Protein C deficiency

Summary. Severe protein C deficiency (i.e. protein C activity <1 IU dL^?1) is a rare autosomal recessive disorder that usually presents in the neonatal period with purpura fulminans (PF) and severe disseminated intravascular coagulation (DIC), often with concomitant venous thromboembolism (VTE). Recurrent thrombotic episodes (PF, DIC, or VTE) are common. Homozygotes and compound heterozygotes often possess a similar phenotype of severe protein C deficiency. Mild (i.e. simple heterozygous) protein C deficiency, by contrast, is often asymptomatic but may involve recurrent VTE episodes, most often triggered by clinical risk factors. The coagulopathy in protein C deficiency is caused by impaired inactivation of factors Va and VIIIa by activated protein C after the propagation phase of coagulation activation. Mutational analysis of symptomatic patients shows a wide range of genetic mutations. Management of acute thrombotic events in severe protein C deficiency typically requires replacement with protein C concentrate while maintaining therapeutic anticoagulation; protein C replacement is also used for prevention of these complications around surgery. Long‐term management in severe protein C deficiency involves anticoagulation with or without a protein C replacement regimen. Although many patients with severe protein C deficiency are born with evidence of in utero thrombosis and experience multiple further events, intensive treatment and monitoring can enable these individuals to thrive. Further research is needed to better delineate optimal preventive and therapeutic strategies.     

HYPERTHYROIDISM DUE TO A THYROTROPHIN-SECRETING MICROADENOMA

We report a 63-year-old female with a TSH-secreting pituitary adenoma causing hyperthyroidism. This case is apparently unique, and challenges the present concept of dividing patients with inappropriate TSH secretion into tumour and non-tumour groups on the basis of conventional pituitary fossa radiology.     

The latent dimensionality of DIS/DSM-III-R nicotine dependence: exploratory analyses

Decisions on DSM-IV criteria for alcohol dependence were based in part on latent structure analyses of field survey data on alcohol problems. Analogously, to investigate the latent structure of nicotine dependence in an epidemiological sample, we carried out a dichotomous item factor analysis of DSM-III-R symptom data gathered from 394 young adults who reported a history of sustained daily smoking. Smokers and their dependence symptoms were identified by means of the NIMH Diagnostic Interview Schedule version III revised, administered to a random sample of 1007 21–30-year-olds who were members of a health maintenance organization in the Detroit area. Comparing different latent structure models using LISCOMP software with bootstrap re-sampling, followed by multiple logistic regression, vie found that a two-factor model indicating a ‘general dependence’ and a ‘failed cessation’ dimension best accounted for the observed data. Current smoking status (persistent vs. past smoking) was associated with the two factors independently. Replication and additional research on construct, discriminant and convergent validity are needed.     

Progression of HIV disease is associated with increased expression of FcγRI and CR1 on alveolar macrophages

The expression of receptors for complement and the Fc region of immunoglobulin by alveolar macrophages (AM) constitutes a valuable aid to effector function of these cells. However, during HIV infection such expression may also act to increase binding of immune complexes, thus facilitating viral infection of these cells. This study was designed to determine whether changes in the expression of these receptors occurs in situ during HIV infection. Lung macrophages were isolated by bronchoalveolar lavage in groups of HIV⁺ subjects segregated on the basis of peripheral CD4 count. A group of normal subjects was also investigated. Expression of CR1 and FcγRI was quantified by measuring the optical density of reaction product following controlled immunoperoxidase staining with MoAbs CD35 and CD64. Both CR1 and FcγRI were increased over normal in all HIV⁺ subjects. This increase was progressive with advancing disease as determined by correlation with declining peripheral CD4 count. Comparison of asymptomatic and symptomatic subjects with HIV infection showed no difference in CR1 expression but a rise in FcγRI expression in the latter group. An overall inverse correlation was also found between peripheral CD4 count and FcγRI expression, but not CR1 expression. These data demonstrate a significant increase in the expression of these receptors on AM from HIV⁺ subjects, and show that this increase may occur before any symptoms in these patients.     

