, caudate, putamen, globus pallidus, hippocampus amygdala, third and fourth ventricles, corpus callosum, operculum, cerebellum, and brain stem. Anterior to posterior neocortical regions, including precallosum, anterior pericallosum, posterior pericallosum, and retrocallosum, with adjacent white matter were also measured. Volumes found different between groups were correlated with Yale-Brown Obsessive Compulsive Scale score and Rey-Osterieth Complex Figure Test measures. RESULTS: Confirming results of our earlier pilot study and expanding the findings to the whole brain, patients with obsessive-compulsive disorder had significantly less total white matter but, in addition, significantly greater total cortex and opercular volumes. Severity of obsessive-compulsive disorder and nonverbal immediate memory correlated with opercular volume. CONCLUSIONS: Replication of volumetric white-matter differences suggests a widely distributed structural brain abnormality in obsessive-compulsive disorder. Whereas determining the etiogenesis may require research at a microscopic level, understanding its functional significance can be further explored via functional neuroimaging and neuropsychological studies.     

Pharmacokinetic basis of nifedipine-digoxin interaction: a commentary

Elevation of plasma digoxin levels following concurrent administration of nifedipine have previously been reported. The mechanism for this interaction has not been fully explained, but may include a reduction in volume of distribution of digoxin and/or reduction in the renal or non-renal clearance of digoxin by nifedipine. The end result is probably an elevation of plasma concentrations of free (pharmacologically active) digoxin, which may lead to manifestation of side effects of digoxin. This communication highlights the possible pharmacokinetic basis of the reported digoxin-nifedipine interaction.     

Osteoporosis: preventive strategies

We compared manual lymph drainage (MLD) with sequential pneumatic compression (SPC) for treatment of unilateral arm lymphedema in 28 women previously treated for breast cancer. After 2 weeks of therapy with a standard compression sleeve (Part I) with maintenance of a steady arm volume, each patient was randomly assigned to either one of two treatment regimens (Part II). MLD was performed according to the Vodder technique for 45 min/day and SPC was performed with a pressure of 40-60 mmHg for 2 hours/day. Both treatments were carried out for 2 weeks. Arm volume was measured by water displacement. Arm mobility, strength, and subjective assessments were also determined. Lymphedema was reduced by 49 ml (7% reduction) (p = 0.01) in the total group during Part I. During Part II, the MLD group decreased by 75 ml (15% reduction) (p < 0.001) and the SPC group by 28 ml (7% reduction) (p = 0.03). The total group reported a decrease of tension (p = 0.004) and heaviness (p = 0.01) during Part I. During Part II, only the MLD group reported a further decrease of tension (p = 0.01) and heaviness (p = 0.008). MLD and SPC each significantly decreased arm volume but no significant difference was detected between the two treatment methods.     

Modeling Enhanced In Situ Denitrification in Groundwater

A two-dimensional numerical solute transport model was developed for simulating an enhanced in situ denitrification experiment performed in a nitrate-contaminated aquifer on Cape Cod, Massachusetts. In this experiment, formate (HCOO?) was injected for a period of 26 days into the carbon-limited aquifer to stimulate denitrification. Calibration of the vertical-profile site model was demonstrated through error analysis and comparison with formate, nitrate, and nitrite concentration data monitored along a transect of three multilevel groundwater sampling wells for 75 days after initial injection. Formate utilization rates were approximately 142 and 38 μM/day for nitrate and nitrite reduction, respectively. Nitrate and nitrite utilization rates were approximately 29 and 8 μM/day, respectively. Nitrate utilization rates under enhanced conditions were 1 order of magnitude greater than previously reported naturally occurring rates. The nitrite production rate was approximately 29 μM/day. Persistence of nitrite was attributed to a combination of factors, including electron donor (formate) limitation late in the experiment, preferential utilization of nitrate as an electron acceptor, and greater nitrite production relative to nitrite utilization.     

