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PurposeNew models of thinking, organization and governance are needed when health systems are under pressure. Inspired by a recent Danish community project called Your Health, this paper sheds light on the nexus of health promotion, sport and well-being, and how an increased focus on synergies can improve public health capacity in the future.Design/methodology/approachThe three areas of interests are presented, and challenges and opportunities are discussed along with the lessons learned from the Danish community project serving as an example of an integrated approach. The project was hosted by a sports club with the aim to enhance the health and well-being of new members, engage volunteers as health motivators and develop new activities in partnership with community organizations.FindingsThe discussion on creating synergies between sport, health promotion and well-being inspired a new model encouraging moving away from silo-thinking towards the sweet-spot where all three perspectives are represented. In this way, public health can be developed to the next level, in particular with regards to actions taking place outside the health sector.Research limitations/implicationsMore research is warranted to develop the evidence that can push for a changed policy agenda and showcase the social and economic return on investments.Practical implicationsThere is a growing interest to support health and well-being. Capacity building is needed to engage non-health stakeholders actively in the health agenda.Originality/valueDespite the need for progress, research is still scarce. Thus, it is important to create a new momentum among relevant stakeholders to facilitate the integration of sport, health promotion and well-being to qualify and expand public health capacity, create better health for all and bridge inequity.

AIMS: To examine the association between personnel resources and organisational features of primary health care centres (PHCCs) and individual HbA1c level in people with Type 2 diabetes mellitus (T ...

Aims: To describe and analyse the associations between primary health care centres’ (PHCCs’) quality of work (QOW) and individual HbA1c levels in people with Type 2 diabetes mellitus (T2DM). Methods: This cross-sectional study invited all 1152 Swedish PHCCs to answer a questionnaire addressing QOW conditions. Clinical, socio-economic and comorbidity data for 230,958 people with T2DM were linked to data on QOW conditions for 846 (73.4%) PHCCs. Results: Of the participants, 56% had controlled (≤52 mmol/mol), 31.9% intermediate (53–69 mmol/mol), and 12.1% uncontrolled (≥70 mmol/mol) HbA1c. An explanatory factor analysis identified seven QOW features. The features having a call-recall system, having individualized treatment plans, PHCCs’ results always on the agenda, and having a follow-up strategy combined with taking responsibility of outcomes/results were associated with lower HbA1c levels in the controlled group (all p

Aims To examine if personnel resources and organisational features in Swedish primary health-care centres (PHCCs) are associated to all-cause mortality (ACM) in people with type 2 diabetes mellitus (T2DM). Methods A total of 187,570 people with T2DM registered in the Swedish National Diabetes Register (NDR) during 2013 were included in this nationwide cohort study. Individual NDR data were linked to data from a questionnaire addressing personnel resources and organisational features for 787 (68%) PHCCs as well as to individual data on socio-economic status and comorbidities. Furthermore, data on ACM were obtained and followed up until 30 January 2018. Hierarchical Cox regression analyses were applied. Results After a median follow-up of 4.2 years, 27,136 (14.5%) participants had died. An association was found between number of whole-time-equivalent (WTE) general practitioner’s (GP’s) devoted to diabetes care/500 people with T2DM and lower risk of early death (hazard ratio 0.919 [95% confidence interval 0.895–0.945] per additional WTE GP; p = 0.002). No other personnel resources or organisational features were significantly associated with ACM. Conclusions This nationwide register-based cohort study suggests that the number of WTE GPs devoted to diabetes care have an impact on the risk of early death in people with T2DM.

To examine the association between personnel resources and organisational features of primary health care centres (PHCCs) and individual HbAPeople with T2DM attending 846 PHCCs (n=230958) were included in this cross-sectional study based on PHCC-level data from a questionnaire sent to PHCCs in 2013 and individual-level clinical data from 2013 for people with T2DM reported in the Swedish National Diabetes Register, linked to individual-level data on socio-economic status and comorbidities. Data were analysed using a generalized estimating equations linear regression models.After adjusting for PHCC- and individual-level confounding factors, personnel resources associated with lower individual HbAIn this large sample, PHCC personnel resources and organisational features were associated with lower HbA

This report concerns two patients, a 43-year-old woman and a 53-year-old man, who developed clinical as well as laboratory signs of permanent gonodal and thyroid failure following an acute intracranial infection--in the woman a meningoencephalitis of unknown origin, and in the man an encephalitis caused by Coxsackie B5. Endocrine investigations were compatible with hypothalamic-pituitary dysfunction, with some of the results favoring a hypothalamic lesion. Perhaps hormone deficiency of hypothalamic and/or pituitary origin is a more common sequel of acute meningoencephalitis than has hitherto been reported.

