Risk of left ventricular dysfunction in patients with probable Alzheimer's disease with APOE*4 allele

OBJECTIVE: To examine the association between the APOE genotype and cardiovascular disease in Alzheimer's disease (AD) patients. DESIGN: Case register study of 100 consecutive referrals to a Memory Clinic where type of dementia and cardiovascular comorbidity were diagnosed and APOE genotype was determined. SETTING: The Memory Clinic, University Hospital Rotterdam Dijkzigt. PARTICIPANTS: One hundred Memory Clinic patients, 59 to 91 years of age, who attended the Memory Clinic in the period between January 1994 and March 1996. MEASUREMENTS: Relative risk of cardiovascular morbidity in probable AD, based on clinical and ECG findings. RESULTS: The diagnosis of probable AD was more frequent in APOE*4 allele-carrying AD patients. When comparing homozygotes for APOE*4 with homozygotes for APOE*3, a nine-fold increase in prevalence of cardiac ischemia on ECG was found in the former. When grouping parameters of left ventricular dysfunction, the prevalence was 7.2 (95% confidence interval 1.2-42.6) times greater in probable Alzheimer patients with APOE4/4. CONCLUSIONS: In patients with probable AD, APOE*4 is associated with cardiac disease indicative of left ventricular dysfunction.     

Respiratory insufficiency in neuronopathic and neuropathic disorders

Twenty-nine patients with a neuronopathic or neuropathic disorder were referred for assessment of respiratory insufficiency between 1978 and 1994. Diagnoses included spinal muscular atrophy (6), chronic idiopathic demyelinating neuropathy (4), Vialetto-van Laere syndrome (3), hereditary motor and sensory neuropathy (3) and a miscellaneous group (5). We also describe seven patients with Guillain-Barré syndrome (GBS) who required long-term ventilatory support for over 6 months to 7 years after the initial illness. Respiratory insufficiency occurred as a consequence of respiratory muscle weakness, impaired bulbar function and restrictive lung defects. In some groups presentation was with progressive nocturnal hypoventilation culminating in acute respiratory failure. Five patients with GBS or chronic idiopathic demyelinating neuropathy were weaned from ventilatory support up to 18 months after the initial illness. The remaining 24 patients required continuous or nocturnal ventilatory support using intermittent positive-pressure ventilation (13), negative pressure ventilation (4), nasal-mask-delivered intermittent positive-pressure ventilation (4), nasal-mask-delivered continuous positive-pressure ventilation (3), mouthpiece-assisted ventilation by day (2) and rocking bed (1). None have been weaned from support after a period of ventilation ranging from one month to 10 years. Eight patients have subsequently died.     

Isolated hyperthermia chemotherapy perfusion for limb melanoma

Safe techniques for regional chemotherapy of the limbs by perfusion are now available. The method is effective in obtaining regionally confined high levels of toxic drugs or chemotherapeutic agents in the isolated areas. The best responses have been observed in limb melanoma with recurrent or intransit disease. Chemotherapy by perfusion as an adjunct to surgical excision reduces the local recurrence and the regional and lymph node metastases. Our survivals for adjunctive perfusion for Stage I melanomas with Level V and lesions 5 mm thick and thicker are better than usually reported. Regional chemotherapy has had an important role in reduction of major amputations for the control of limb melanoma. Multiple chemotherapeutic limb perfusions can further extent survival in patients with recurring melanoma.     

Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF

For 10 consecutive patients in our unit who did not show a significant rise in blood progenitor cells within 14 days following chemotherapy and G-CSF, we increased the G-CSF dose from 5 to 10 microg/kg/day (n = 9) or from 10 to 15 microg/kg/day (n = 1). As a result, there were significant increases in total yield as well as yield per apheresis of mononuclear cells, CD34+ cells and CFU-GM (P < 0.025, <0.01 and <0.005, respectively). After G-CSF dose escalation, six of the 10 patients had sufficient CD34+ cells for performing transplantation. These results demonstrate a dose-dependent response of progenitor cell mobilization by G-CSF when used in combination with chemotherapy. Moreover, increasing the dose of G-CSF as late as the third week of mobilization may still provide sufficient cell yield even with patients who did not show a significant mobilization with conventional doses of G-CSF.     

