Olfactory discrimination in the rabbit olfactory glomerulus.

Slow potentials evoked by odor stimulation were recorded from individual glomeruli in the olfactory bulb. Systematic analysis of responses to nine different, arbitrarily selected stimuli strongly suggests a certain amount of discrimination. This fact seems to reflect in the first synapse of the olfactory tract the type of discrimination that was recently demonstrated within olfactory neuroepithelium.

Fibrosing mediastinitis: successful stenting of the pulmonary artery.

Fibrosing mediastinitis is a rare benign condition, which can cause compression of the pulmonary or systemic vessels, tracheobronchial tree, coronary arteries or esophagus, leading to disabling clinical symptoms and even death. The case of a 26-year-old woman who presented with dyspnea is described. She was found to have 80% stenosis of the right pulmonary artery secondary to fibrosing mediastinitis. The stenosis was managed successfully with an endovascular Palmaz-Schatz stent, and the patient remains symptom-free 10 years later.

Lost in translation: translational interference from a recurrent mutation in exon 1 of MECP2.

BACKGROUND: Rett syndrome (RTT) is an X linked neuro-developmental disorder affecting mostly girls. Mutations in the coding region of MECP2 are found in 80% of classic RTT patients. Until recently, the region encoding MECP2 was believed to comprise exons 2, 3, and 4 with the ATG start site located at the end of exon 2 (MeCP2_e2). METHODS: Recent reports of another mRNA transcript transcribed from exon 1 (MeCP2_e1) prompted us to screen exon 1 among RNA samples from 20 females with classic or atypical RTT. RESULTS: A previously reported 11 base pair deletion in exon 1 was detected in one subject with a milder phenotype. Although RNA expression for both protein isoforms was detected from the mutant allele, evaluation of MeCP2 protein in uncultured patient lymphocytes by immunocytochemistry revealed that MeCP2 protein production was restricted to only 74-76% of lymphocytes. X chromosome inactivation studies of genomic DNA revealed similar XCI ratios at the HUMARA locus (73:27 with HpaII and 74:26 with McrBC). We have demonstrated that translation but not transcription of the MeCP2_e2 isoform is ablated by the 11 nucleotide deletion, 103 nucleotides upstream of the e2 translation start site. CONCLUSIONS: These findings reveal that nucleotides within the deleted sequence in the 5'-UTR of the MeCP2_e2 transcript, while not required for transcription, are essential for translation.

Identification of germ-line E-cadherin mutations in gastric cancer families of European origin.

E-cadherin germ-line mutations have recently been described as a molecular basis for early-onset familial gastric cancer in Maori kindred. We screened 18 gastric cancer families of European origin for germ-line mutations to determine the proportion in which E-cadherin mutations occur and the clinical characteristics of the affected families. Truncating mutations were identified in three kindred with familial diffuse gastric cancer. In these families, the age of onset of gastric cancer was variable, the penetrance was incomplete, and one kindred contained individuals with cancers at other sites. Here, we show that a proportion of diffuse gastric cancer families of European origin have germ-line E-cadherin mutations; however, these mutations are absent in intestinal gastric cancer families.

Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria.

BACKGROUND: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations. METHODS: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing. RESULTS: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families. CONCLUSION: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.

Vitamin B6 status in women with postpartum depression.

We have assessed the vitamin B6 status of 40 nonpregnant women of reproductive age, 30 pregnant women, 20 postpartum, not depressed, women and 24 postpartum, depressed women by means of the erythrocyte glutamate-oxaloacetate transaminase activation test (alpha EGOT). The level of mental depression was evaluated in the nonpregnant controls, the postpartum controls and the postpartum, depressed patients by the Beck Depression Inventory and the Depression Adjective Check Lists. The results of the alpha EGOT did not indicate any significant differences between the postpartum, depressed patients and any of the control groups. The Beck and Depression Adjective Check Lists scores were significantly higher in the postpartum depressed patients than in the postpartum controls or nonpregnant controls. On the basis of this study, there is no evidence for vitamin B6 deficiency in women suffering from postpartum depression.

The familial nature of multiple sclerosis: empiric recurrence risks for first, second-, and third-degree relatives of patients.

Although the risks are low, relatives of multiple sclerosis (MS) patients have a greater risk of developing the disease than the general population. Since this is true of second- and third-degree relatives as well as first-degree relatives, the increased risk cannot be explained solely by environmental factors. This observation is part of the evidence that the etiology of MS may have a genetic component. Genetic counseling is recommended for MS patients. Empiric recurrence risks have been derived and give the counselor necessary information with which to provide this service.

Isoniazid therapy of Huntington disease.