In a longitudinal study, 21 patients with familial amyloidosis with polyneuropathy (FAP) were followed up for more than three years. Gastrointestinal symptoms ultimately evolved in all patients. In the advanced stage of the disease, 13 patients had diarrhea together with anal incontinence. Weight loss was very common and related to both malabsorption and motility disturbances with anorexia and also to muscular atrophy. Steatorrhea was found in 19 patients at least once during the follow-up. The duration of the disease was significantly correlated to fecal fat output. The conclusion was drawn that the gastrointestinal involvement in FAP is very common and of great clinical importance. The consequences of malnutrition also influence the outcome of the disease.

Eighteen Swedish patients with familial amyloidotic polyneuropathy were tested for the met30 mutation of the transthyretin (TTR) (prealbumin) gene by RFLP analysis of genomic DNA using the restriction enzyme NsiI. The results confirmed previous findings that the Swedish variant of familial polyneuropathy has the same valine by methionine substitution at position 30, as seen in patients with FAP from Japan, Portugal or patients of Swedish descent from USA. However, two of the patients were homozygous, totally lacking the wild type allele. Measurable serum values for the variant transthyretin (TTR) was detected with a RIA-method in all the 18 Swedish FAP patients studied with a mean concentration of 12.1 +/- 5.1 (SD) mg/100 ml, (11.0 +/- 4.1 when the two homozygotes were excluded). In 45 Japanese patients the mean was 9.2 +/- 2.7 mg/100 ml. The variant TTR was not detected in the healthy controls. The value for the variant TTR was nearly twice that high in the two homozygous patients, 21.14 and 21.16 mg/100 ml, respectively. There was no correlation between the serum levels of variant TTR and the duration of disease or levels of serum albumin in the FAP-patients.

Twenty-four consecutive patients with familial amyloidosis with polyneuropathy (type 1), who were at different stages of the disease were investigated. The purpose was to report the electrophysiological features and to compare them with those found in other generalized neuropathies; 12 cases were familiar and 12 cases were sporadic. The diagnosis was confirmed by examining the occurrence of amyloid substance in rectal or skin biopsies or both. Single fiber EMG with fiber density determination showed signs of collateral innervation, prominent in advanced cases, and a disturbance of neuromuscular function similar to that of progressive spinal motorneurone diseases. Action potentials from afferent fibers were not obtained in 91 % of the nerves in the lower and 49 % of the nerves in the upper extremities. When sensory or motor action potentials were obtained, the conduction velocities were normal or slightly subnormal. The neurophysiological findings indicate a symmetrical axonal degeneration, starting in the legs. Familial amyloidosis with polyneuropathy should be suspected in cases of rapidly progressing polyneuropathy of axonal type with onset in middle age, irrespective of whether they are hereditary or not.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The amyloid fibrils contain a variant transthyretin (TTR) molecule (TTR met30), over 90% of which is produced in the liver. After liver transplantation in two patients with severe symptomatic FAP, only normal TTR was detectable in circulation. The two patients are being monitored at regular intervals, and, although in one patient there was no evidence of reduction in the quantity of amyloid present at 6 months, there had been no further progression of the neuropathy.

