Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. REPORT: Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. DISCUSSION: Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from 'Classical' OI. CONCLUSIONS: Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.

Estimates of genetic variance and variance of predicted genetic merits using pedigree or genomic relationship matrices in six Brown Swiss cattle populations for different traits.

The amount of variance captured in genetic estimations may depend on whether a pedigree-based or genomic relationship matrix is used. The purpose of this study was to investigate the genetic variance as well as the variance of predicted genetic merits (PGM) using pedigree-based or genomic relationship matrices in Brown Swiss cattle. We examined a range of traits in six populations amounting to 173 population-trait combinations. A main aim was to determine how using different relationship matrices affect variance estimation. We calculated ratios between different types of estimates and analysed the impact of trait heritability and population size. The genetic variances estimated by REML using a genomic relationship matrix were always smaller than the variances that were similarly estimated using a pedigree-based relationship matrix. The variances from the genomic relationship matrix became closer to estimates from a pedigree relationship matrix as heritability and population size increased. In contrast, variances of predicted genetic merits obtained using a genomic relationship matrix were mostly larger than variances of genetic merit predicted using pedigree-based relationship matrix. The ratio of the genomic to pedigree-based PGM variances decreased as heritability and population size rose. The increased variance among predicted genetic merits is important for animal breeding because this is one of the factors influencing genetic progress.

Problems with continuous-time malaria models in describing gametocytogenesis.

Most mathematical models of malaria infection represent parasites as replicating continuously at a constant rate whereas in reality, malaria parasites replicate at a fixed age. The behaviour of continuous-time models when gametocytogenesis is included, in comparison to a more realistic discrete-time model that incorporates a fixed replication age was evaluated. Both the infection dynamics under gametocytogenesis and implications for predicting the amount parasites should invest into gametocytes (level of investment favoured by natural selection) are considered. It is shown that the many malaria models with constant replication rates can be represented by just 3 basic types. For these 3 types, it is then shown that under gametocytogenesis (i) in 2 cases, parasite multiplication and gametocyte production is mostly much too low, (ii) in the third, parasite multiplication and gametocyte production is mostly much too high, (iii) the effect of gametocyte investment on parasite multiplication is mostly too high, (iv) the effect of gametocyte investment on gametocyte production is nearly always too low and (v) with a simple approximation of fitness, the predicted level of gametocyte investment is mostly much too low. However, a continuous model with 48 age-compartments compares well to the discrete model. These findings are a further argument for modelling malaria infections in discrete time.

Ultrasound-detected thyroid nodule prevalence and radiation dose from fallout.

Settlements near the Semipalatinsk Test Site (SNTS) in northeastern Kazakhstan were exposed to radioactive fallout during 1949-1962. Thyroid disease prevalence among 2994 residents of eight villages was ascertained by ultrasound screening. Malignancy was determined by cytopathology. Individual thyroid doses from external and internal radiation sources were reconstructed from fallout deposition patterns, residential histories and diet, including childhood milk consumption. Point estimates of individual external and internal dose averaged 0.04 Gy (range 0-0.65) and 0.31 Gy (0-9.6), respectively, with a Pearson correlation coefficient of 0.46. Ultrasound-detected thyroid nodule prevalence was 18% and 39% among males and females, respectively. It was significantly and independently associated with both external and internal dose, the main study finding. The estimated relative biological effectiveness of internal compared to external radiation dose was 0.33, with 95% confidence bounds of 0.09-3.11. Prevalence of papillary cancer was 0.9% and was not significantly associated with radiation dose. In terms of excess relative risk per unit dose, our dose-response findings for nodule prevalence are comparable to those from populations exposed to medical X rays and to acute radiation from the Hiroshima and Nagasaki atomic bombings.

Oliguric acute renal failure in mycosis fungoides with lymphomatous infiltrates in the kidneys.