Total parenteral nutrition in critical patients. The metabolic-nutritional aspects and effects on immune function of 2 different isocaloric-isonitrogenous regimens

Fine needle aspirates (FNA) from 31 invasive carcinomas of tubular type and 22 radial scar/complex sclerosing lesions (RS/CSL), diagnosed in Edinburgh between 1986 and 1991, were reviewed. The lesions in this study varied in size and palpability at presentation, but are of increasing interest in the differential diagnosis of non-palpable areas of increased mammographic density. In agreement with previously published information, it was found that the tubular cancers were usually selected for biopsy following aspiration, but less often definitively diagnosed as malignant. Nearly 50% of the RS/CSL group were correctly reported benign on cytology, but in 40%, biopsy was recommended to exclude malignancy. In addition, cytological features helpful in suggesting malignancy in aspirates from tubular cancers, also raised suspicion in aspirates from the RS/CSL group, with a risk of overdiagnosis of cancer.     

Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.     

Preparation and in vitro dissolution profile of dual polymer (Eudragit RS100 and RL100) microparticles of diltiazem hydrochloride

A microparticulate dosage form for a highly soluble drug, diltiazem hydrochloride, was formulated with Eudragit RS100 and RL100 using a novel dual polymer technique. A mixture of diltiazem with Eudragit RS100 (low water permeability) in acetone was coacervated into soft polymer microdrops, following which a mixture of diltiazem and RL100 (high water permeability) was added to produce microparticles consisting of both polymers with diltiazem dispersed in the matrix. A second formulation was developed using the same method except using Eudragit RS100 for both steps. For a comparative study, diltiazem, Eudragit RS100 and RL100 were combined together in a single matrix and formulated into microparticles. In vitro drug release profiles using USP paddle dissolution apparatus 2 revealed that dual polymer matrix microparticles containing Eudragit RS100 in the inner and Eudragit RL100 in the outer core exhibit a suitable release profile with an initial release of the drug followed by a plateau level for the test period of 5 h. Differential scanning calorimetric analysis showed no interaction of the drug with the polymers.     

Anterior temporal white matter lesions in myotonic dystrophy with intellectual impairment: an MRI and neuropathological study

We studied 12 patients with myotonic dystrophy using MRI and the Mini-mental state examination (MMSE), to see it specific MRI findings were associated with intellectual impairment. We also compared them with the neuropathological findings in an autopsy case of MD with intellectual impairment. Mild intellectual impairment was found in 8 of the 12 patients. On T2-weighted and proton density-weighted images, high-intensity areas were seen in cerebral white matter in 10 of the 12 patients. In seven of these, anterior temporal white-matter lesions (ATWML) were found; all seven had mild intellectual impairment (MMSE 22-26), whereas none of the four patients with normal mentation had ATWML. In only one of the eight patients with intellectual impairment were white-matter lesions not found. Pathological findings were severe loss and disordered arrangement of myelin sheaths and axons in addition to heterotopic neurons within anterior temporal white matter. Bilateral ATWML might be a factor for intellectual impairment in MD. The retrospective pathological study raised the possibility that the ATWML are compatible with focal dysplasia of white matter.     

Prevalence and duration of postoperative pneumoperitoneum: sensitivity of CT vs left lateral decubitus radiography

