The impact of REACH on classification for human health hazards.

The REACH Regulation represents a major piece of chemical legislation in the EU and requires manufacturers and importers of chemicals to assess the safety of their substances. The classification of substances for their hazards is one of the crucial elements in this process. We analysed the effect of REACH on classification for human health endpoints by comparing information from REACH registration dossiers with legally binding, harmonised classifications. The analysis included 142 chemicals produced at very high tonnages in the EU, the majority of which have already been assessed in the past. Of 20 substances lacking a harmonised classification, 12 chemicals were classified in REACH registration dossiers. More importantly, 37 substances with harmonised classifications for human health endpoints had stricter classifications in registration dossiers and 29 of these were classified for at least one additional endpoint not covered by the harmonised classification. Substance-specific analyses suggest that one third of these additional endpoints emerged from experimental studies performed to fulfil information requirements under REACH, while two thirds resulted from a new assessment of pre-REACH studies. We conclude that REACH leads to an improved hazard characterisation even for substances with a potentially good data basis.

[Recurrent hypoglycemia and a large intraabdominal tumor in a 61-year-old woman]. / Rezidivierende Hypoglykämien und ein großer intraabdominaler Tumor bei einer 61-jährigen Patientin.

HISTORY AND ADMISSION FINDINGS: A 61-year-old woman was found unconscious by her husband. The emergency doctor detected hypoglycemia (blood glucose 1.7 mmol/l). This was the first such event, the patient had not been known to have diabetes mellitus. At admission the physical examination and the laboratory findings revealed no abnormalities. INVESTIGATIONS: A fasting test was aborted shortly after the start because of the onset of neurological symptoms. An insulinoma was excluded by detecting suppressed levels of insulin and C-peptide. Computed tomography of the abdomen revealed a mesenteric tumour of 9 cm in diameter, which was identified immunhistologically as a grade 1 follicular lymphoma (FL).  After exclusion of endocrinological causes the recurrent hypoglycaemia was diagnozed as part of a paraneoplastic syndrome associated with a non-islet cell tumour hypoglycaemia (NICTH) with a newly diagnosed FL. TREATMENT AND COURSE: Specific medication with the CD20 antibody rituximab (375 mg/m2, once per week for a total of four cycles) was initiated. There were no further episodes of hypoglycaemia. After one year the patient remains free of any symptoms. CONCLUSIONS: After exclusion of any endocrinological reasons for hypoglycemia, differential diagnosis should include NICTH as paraneoplastic syndrome. In rare cases a hematological malignancy may be the underlying disease. The specific treatment of this disease likewise represents the causal treatment of NICTH.

[Effect of stimulus rise time and high-pass masking on early auditory evoked potentials]. / Der Einfluss der Reizanstiegszeit und der Hochpassmaskierung auf die frühen auditorisch evozierten Potentiale.

BACKGROUND: Problems of frequency-specific objective assessment of hearing threshold by means of auditory brainstem response (ABR) have been discussed recently. While a number of workers have recommended methods of selective masking to improve the frequency specificity, others believe that frequency-specific potentials can also be obtained without masking. In this context, the effects of rise-decay time and high-pass masking on ABRs were investigated. METHOD: ABRs were recorded in normal-hearing subjects and patients with high and low frequency hearing loss by means of surface electrodes between the vertex and the ipsilateral mastoid. The frequency of the stimulus was 1 kHz, and the rise-decay time 1 ms (1-0-1) or 2 ms (2-0-2). High-pass filtered noise (cutoff frequency 1.5 kHz; filter slope 250 dB/octave) was employed for masking. Particular attention was paid to the problem of efficient masking. RESULTS: In normal-hearing subjects under the influence of high-pass masking compared to non-masked ABRs, longer mean latencies and diminished means of the amplitudes of wave V were found, with differences in the near-threshold domain being less pronounced. Similar results were observed in patients with high frequency hearing loss. In patients with low frequency hearing loss, the influence of high-pass masking was especially marked distinctly near to threshold. Furthermore, latency and amplitude differences of wave V of the 1-0-1 and the 2-0-2 stimuli were determined from the ABRs obtained with and without high-pass masking. The differences between the latency differences of both stimuli in the suprathreshold range (70 dB nHL) only were statistically significant. CONCLUSIONS: The results are suggestive of an inadequate frequency specificity of unmasked stimuli in the suprathreshold range. Evaluation of the latencies revealed for both rise-decay times a similar frequency specificity near the threshold and a higher frequency specificity of the longer stimulus in the suprathreshold range.

Ultrastructural localization of the putative precursors of the A4 amyloid protein associated with Alzheimer's disease.

Any explanation of the causes of Alzheimer's disease and of its unique cerebral pathologic features must take into account the distribution and ultrastructural localization of the pre-A4 amyloid proteins in tissues and organs. The authors have analyzed the expression of the pre-A4 amyloid proteins in several tissues by immunogold electron microscopy and by immunofluorescence. For this purpose, they have used a mouse monoclonal antibody and a guinea pig antiserum raised against two synthetic peptides corresponding to two different sequences common to all the full-length forms of the A4 amyloid precursors. They observed a tissue-specific distribution of the secreted and the transmembrane form of the precursors. The authors could determine that the secreted form is generated in vivo within the cytoplasm. In the salivary glands and in the adenohypophysis, all the immunoreactivity is associated with the process of secretion, whereas in the muscle, a staining pattern compatible with the presence of the pre-A4 amyloid proteins in the sarcoplasmic reticulum has been observed. This difference in the localization may reflect tissue-specific processing pathways and suggests that posttranslational modifications such as proteolytic removal of the transmembrane and cytoplasmic domains contribute to the structural and thus functional diversity of the A4 amyloid precursors.

Identification, biogenesis, and localization of precursors of Alzheimer's disease A4 amyloid protein.

To study the putative precursor proteins (PreA4(695), PreA4(751), and PreA4(770] of Alzheimer's disease A4 amyloid protein, polyclonal and monoclonal antibodies were raised against a recombinant bacterial PreA4(695) fusion protein. These antibodies were used to identify the precursors in different cell lines as well as in human brain homogenates and cerebrospinal fluid (CSF). The precursors are tyrosine-sulfated, O- and N-glycosylated membrane proteins and have half-lives of 20-30 min in cells. Cells express the polypeptides at their surface but also secrete C-terminal truncated proteins into the medium. These proteins are also found in CSF of both Alzheimer's disease patients and normal individuals. The proteins are derived from their cognate membrane-associated forms by proteolysis and have apparently lost the cytoplasmic and the transmembrane domains. Since the latter contributes to the A4 amyloid sequence, it seems possible that this proteolytic cleavage represents the first step in the formation of A4 amyloid deposits.