OBJECTIVE: To present the clinical picture of acute renal failure in patients with mycosis fungoides (MF) and renal lymphomatous infiltrates. To analyze the pathogenesis of renal failure. METHODS: Correlation of clinical picture, urinary findings, imaging reports and autopsy findings in two patients with long-standing MF who died with renal failure. CASE SUMMARIES: Both subjects had sustained oliguria in the last 2 weeks. One patient had persistent hypotension, normal urinalysis, normal renal sonogram, and scarce interstitial lymphomatous infiltrates with preservation of renal parenchymal architecture. He was thought to have ischemic acute renal failure not directly linked to the lymphomatous infiltrates. The second patient developed hypertension one month prior to death, and had moderate proteinuria, hematuria, pyuria, grossly enlarged kidneys with hypoechoic masses, and extensive replacement of the renal parenchyma by lymphomatous infiltrates. This picture is typical of renal failure secondary to lymphomatous replacement of the kidneys. CONCLUSIONS: The development of oliguric renal failure in MF with renal lymphomatous infiltrates may have varying clinical and imaging manifestations and pathogeneses. Potentially reversible pathogenic mechanisms should be systematically investigated, particularly if the overall clinical picture is not characteristic of renal failure secondary to lymphomatous replacement of the parenchyma.

Pulmonary capillary hemangiomatosis-like foci. An autopsy study of 8 cases.

Pulmonary capillary hemangiomatosis (PCH) typically occurs in young patients who have signs and symptoms of pulmonary hypertension. It commonly is misdiagnosed in life as pulmonary veno-occlusive disease, and the correct diagnosis usually is not made until autopsy. Autopsy records, including reports, gross photographs, histologic slides, clinical histories, and radiographic images, were reviewed to identify cases with morphologic changes characteristic of PCH. The previous case reports describe PCH as a diffuse process throughout both lung fields. All patients were symptomatic, and most died of the disease. This article details 8 cases of PCH-like foci that were incidental findings at autopsy in which the patients did not have symptoms of pulmonary hypertension nor did PCH contribute in any way to death. This is the first case series that describes pathologic changes of PCH occurring in this setting, and we hope to provide more interest in PCH and its natural history.

Plasmodium chabaudi: effect of antimalarial drugs on gametocytogenesis.

The proportion of asexual blood-stage malaria parasites that develop into transmission stages (gametocytes) can increase in response to stress. We investigated whether stress imposed by a variety of antimalarial drugs administered before or during infection increased gametocyte production (gametocytogenesis) in vivo in the rodent malaria parasite, Plasmodium chabaudi. All methods of drug treatment greatly reduced the numbers of asexual parasites produced during an infection but resulted in either no reduction in numbers of gametocytes or a smaller reduction than that experienced by asexuals. We used a simple model to estimate temporal variation in gametocyte production. Temporal patterns of gametocytogenesis did not greatly differ between untreated and prophylaxis infections, with rates of gametocytogenesis always increasing as the infection progressed. In contrast, administration of drugs 5 days after infection stimulated increased rates of gametocytogenesis early in the infection, resulting in earlier peak gametocyte densities relative to untreated infections. Given the correlation between gametocyte densities and infectivity to mosquito vectors, and the high frequency of subcurative drug therapy and prophylaxis in human populations, these data suggest that antimalarial drugs may frequently have only a small effect on reducing malaria transmission and may help to explain the rapid spread of drug-resistant geno-types.

Corpus gastritis is protective against reflux oesophagitis.