OBJECTIVE: The purpose of this study was to evaluate the prevalence, location, and duration of pneumoperitoneum in postoperative patients and to compare the sensitivities of CT and left lateral decubitus radiography in the detection of postoperative pneumoperitoneum. SUBJECTS AND METHODS: Twenty-seven CT scans and 27 abdominal radiographs with the patient in the left lateral decubitus position were obtained prospectively in 17 patients after uncomplicated abdominal surgery. Fifteen patients were examined 3 days after surgery and 12 were examined 6 days after surgery. The studies were evaluated in a blinded fashion for the presence, location, and volume of free air. The presence of air on the radiographs and the presence and quantity of air on the CT scans were correlated with each subject's surgical procedure, age, sex, and body habitus. RESULTS: Pneumoperitoneum was seen on 13 (87%) of 15 CT scans and eight (53%) of 15 radiographs obtained 3 days after surgery and on six (50%) of 12 CT scans and one (8%) of 12 radiographs obtained 6 days after surgery. The calculated volume of free air seen on the CT scans ranged from 0.3 to 5.8 ml. Sixty-two percent of collections by volume were located in the midline/parahepatic space, 22% in the pelvis, and 16% in the mesentery. Radiographs showed pneumoperitoneum in only nine (47%) of 19 examinations in which the corresponding CT scans showed free air. Findings on radiographs were false-negative in seven (87%) of eight obese patients in whom pneumoperitoneum was detected on CT scans. CONCLUSION: The prevalence of pneumoperitoneum in the postoperative period based on CT findings is greater than that previously reported. Small amounts of pneumoperitoneum frequently collect along the anterior abdominal wall in two preferential spaces, the pararectus and midrectus recesses. The results of this study show that CT is significantly more sensitive than plain radiography for detecting small amounts of free intraperitoneal air in postoperative patients. Radiography is particularly insensitive for imaging obese and heavy patients.     

Cooperative relaxation of supercoils and periodic transcriptional initiation within polymerase batteries

OBJECTIVE: To examine quantitatively white-matter changes at different sites in patients with definite vascular dementia and Alzheimer's disease. DESIGN: Prospective clinical and neuropathological series. SETTING: University Hospital clinics (Helsinki, Finland and London, Ontario). SUBJECTS: Twenty-two patients with a clinical and neuropathological diagnosis of vascular dementia and 20 patients with Alzheimer's disease. MEASURES: The frequencies of focal white-matter lesions, arteriolosclerosis, and cerebral amyloid angiopathy were assessed. Validated ratings and cell counts were done in the subcortical U-fiber, centrum semiovale, and periventricular areas of the frontal white matter. Degrees of abnormality (none, mild, moderate, severe) were rated for spongiosis (vacuolization of white matter), état criblé (widening of perivascular spaces), myelin loss, oligodendrocyte density, axonal loss, and overall. Densities of oligodendrocytes and astrocytes (cells per square millimeter) were determined. RESULTS: Patients with vascular dementia showed focal white-matter lesions and arteriolosclerosis more often than patients with Alzheimer's disease. The patients with vascular dementia also had significantly greater spongiosis (P<.001), état criblé (P=.004), myelin loss (P<.005) and overall white-matter abnormality (P<.001). Arteriolosclerosis was found in association with spongiosis but not with état criblé. Cerebral amyloid angiopathy did not appear to be related to any of the white-matter changes in patients with either vascular dementia or Alzheimer's disease. The U-fiber area showed fewer changes, and the periventricular area tended to be most affected. CONCLUSION: In addition to focal infarcts, patients with vascular dementia showed widespread diffuse changes, including spongiosis and arteriolosclerosis, along with état criblé and myelin loss. White-matter changes in patients with Alzheimer's disease could not be related to infarction. Pathologic changes in small blood vessels are associated with diffuse white-matter changes and may have a distinct role in the genesis of vascular dementia.     

Eutectic structures of Ag-Cu after melting and solidification in microgravity and on earth

Results obtained on a eutectic alloy of Ag-Cu after melting and solidification in μ-g are reported. In microgravity the specimens show a regular eutectic structure both lamellar and rod-like shaped and a dendritic one with random orientations and volume fraction higher than l-g. On earth, instead, they exhibit an irregular eutectic structure, almost completely lamellar and a dendritic one with preferential orientations. These differences are consistent with a considerable reduction of convection in the specimens treated in μ-g. This paper is based on a presentation made in the symposium “Experimental Methods for Microgravity Materials Science Research” presented at the 1988 TMS-AIME Annual Meeting in Phoenix, Arizona, January 25–29, 1988, under the auspices of the ASM/MSD Thermodynamic Data Committee and the Material Processing Committee.     