The impact of mammalian reproduction on cancellous bone architecture

Pregnancy and lactation make demands on maternal calcium homeostasis which may affect bone strength. Recently, changes in cancellous architecture have been described in iliac crest bone biopsies from normal pregnant women but the rarity of such human material means an animal model is essential. The microanatomy of cancellous bone was compared in uniparous and multiparous rats using undecalcified histological sections of lumbar and caudal vertebrae and also proximal femora. An automated trabecular analysis system (TAS) measured a comprehensive range of structural variables including the trabecular number, connectivity and width. In the first pregnancy cycle an early stimulation of bone formation (which quadrupled at some sites) was indicated by an increase in the skeletal uptake and spacing of double calcein labels and the immediate generation of thicker more numerous and interconnected trabeculae. A 40% increase in cancellous bone volume was observed in the lumbar spine in comparison with age-matched virgin controls. In contrast, a rapid succession of 3 pregnancy cycles (including lactation) culminated in cancellous atrophy of 15% at the same site, with a loss in trabecular number ranging from 20% (caudal vertebra) to 30% (lumbar vertebrae). In comparison, the proximal femur lost 40% of its struts but, nevertheless, uniquely sustained its cancellous bone volume. When lactation was excluded the number of struts lost was halved although trabecular thinning then took place which was sufficient to maintain the previous 15% deficit in bone volume. It was concluded that a single pregnancy strengthens the cancellous component of the maternal skeleton while a quick succession of pregnancies weakens it. Lactation influences the pattern of bone loss but not its amount.     

Influence of Aetiology, Clinical and Histological Features on Survival in Chronic Active Hepatitis: An Analysis of 204 Patients

To determine which clinical and laboratory features may influencesurvival in patients with chronic active hepatitis, we undertooka retrospective study of 204 patients seen on this unit overa 15-year period and applied logistic regression analysis. Onehundred and six patients had autoimmune chronic active hepatitis,69 ‘cryptogenic’ chronic active hepatitis (no autoimmunemarkers or other aetiological factors identified), and 29 wereHBsAg-seropositive. Variceal haemorrhage, encephalopathy andascites were common presenting features in the cryptogenic groupwhile the presence of jaundice and other immunopathic diseasesdid not differ between the groups. Cirrhosis was more commonat presentation in the cryptogenic group. Remission was inducedwith corticosteroids and azathioprine in 82 per cent of patientswith autoimmune chronic active hepatis and in 77 per cent ofpatients with cryptogenic chronic active hepatitis and the annualrelapse rate was similar in the autoimmune and cryptogenic groups.Five-year survival was 87 per cent in the autoimmune group,65 per cent in the cryptogenic group, and 80 per cent in thosewith HBsAg-positive disease, and on logistic regression analysis,the presence of cirrhosis at presentation was the only independentfactor which adversely affected survival. Overall survival inthe cirrhotic patients at five and 12 years was 63 and 48 percent respectively compared with 95 and 92 per cent in thosewithout cirrhosis.     

COLON CANCER AND POLYPS IN ACROMEGALY: INCREASED RISK ASSOCIATED WITH FAMILY HISTORY OF COLON CANCER

A cohort of 52 subjects diagnosed with acromegaly in southeastern Michigan and northern Ohio between 1935 and 1985 were followed to determine the incidence of colon cancer and polyps. Medical records were reviewed, subjects or their next-of-kin were interviewed, and screening examinations of the colon were offered to the living patients who were located. Data on demographics, personal histories of cancer and colon polyps, family history of colon cancer, and cure from acromegaly were obtained for both living and deceased subjects. The risk for colon cancer compared to the general population was estimated using standardized incidence ratios (SIRs). The expected number of cases was determined utilizing age, sex and race-specific rates provided by the cancer registry in southeastern Michigan. Among the 52 subjects, one could not be located and nine were deceased, none from colon cancer, with one known to have a history of colon polyps. Of 13 (31%) who declined the screening physical, one had a history of polyps and none reported a history of colon cancer. Two of 29 screened patients were found to have right-sided adenocarcinoma of the colon. Of the entire cohort, eight people (including one deceased) had a current or previous diagnosis of polyps, with five known to be histologically adenomatous. The SIR for colon cancer was 4.7 (95% confidence interval 0.6-17.1). Seven subjects, including the two with detected adenocarcinoma and four of the six living subjects with polyps only, reported a family history of colon cancer. The SIR for the subset of subjects with a family history of colon cancer was 29.1 (95% confidence interval of 3.5-104.6).(ABSTRACT TRUNCATED AT 250 WORDS)