BACKGROUND: Gastric acid is important in the pathogenesis of reflux oesophagitis. Acid production by the gastric corpus is reduced in corpus gastritis. AIMS: To determine whether corpus gastritis protects against reflux oesophagitis. METHODS: Patients presenting for elective oesophagogastroduodenoscopy were studied. Two biopsy specimens were taken from the antrum, corpus, and cardia and stained with haematoxylin/eosin and Diff-Quick II stains. The presence and severity of gastritis were graded according to a modified updated Sydney classification. RESULTS: Of 302 patients, 154 had endoscopic signs of reflux oesophagitis. There was no difference between patients with and controls without oesophagitis in the overall infection rates with Helicobacter pylori. Acute or chronic corpus gastritis occurred less often in patients with than those without reflux oesophagitis. Compared with controls, corpus gastritis was less severe in patients with reflux oesophagitis. The presence of acute or chronic gastritis in the corpus was significantly correlated with either type of gastritis in other areas of the stomach. In a multivariate logistic regression, age, sex, smoking status, and the presence of chronic corpus gastritis all exerted a significant influence on the presence of reflux oesophagitis. Chronic corpus gastritis was associated with a 54% reduced risk for reflux oesophagitis. CONCLUSIONS: While infection with H pylori alone may not affect the occurrence of reflux oesophagitis, the development of chronic corpus gastritis seems to be protective.

Characteristics of intestinal metaplasia in the gastric cardia.

OBJECTIVE: Intestinal metaplasia of the gastroesophageal junction is frequently grouped together with Barrett's esophagus. The area of the gastroesophageal junction is comprised of the distal esophagus and the gastric cardia. The aim of the present study was to assess whether intestinal metaplasia in the distal esophagus and gastric cardia represent two different entities with a different set of risk factors. METHODS: Patients presenting for elective upper endoscopy were enrolled into a prospective study. The presence of gastritis and intestinal metaplasia was evaluated in gastric biopsies taken from the antrum, corpus, and cardia. Barrett's esophagus was defined by the presence of any length of columnar mucosa above the gastroesophageal junction. RESULTS: Of 302 patients, 50 patients had intestinal metaplasia of the gastric cardia, 73 Barrett's esophagus, and 116 erosive esophagitis. Men were more prone than women to develop Barrett's esophagus or erosive esophagitis. Both conditions were also more common among whites than nonwhites. Smoking was particularly common among patients with Barrett's esophagus. Patients with cardiac intestinal metaplasia did not share these demographic characteristics. The prevalence of daily reflux symptoms, erosive esophagitis, and Barrett's esophagus was similar among patients both with and without cardiac intestinal metaplasia. However, atrophy and intestinal metaplasia of the gastric antrum and corpus were found more frequently among patients with than without cardiac intestinal metaplasia. CONCLUSIONS: Intestinal metaplasia of the gastric cardia is different from Barrett's esophagus. Although cardiac intestinal metaplasia is closely associated with signs of gastritis in other parts of the stomach, gastroesophageal reflux disease does not seem to be a risk factor. A diagnosis of Barrett's esophagus should not be made based on the presence of intestinal metaplasia within the cardiac portion of the gastroesophageal junction.

Reconstruction of a hemisectioned tooth with an adhesive ceramic restoration using intraradicular retention.

Hemisection may be a valuable form of treatment for molar teeth when one root is considered unrestorable. However, following hemisection the clinician may encounter difficulty in restoring the remaining tooth fragment, which may not possess adequate bulk for the placement of a post. This case report describes an adhesive technique in which a ceramic crown is bonded intraradicularly to the hemisectioned root.

Who follows whom? Shoaling preferences and social learning of foraging information in guppies.