The use of health care services by people with diabetes in rural areas

Stapled lung volume reduction surgery (LVRS) has recently been described for treatment of emphysema. Many questions arise regarding physiologic mechanisms of response from surgical treatment of emphysema. The objective of this study was to develop an animal model for the study of lung volume reduction surgery in diffuse heterogeneous emphysema. We hypothesized that elastic recoil would increase, static respiratory system compliance would decrease, and expiratory flows would increase after lung volume reduction surgery in animals with emphysema. In the study, emphysema was induced in 31 New Zealand White rabbits (3-5 kg) with endotracheally aerosalized porcine elastase (10,000-12,000 U). Lateral thoracotomies were performed 4-6 weeks postinduction under general anesthesia and mechanical ventilatory support. Stapled volume reduction was performed on the right lower lobe using a standard multirow pediatric stapler (U.S. Surgical). Pulmonary function tests were performed at baseline (preinduction), before stapling LVRS (postemphysema induction), immediately post stapling LVRS, and 1 week poststapling. Static respiratory system compliance, flow, conductance and forced expiratory flows, and peak flows at 20 and 40 cm3 of exhaled volume were analyzed. Animals were sacrificed 1 week poststapling, and bilateral lungs were harvested for histopathology. Diffuse but heterogeneous pulmonary emphysema was seen in these animals treated with high-dose aerosolized elastase. Static compliance increased, while expiratory flows and conductance decreased after induction of emphysema. Immediately post stapled volume reduction therapy, animals had decreased static compliance. By 1 week following surgery, animals showed increased forced expiratory flows and decreased expiratory resistance, although compliance was similar to preoperative levels. In conclusion, we describe initial results in an animal model of obstructive emphysema suitable for the study of lung volume reduction surgery. Changes in pulmonary function indicate that unilateral lower lobe LVRS increases airway conductance in the rabbits. Findings from LVRS studies in animal models such as this may help explain clinical improvement following LVRS in humans.     

Cytogenetic and molecular-cytogenetic investigation of Rett syndrome: analysis of 31 cases

Rett syndrome (RS) is a progressive encephalopathy restricted to the female sex. In the present study we investigated 30 females and one male with RS by cytogenetic and molecular-cytogenetic methods. We failed to identify any chromosomal rearrangements within the female groups and no correlation between fra(X)(p22) and RS in either the female group or the male. The boy with RS has karyotype 46,XY/47,XXY with abnormal cell clone (47,XXY) in 6-12% of his lymphocytes (revealed by fluorescence in situ hybridization analysis (FISH) of interphase cells with chromosome X-specific DNA probe). Our results indicated a possible connection between RS and X-chromosome replication disturbance. A late-replicating X-chromosome with a specific banding pattern (type 'C') has been observed in RS patients only. We propose to analyse the X-chromosome replication pattern as a test for confirmation of RS at preclinical diagnosis.     

Thermally-induced changes in the metabolism of the eye of the crayfish Paranephrops planifrons: respiration and substrate utilization at three distinct temperatures

Gleason's score (GS) has been reported to be the most valuable prognostic factor in cases of prostate cancer. GS is solely dependent on the histological architecture of the prostate cancer, but, it seems doubtful that histological patterns are sufficient for evaluating the degree of malignancy of prostate cancer. We previously reported that the estimation of volume-weighted mean nuclear volume (MNV) might be a more useful prognosticator for prostate cancer than subjective histological grading. However, the previous study was conducted on patients treated in a single hospital, and the number of subjects was too small to draw a definitive conclusion. In this study, we analyzed a larger number of subjects at another institution using a blinded study design. A retrospective prognostic study of 195 patients with prostate cancer diagnosed between January 1966 and December 1988 at Kyoto University Hospital, and treated by conservative therapy, was conducted. Unbiased estimates of MNV were compared with the clinical stage and histological grading according to GS with regard to the prognostic value. Univariate analysis revealed that estimates of MNV, clinical stage, and GS all correlated significantly with disease-specific survival in cases of prostate cancer. Multivariate analysis of all cases also revealed that all of these factors were significant independent prognosticators of disease-specific survival. However, focusing on clinically localized cases (stages A, B, and C), multivariate analysis revealed that the estimation of MNV was the only powerful prognosticator of prostate cancer. This study indicates that the estimation of MNV is prognostically equal or superior to GS in cases of prostate cancer. We emphasized that the estimates of MNV is a more objective method for histological grading to predict the malignant potential of prostate cancer.     