We describe clinical and biochemical changes in seven patients with Huntington disease given isoniazid (INH) in dosages three to five greater than normally used in tuberculosis. Because INH inhibits the enzyme gamma-aminobutyric acid aminotransferase (GABA-T), and increases GABA content in the brains of experimental animals, it might correct the brain GABA deficiency characteristic of Huntington disease. Of six patients treated long enough to be clinically evaluated, one showed marked and two others showed signifciant improvement. High-dose INH therapy carries serious toxic risks, which are influenced by patients' acetylator phenotypes. Nevertheless, results are sufficiently promising to warrant further controlled trials of INH or other GABA-T inhibitors in Huntington disease.

Progressive cerebellar ataxia, spasticity, psychomotor retardation, and hexosaminidase deficiency in a 10-year-old child: juvenile Sandhoff disease.

During the course of investigating a 10-year-old boy because of progressive deterioration of intellectual functioning, ataxia, and hemiplegia, an absence of serum hexosaminidase activity was noted. A skin biopsy examined by electron microscopy showed axonal accumulations of dense osmiophilic deposits. Because of the patient's age at onset and the slowly progressive nature of his ilness, we are reporting an atypical juvenile case of Sandhoff disease.

Fluorodopa and raclopride PET analysis of patients with Machado-Joseph disease.

We performed [18F]6-fluoro-L-dopa (6-FD) and [11C]raclopride (RAC) PET studies in six patients with Machado-Joseph disease (MJD) (age, 17 to 61 years; duration of illness, 3 to 10 years), normal controls (n = 10 in 6-FD-PET, n = 8 in RAC-PET), and patients with idiopathic parkinsonism (n = 15 in 6-FD-PET). The youngest patient with MJD had prominent dystonia and pyramidal features (type 1 MJD), whereas the remainder were prominently ataxic (types 2 and 3 MJD). Striatal RAC binding was normal in patients with MJD. Striatal 6-FD influx constants (Ki) were low in the range of idiopathic parkinsonism in two patients with MJD (youngest and oldest patients), whereas striatal Ki were normal in the remaining patients with MJD. The impairment of the nigrostriatal dopaminergic pathway did not correlate with the phenotype, CAG repeat length, disease duration, or age of onset of patients with MJD. Our results suggest that striatal D2 receptors are normal and the nigral damage is diverse in MJD.

Failure of aminooxyacetic acid therapy in Huntington disease.

Seven patients with Huntington disease were treated with aminooxyacetic acid (AOAA), an inhibitor of gamma-aminobutyric acid aminotransferase (GABA-T), in an effort to alleviate symptoms by increasing brain GABA content. AOAA was given orally in a placebo-controlled crossover trial in which patients, relatives, and three of the evaluating physicians remained blind. Toxic symptoms occurred in all seven patients when AOAA dosage was increased beyond 2 mg per kilogram per day, and included drowsiness, ataxia, seizures, and psychotic behavior. In five patients who took AOAA for 4 months, no clinical improvement was observed. Biochemical monitoring showed that less inhibition of hepatic GABA-T enzyme activity was achieved than in patients treated with large doses of isoniazid. Results of this trial neither support nor exclude the possible therapeutic usefulness of increasing brain GABA content in Huntington disease.

Frequency of spinocerebellar ataxia type 1, dentatorubropallidoluysian atrophy, and Machado-Joseph disease mutations in a large group of spinocerebellar ataxia patients.

The spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders varying in both clinical manifestations and mode of inheritance. Six different genes causing autosomal dominant SCA are mapped: SCA1, SCA2, Machado-Joseph disease (MJD)/SCA3, SCA4, SCA5, and dentatorubropallidoluysian atrophy (DRPLA). Expansions of an unstable trinucleotide CAG repeat cause three of these disorders: SCA type 1 (SCA1), MJD, and DRPLA. We determine the frequency of the SCA1, DRPLA, and MJD mutations in a large group of unrelated SCA patients with various patterns of inheritance and different ethnic backgrounds. We studied 92 unrelated SCA patients. The frequency of the SCA1 mutation was 3% in the overall patient group and 10% in the non-Portuguese dominantly inherited SCA subgroup. We found that DRPLA mutation in only one Japanese patient, who was previously diagnosed with this disease. We identified the MJD mutation in 41% of the overall patient group, which included 38 autosomal dominant kindreds of Portuguese origin; the frequency of the MJD mutation among the non-Portuguese dominantly inherited cases was 17%. These results suggest that SCA may be occasionally caused by the SCA1 mutation and rarely caused by the DRPLA mutation and that, to date, the MJD mutation seems to be the most common cause of dominantly inherited SCA. Finally, our results suggest that recessively inherited cases of SCA are not caused by the known trinucleotide repeat expansions.

A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone.

The palliative efficacy of strontium-89 chloride has been evaluated in a prospective double-blind crossover study comparing it with stable strontium as placebo in 32 patients with prostate cancer metastatic to bone. Response was assessed 5 weeks after each treatment. 26 patients were evaluable. Complete pain relief was only reported following strontium-89 injection. Statistical comparison between placebo and strontium-89 showed clear evidence of a therapeutic response to strontium-89 compared with only a limited placebo effect (P less than 0.01).