Preferences of fish for different types of shoals may influence the transmission of novel information through them. We investigated the factors influencing the preferences of guppies, Poecilia reticulata, for different shoals in order to shed some light on how information transmission occurs. Adult subjects were given a choice between swimming with two diverging shoals of conspecifics that differed with respect to key characteristics. In six choice experiments, subjects discriminated between shoal partners on the basis of: (1) shoal size, subjects preferring a shoal of 10 to a single fish; (2) size of shoaling fish, small fish preferring small conspecifics rather than an equal number of large fish, while large fish showed no preference; (3) local foraging experience of shoaling fish, shoals containing fish that had previously been repeatedly fed in the experimental tank being preferred to shoals with no such experience; and (4) familiarity of shoaling fish, guppies preferring familiar rather than unfamiliar conspecifics. No discrimination on the basis of colour or hunger was observed. In addition, following a shoal to a food site on just three trials allowed guppies to learn a route, or food site, preference. Guppies were considerably more likely to learn to adopt the behaviour shown by members of a shoal of several demonstrators than an alternative behaviour shown by a single conspecific demonstrator. The relationship between preferences for different shoals and the social transmission of information is discussed in the light of these findings. The results suggest that shoaling preferences may strongly influence the social transmission of novel foraging information or feeding preferences through fish populations, and imply that learned infor-mation may diffuse through fish populations in a nonrandom, or directed, manner. Copyright 1998 The Association for the Study of Animal Behaviour.

I-131 uptake in the breast for thyroid cancer surveillance with biopsy-proven benign tissue.

A 37-year-old woman was seen for recurrent papillary carcinoma of the thyroid after thyroidectomy. After repeated surgery and I-131 therapy, follow-up I-131 scanning and thyroglobulin levels were negative. Subsequent I-131 surveillance, however, demonstrated bilateral breast uptake. A biopsy taken of this area in the right breast proved that the increased uptake was secondary to benign disease.

Thyroid palpation versus high-resolution thyroid ultrasonography in the detection of nodules.

Detection of thyroid nodules by physical examination and high-resolution ultrasonography was compared using small groups of blinded, experienced physician examiners working with a sample of 2441 persons from Estonia, most of whom were Chernobyl nuclear reactor clean-up workers. A random subsample of 113 (5%) persons was subjected to triple control examinations with both physical examination and high-resolution ultrasonography. Positive high-resolution ultrasonographic findings were considerably more reproducible among different observers than were positive physical examination findings. Agreement between methods was poor. Nodules were found in 169 (6.9%) subjects by physical examination and in 249 (10.2%) subjects by high-resolution ultrasonography. Physical examination found only 53 (21%) of the 249 nodules found by high-resolution ultrasonography. High-resolution ultrasonography did not confirm the existence of 115 (68%) of the 169 nodules found by physical examination. Only 6.4% of nodules less than 0.5 cm in diameter, as based on high-resolution ultrasonographic results, were detected by physical examination. Physical examination detection improved with increasing nodule size but was still only 48.2% for nodules larger than 2 cm. Physical examination was relatively effective in detecting nodules in the isthmus of the thyroid gland but much less so for nodules in the upper pole of the gland. Clinical evaluation and epidemiologic studies of nodular thyroid disease stand to benefit from the greater sensitivity and specificity of ultrasonographic examinations.

Small cell carcinoma of the vagina causing Cushing's syndrome by ectopic production and secretion of ACTH: a case report.

BACKGROUND: Small cell carcinomas of pulmonary or extrapulmonary origin are neuroendocrine tumors classically associated with ectopic hormone production, particularly ACTH secretion resulting in Cushing's syndrome. However, ectopic Cushing's syndrome has not previously been reported in the setting of small cell carcinoma of the vagina. METHODS: A primary vaginal tumor with hepatic metastases was evaluated with light microscopy. Serum cortisol and plasma ACTH levels were evaluated by radioimmunoassay and immunoradiometric assay, respectively, during a standard high-dose (8 mg) overnight dexamethasone suppression test. RESULTS: Vaginal small cell carcinoma with hepatic metastases was demonstrated. Electrolyte abnormalities, elevated cortisol and ACTH levels, and failure to suppress ACTH secretion during high-dose dexamethasone administration confirmed the diagnosis of ectopic ACTH syndrome. CONCLUSIONS: This case report establishes a clinical association between vaginal small cell carcinoma and ectopic Cushing's syndrome, confirming the neuroendocrine potential of this malignancy and features common to small cell neoplasms originating in other sites.

Thyroid nodularity and cancer among Chernobyl cleanup workers from Estonia.