Alteration of the cytokine phenotype in an experimental lung granuloma model by inhibiting nitric oxide

Pulmonary granulomatous inflammation modulated by IFN-gamma and IL-12 is also associated with augmented inducible nitric oxide synthase (NOS II). To address the role of increased nitric oxide synthesis in this model, mice received daily i.p. injections of NG-nitro-L-arginine-methyl ester (L-NAME; 8 mg/kg) during both the 2-wk immunization period with purified protein-derivative (PPD) and the subsequent lung challenge with PPD-coated Sepharose beads. Other groups of animals received saline, L-NAME or NG-nitro-D-arginine-methyl ester (D-NAME; 8 mg/kg) during the pulmonary embolization period and not the PPD sensitization period. On day 4 post-PPD bead challenge, PCR analysis of the whole lung revealed that NOS II expression appeared to be similar in both of the L-NAME treatment protocols. L-NAME-treated mice in both dosing protocols had lung lesions that were significantly larger than granuloma lesions measured in mice that received saline or D-NAME. The enlarged lesions from L-NAME-treated mice contained markedly greater numbers of neutrophils and eosinophils. Equivalent numbers of PPD-activated dispersed cells from whole lungs of L-NAME-treated mice produced significantly higher levels of IL-4 and IL-10 and smaller amounts of IL-12 and IFN-gamma compared with similar lung cultures derived from control or D-NAME-treated mice. Levels of C-C chemokines such as monocyte chemoattractant protein-1 (MCP-1), C10, and macrophage inflammatory protein-1alpha (MIP-1alpha) were also significantly elevated in lung cultures from L-NAME-treated mice compared with controls. Thus, nitric oxide regulates the size and cellular composition of the Th1-type lung granuloma, possibly through its effects on the cytokine and chemokine profile associated with this lesion.     

Accidental exposure to blood and the risk of transmission of virus infections for various occupational groups in Amsterdam, 1986-1996

Since 1986 the number of parenteral exposures to potentially infectious blood reported to the Amsterdam Public Health Service increases every year. The number of needlestick accidents increased significantly from 64 in 1986 to 166 in 1996 whereas the number of other exposures decreased from 59 to 44 in these years. The increase was mainly seen in nonhospital based (para)medics. A possible explanation of this increase is greater awareness of the potential infection risk with HIV, hepatitis B or C virus leading to a tendency to report more readily. This assumption is in contradiction with results of studies in hospital-based personnel where a decrease is observed as a result of educational programmes. Other explanations are a higher frequency of use of sharp instruments and (or) an increase in the workload. Out of a total of 1886 needlestick accidents in 1986-1996 one woman became HIV positive; she was deliberately infected by her ex-partner who injected her with blood of an AIDS patient, and one person contracted an hepatitis C virus infection: a policeman wounded by a needle used by a drug addict.     

A distinct form of spondyloepimetaphyseal dysplasia with multiple dislocations

Three unrelated patients with identical radiological features are presented. Hypotonia was noted at birth and one patient was diagnosed as having congenital fibre type disproportion in the neonatal period. Later muscle biopsies, however, were entirely normal. All patients, now in their teens and twenties, are of normal intelligence, show striking epiphyseal and metaphyseal changes of the long bones, and have joint laxity and multiple dislocations of large joints, which are particularly incapacitating at the knees. These three cases represent a sporadic, previously unreported skeletal dysplasia with spondyloepimetaphyseal distribution and multiple large joint dislocations.     

Fewer bone histomorphometric abnormalities with intermittent than with continuous slow-release sodium fluoride therapy

To help resolve the uncertainty whether sodium fluoride (NaF) therapy should be given intermittently or continuously, we examined iliac crest bone biopsies (before and after treatment) and fragility fracture rates in 35 intermittently treated (group I) and 69 continuously treated (group C) patients; all received calcium. The following statistically significant results were obtained. Reduction in vertebral fracture rate was similar in the two groups. Trabecular thickness and the structurally more important mineralized thickness increased only in group I. Group I also accumulated less excess osteoid (surface, volume). Mean osteoid thickness did not change in either group because of a bimodal distribution of wide seams with osteoblasts and double tetracycline labels, and thin seams without osteoblasts or labels. Osteoid was lamellar. Osteoid in abnormal sites (within bone marrow or bone, or around osteocytes) was found less frequently in group I. Adjusted apposition rate declined and mineralization lag time increased in both groups because of extended unlabelled osteoid seams. Erosion surface increased only in group C. Hook and/or tunnel erosion was seen less frequently in group I; it was closely associated with osteoid in abnormal sites and correlated with osteoid surface. Extended osteoid surface may have forced osteoclasts to hollow out trabeculae, leaving the empty osteoid shell in marrow. Excess osteoid volume and eroded surface and osteoid and erosion in abnormal sites correlated with bone fragility in group C. We conclude that intermittent therapy is to be preferred because it (1) increased mineralized trabecular thickness, (2) did not cause excessive osteoid accumulation and erosion, (3) showed less osteoid and erosion in abnormal sites and (4) led to a similar reduction in the vertebral fracture rate as did continuous treatment. The question of whether intermittency of therapy has some other effect independent of the cumulative dose of fluoride administered cannot be answered by this study.