The role of radiotherapy in in-situ carcinoma of the larynx.

Twenty patients with in situ carcinoma of the vocal cord treated with radical radiotherapy over a 16-year period have been assessed for local control and survival. Seventy-one patients with Stage T1 invasive carcinomas treated in the same period have been similarly assessed and the results are compared. All patients were treated with megavoltage wedge pair techniques using fields of mean size 4.5 x 4.5 cm. Patients were treated to radical intent, the Tis group receiving a mean nominal standard dose (NSD) of 1759 ret and the T1 invasive group a mean NSD of 1743 ret. In the Tis group, radiotherapy resulted in local control in 70% (14/20) of patients with an ultimate local control, after surgery, of 90% (18/20). This is not statistically different to the primary local control rate for T1 invasive lesions of 83% (59/71) with an ultimate control rate, after surgery, of 94% (68/71), chi 2 p greater than 0.2. Five and 10-year actuarial survival rates were 100% in the Tis group and 96.8% and 92.6%, respectively, in the T1 invasive group (chi 2 p = 0.275). Five and 10-year actuarial recurrence-free survival rates were 78.8% and 69% for the Tis group and 86.1% and 78.4% for the T1 invasive group (chi 2 p = 0.548). Analysis of failures suggests that extent of disease, field size, and total dose given are not contributory factors to local control or survival in this group of patients. There is no indication that in situ lesions respond to radiotherapy less favorably than T1 invasive lesions and we would support the use of radiotherapy as a therapeutic option in this condition.

Diagnosis and management of infantile marfan syndrome.

Marfan syndrome is infrequently diagnosed early in infancy. The experience of the authors with 22 severely affected infants diagnosed as having Marfan syndrome in the first 3 months of life is described and the literature on 32 additional infants with Marfan syndrome is reviewed. It was found that serious cardiac pathology (82% of the patients described in the article, 94% of those described in the literature) may be present at birth, and that congenital contractures (64% of our cases, 47% of literature cases) are often an associated finding. Other useful clinical findings included arachnodactyly, dolichocephaly, a characteristic facies, a high-arched palate, micrognathia, hyperextensible joints, pes planus, anterior chest deformity, iridodenesis, megalocornea, and dislocated lenses. Echocardiography was useful as a noninvasive method for defining the extent of cardiovascular involvement and following its course. Characteristic cardiac findings in early life included mitral valve prolapse, valvular regurgitation, and aortic root dilation. Cardiac function ranged from normal to poor, with a tendency to worsen. Of the 22 cases 3 infants died during the first year of life. Morbidity and mortality may be high when Marfan syndrome is diagnosed during infancy, and prompt recognition of this phenotype can facilitate management and counseling. Most such severe cases appear to be due to a sporadic mutation in a single germ cell of one parent. Many familial cases may have milder manifestations, be more difficult to detect during infancy, and have a better prognosis.

Possible new autosomal recessive syndrome with unusual renal histopathological changes.

We report a couple with repeated pregnancy loss--two spontaneous first trimester abortions and two stillbirths with diffuse hypoplasia of the renal tubules. Both parents have been investigated to exclude occult unilateral renal agenesis. We raise the possibility that this is a new autosomal recessive condition.

Carrier detection and prenatal diagnosis of Pelizaeus-Merzbacher disease using a combination of anonymous DNA polymorphisms and the proteolipid protein (PLP) gene cDNA.

We report carrier identification and a prenatal diagnosis using DNA polymorphisms in 2 families with X-linked Pelizaeus-Merzbacher disease (PMD). In both families, the proteolipid protein (PLP) gene in the single affected male could be traced back to his unaffected maternal grandfather. Therefore, each family contains a new mutation. In the case of the prenatal diagnosis, the fetus was shown by cytogenetic analysis to be a female, who we predict will be a noncarrier of PMD based on her genotype with the PLP intragenic polymorphism.

Growth and development in thanatophoric dysplasia.

Two cases of prolonged survival of thanatophoric dysplasia are presented, in which ventilatory support was initiated in the neonatal period because of respiratory distress. Both patients required a ventriculoperitoneal shunt for hydrocephalus and had decompression of the posterior fossa. The history of each patient has been characterized by profound developmental delay and dramatic growth failure.

Prenatal diagnosis of neuronal ceroid-lipofuscinoses.

We report on the successful prenatal diagnosis of the late infantile "Jansky-Bielschowsky" variant of the neuronal ceroid-lipofuscinoses (NCL). The fetus was studied at 16 weeks of gestation because of an affected sib. Uncultured amniotic fluid cells were studied by conventional electron microscopic techniques. About one-third of a subpopulation of dark, elongated cells contained one or more deposits of curvilinear cytosomes bound by a single unit membrane. These findings were considered typical of the late infantile variant of NCL. After delivery at term, a skin punch biopsy and a buffy coat preparation from the baby were examined and found to have similar characteristic inclusions, which confirmed our prenatal diagnosis.