Thyroid examinations, including palpation, ultrasound and, selectively, fine-needle aspiration biopsy, were conducted on nearly 2,000 Chernobyl cleanup workers from Estonia to evaluate the occurrence of thyroid cancer and nodular thyroid disease among men with protracted exposure to ionizing radiation. The examinations were conducted in four cities in Estonia during March-April 1995, 9 years after the reactor accident. The study population was selected from a predefined cohort of 4,833 cleanup workers from Estonia under surveillance for cancer incidence. These men had been sent to Chernobyl between 1986 and 1991 to entomb the damaged reactor, remove radioactive debris and perform related cleanup activities. A total of 2,997 men were invited for thyroid screening and 1,984 (66%) were examined. Estimates of radiation dose from external sources were obtained from military or other institutional records, and details about service dates and types of work performed while at Chernobyl were obtained from a self-administered questionnaire. Blood samples were collected for assay of chromosomal translocations in circulating lymphocytes and loss of expression of the glycophorin A (GPA) gene in erythrocytes. The primary outcome measure was the presence or absence of thyroid nodules as determined by the ultrasound examination. Of the screened workers, 1,247 (63%) were sent to Chernobyl in 1986, including 603 (30%) sent in April or May, soon after the accident. Workers served at Chernobyl for an average of 3 months. The average age was 32 years at the time of arrival at Chernobyl and 40 years at the time of thyroid examination. The mean documented radiation dose from external sources was 10.8 cGy. Biological indicators of exposure showed low correlations with documented dose, but did not indicate that the mean dose for the population was higher than the average documented dose. Ultrasound examinations revealed thyroid nodules in 201 individuals (10.2%). The prevalence of nodules increased with age at examination, but no significant associations were observed with recorded dose, date of first duty at Chernobyl, duration of service at Chernobyl, building the sarcophagus or working on the roof of neighboring buildings or close to the damaged reactor. Nodularity showed a nonsignificant (p(1) = 0.10) positive association with the proportion of lymphocytes with chromosome translocations, but associations with the frequency of variant erythrocytes in the GPA assay were weak and unstable (p(1) > or = 0.46). The majority of fine-needle biopsies taken on 77 study participants indicated benign nodular disease. However, two cases of papillary carcinoma and three benign follicular neoplasms were identified and referred for treatment. Both men with thyroid cancer had been sent to Chernobyl in May of 1986, when the potential for exposure to radioactive iodines was greatest. Chernobyl cleanup workers from Estonia did not experience a markedly increased risk of nodular thyroid disease associated with exposure to external radiation. Possible reasons for the apparent absence of effect include low radiation doses, the protracted nature of the exposure, errors in dose measurement, low sensitivity of the adult thyroid gland or the insufficient passage of time for a radiation effect to be expressed.

Detection of trisomy 7 in nonmalignant bronchial epithelium from lung cancer patients and individuals at risk for lung cancer.