Excitatory amino acid receptor antagonists: resolution, absolute stereochemistry, and pharmacology of (S)- and (R)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA)

We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation using N-BOC protected ATAA and (R)- and (S)-phenylethylamine. Enantiomeric purities (ee > 98%) of (R)- and (S)-ATAA were determined using the Crownpak CR(-) and CR(+) columns, respectively. The absolute configuration of (R)-ATAA was established by an X-ray crystallographic analysis of the (R)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation (Ki > 1,000 microM).     

Rett syndrome, classical and atypical: genealogical support for common origin

AIMS OF THE STUDY: By using genealogical methods in atypical females with Rett syndrome (RS) we looked for support for the assumption that atypical RS cases are true variants of classical RS. SUBJECTS: We selected from the Swedish national RS series the "milder" RS cases, 10 years of age and older, fulfilling the criteria for the "forme fruste" (FF) type of RS. For 32 FF cases we were able to carry out complete genealogical analyses on 61 parental lines. The pedigrees contained details of about 3200 ancestors. COMMON GEOGRAPHICAL ORIGINS: Eleven (34%) of the FF females could be traced to a previously defined "Rett area" and no fewer than six females had their origin in the same homestead as another previously examined classical RS patient. ANCESTRY: In four pedigrees, two each contained one FF and two classical RS and two each contained one FF and one classical RS, all 10 being descendants of the same four couples who lived several generations ago. CONSANGUINITY: Consanguinity in four grandparents (6.6% (SD 3.2%)) is probably a higher frequency than in the average Swedish population and supported our findings from a series of classical RS. TRANSMISSION: The data indicate that transmission starts with a premutation that over generations can result in a full mutation giving rise to RS. Both the X chromosomes and a pair of autosomes may be involved. CONCLUSION: Many, or most, atypical FF cases are true variants of RS.     

Blood flow to the brown adipose tissue of conscious young rabbits during hypoxia in cold and warm conditions

Histidine-proline-rich glycoprotein (HPRG) is a protein that is synthesized by parenchimal liver cells. The protein has been implicated in a number of plasma-specific processes, including blood coagulation and fibrinolysis. We have recently reported the association of an HPRG-like protein with rabbit skeletal muscle AMP deaminase (AMPD). The results of the immunological analysis reported here demonstrate that an antibody against human plasma HPRG reacts with an AMPD preparation from human skeletal muscle. To probe the localization of the putative HPRG-like protein in human skeletal muscle, serial sections from frozen biopsy specimens were processed for immunohistochemical and histoenzymatic stains. A selective binding of the anti-HPRG antibody to Type IIB muscle fibers was detected, suggesting a preferential association of the novel protein to the AMPD isoenzyme contained in the fast-twitch glycolytic fibers.     

Meloxicam in acute UV dermatitis--a pilot study

The non-steroidal anti-inflammatory drug (NSAID) meloxicam is a preferential cyclooxygenase-2 (COX-2) antagonist. The UV protective potential of this drug was studied to compare it with the reported beneficial effects of such preferentially COX-1 specific NSAIDs as indomethacin and acetylsalicylic acid in the literature. In a pilot study (open-label, non-randomized, non-controlled, unblinded), 10 patients received UV irradiation with the minimal erythema dose (MED), first with meloxicam (7.5 mg/die) to reduce post-operative pain and second without ingestion of meloxicam. The factor of UV protection was evaluated. In six of ten patients meloxicam showed no benefit, whereas four of ten patients had a 1.3- up to 3-fold UV protection. In this study, the benefit in UV protection of meloxicam as a preferential COX-2 antagonist was not above the reported benefit of the "old" COX-1 inhibiting NSAIDS.