Early identification and subsequent intervention are needed to decrease the high mortality rate associated with lung cancer. The examination of bronchial epithelium for genetic changes could be a valuable approach to identify individuals at greatest risk. The purpose of this investigation was to assay cells recovered from nonmalignant bronchial epithelium by fluorescence in situ hybridization for trisomy of chromosome 7, an alteration common in non-small cell lung cancer. Bronchial epithelium was collected during bronchoscopy from 16 cigarette smokers undergoing clinical evaluation for possible lung cancer and from seven individuals with a prior history of underground uranium mining. Normal bronchial epithelium was obtained from individuals without a prior history of smoking (never smokers). Bronchial cells were collected from a segmental bronchus in up to four different lung lobes for cytology and tissue culture. Twelve of 16 smokers were diagnosed with lung cancer. Cytological changes found in bronchial epithelium included squamous metaplasia, hyperplasia, and atypical glandular cells. These changes were present in 33, 12, and 47% of sites from lung cancer patients, smokers, and former uranium miners, respectively. Less than 10% of cells recovered from the diagnostic brush had cytological changes, and in several cases, these changes were present within different lobes from the same patient. Background frequencies for trisomy 7 were 1.4 +/- 0.3% in bronchial epithelial cells from never smokers. Eighteen of 42 bronchial sites from lung cancer patients showed significantly elevated frequencies of trisomy 7 compared to never smoker controls. Six of the sites positive for trisomy 7 also contained cytological abnormalities. Trisomy 7 was found in six of seven patients diagnosed with squamous cell carcinoma, one of one patient with adenosquamous cell carcinoma, but in only one of four patients with adenocarcinoma. A significant increase in trisomy 7 frequency was detected in cytologically normal bronchial epithelium collected from four sites in one cancer-free smoker, whereas epithelium from the other smokers did not contain this chromosome abnormality. Finally, trisomy 7 was observed in almost half of the former uranium miners; three of seven sites positive for trisomy 7 also exhibited hyperplasia. Two of the former uranium miners who were positive for trisomy 7 developed squamous cell carcinoma 2 years after collection of bronchial cells. To determine whether the increased frequency of trisomy 7 reflects generalized aneuploidy or specific chromosomal duplication, a subgroup of samples was evaluated for trisomy of chromosome 2; the frequency was not elevated in any of the cases as compared with controls. The studies described in this report are the first to detect and quantify the presence of trisomy 7 in subjects at risk for lung cancer. These results also demonstrate the ability to detect genetic changes in cytologically normal cells, suggesting that molecular analyses may enhance the power for detecting premalignant changes in bronchial epithelium in high-risk individuals.

Predictive value of flow cytometric analysis in DNA contents in patients with locally advanced head and neck carcinoma.

A retrospective study was performed on 61 eligible patients with stage III and IV (AJC/UICC Staging System) squamous carcinomas of the head and neck region who were treated with definitive radiotherapy with, or without, surgery. DNA contents were measured by flow cytometric analysis of archival paraffin blocks and were correlated with clinicopathological findings, tumour response and patient survival. Comparison of variables including treatment modality was performed for identification of significant prognostic factors. There were 28 diploid, 27 aneuploid tumours and the remaining six were questionable. All patients were followed-up for at least two years or until death. Aneuploid tumours had a significantly higher S-phase fraction (percentage S-phase) (p < 0.001). Neither ploidy nor percentage S-phase were found to have predictive value in tumour response or patient survival within the power of a sample size of 61. Twenty of the 27 (74 per cent) aneuploid tumours had a complete response (CR) whereas 19 out of 28 (68 per cent) diploid tumours achieved CR. Five-year survival by the Kaplan-Meier method was 33 per cent for both aneuploid and diploid tumours. However, nodal stage (N stage) was found to have significant predictive value in both tumour response and patient survival. The complete response for stage N0 patients was 96 per cent, N1 patients 61 per cent, N2 patients 60 per cent and 43 per cent for N3 patients (p < 0.002). Similarly, the five year survival for the N0 and N3 groups of patients was 53 per cent and 29 per cent respectively (p < 0.05).

Anxiety in community-based AIDS caregivers before and after personal construct counseling.

Personal construct counseling was provided for voluntary AIDS caregivers based in the community, with the goal of reducing their anxiety levels. Seventy-five caregivers participated in the project, 33 of whom received counseling. They were interviewed on three occasions--before, immediately after, and 3 months after counseling. Their responses to an open-ended question were subjected to six subscales of a content analysis scale in order to measure levels of anxiety from six different sources. At time 2, the anxiety of the counseled caregivers was significantly less than that of those not counseled, specifically their anxiety about bodily mutilation and guilt. These differences were not sustained at time 3 because the anxiety of those not counseled dropped. Some criticisms of the project are examined before the meaning of these findings for meeting the mental health needs of AIDS caregivers is discussed.