Aim: To compare effects of early insulin vs. glibenclamide treatment on beta-cell function, metabolic control and quality of life (QL) in recently diagnosed patients with type 2 diabetes. Methods: Forty-nine patients with type 2 diabetes diagnosed 0-2 years before inclusion were randomized to two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide at six diabetic clinics in Sweden. C-peptide-glucagon tests were performed yearly after 3 days of withdrawal of treatment. Results: Thirty-four patients completed 4 years of study. Daily dose of insulin was increased from 20.4 +/- 1.8 U at year 1 to 26.1 +/- 2.9 U at year 4 (p = 0.005). Glibenclamide dosage increased from 2.7 +/- 0.4 mg at year 1 to 4.5 +/- 0.8 mg at year 4 (p = 0.02). Weight increased more in insulin than in glibenclamide treated (+4.4 +/- 0.8 vs. +0.3 +/- 1.0 kg, p < 0.005). Following short-term withdrawal of treatment, the C-peptide responses to glucagon were significantly higher in the insulin vs. glibenclamide group at years 1 (p < 0.01) and 2 (p < 0.02). HbA1c improved identical during the first year but thereafter deteriorated in the glibenclamide group (p < 0.005 for difference at year 4). Ratios of proinsulin to insulin were higher during treatment in glibenclamide- vs. insulin-treated patients after year 2. QL after 4 years as measured by the MOS 36-item Short-Form Health Survey (SF-36) form was not significantly altered. Conclusions: In a 4-year perspective, beta-cell function deteriorated in both groups. However, deterioration occurred faster in the glibenclamide group, indicating that alleviating demands on secretion by insulin treatment is beneficial. (Less)

As part of the preparations for the accession of Slovenia to the European Union, the National Health Insurance Institute has introduced a European model for quality management. In this regard, a benchmarking has been carried out, comparing the Health Insurance Institute of Slovenia with the Accounts Office of Cumbernauld in the UK. This was a so‐called generic benchmarking between two public service organisations in different fields and it was made by third parties focusing on the quality of the processes of the two organisations. The results of the comparative analysis show that the health insurance institute has strong financial management, supported by a well‐developed model for partnership negotiations and advanced applications of information technology. There are, however, weaknesses in the management of human resources and quality improvements. To counteract these weaknesses requires a cultural change within the health insurance institute.

Holmgren G, Bergstrom S, Drugge U, Lundgren E, Nording-Sikstrom C, Sandgren O, Steen L. Homozygosity for the transthyretin-Met30-gene in seven individuals with familial amyloidosis with polyneuropathy detected by restriction enzyme analysis of amplified genomic DNA sequences. Clin Genet 1992:41:39–41. Familial amyloidotic polyneuropathy (FAP) with a mutation in position 30 of transthyretin (TTR) (previously called prealbumin) is an autosoma! dominant inherited disorder characterized by varying degrees of peripheral neuropathy, nephropathy, gastrointestinal problems, and vitreous amyloid. We have earlier diagnosed homozygosity for the TTR-Met30-gene using Southern analysis in four Swedish individuals. We have found it possible to detect homozygosity for the Met-30 mutation by amplifying discrete regions of the TTR-gene using polymerase chain reaction (PCR), and the amplification products restricted with Nsil analysed by gel electro-phoresis. Clinical data on seven homozygous individuals, including three new cases, are presented.

L-threo-DOPS is a synthetic precursor to norepinephrine (NE). In order to study its efficacy and dosage, we carried out an open pilot study in ten patients with orthostatic hypotension and a confirmed diagnosis of familial amyloidoticpolyneuropathy (FAP). The initial dosage was 200 mg of L-threo-DOPS daily, with a weekly increment of 100 mg, until a maintenance dose was reached. Ten patients were treated for 12 weeks and five of them for 24 weeks. The blood pressure (BP) and pulse rate were monitored weekly. Before treatment, after four and 12 weeks, the patients underwent clinical and laboratory examinations. Nine patients completed the study. There was a rise in mean BP values in all measurements. After 12 weeks of treatment the rise in mean systolic BP values were statistically significant (p < 0,01) in all measurements in upright position. When treatment was withdrawn BP fell to almost the same levels as before and when treatment was restarted (five patients), there was again a rise in mean BP values....

Familial amyloidotic polyneuropathy (FAP) is an inherited fatal form of amyloidosis caused by mutant transthyretin. The disease is characterized by progressive peripheral and autonomic neuropathy. Most of the transthyretin is produced by the liver, and we have shown previously that the metabolic deficiency can be corrected by liver transplantation. In the present study, the clinical results from the first 20 patients who underwent liver transplantation for FAP in Sweden are evaluated. Three of the patients suffered from renal failure and underwent a simultaneous kidney transplantation. Fourteen of the 20 patients (70%) are alive 10-52 months after transplantation. The patients' nutritional status at the time of transplantation had a significant impact on mortality and morbidity (P < 0.007). Long-standing disease was another negative prognostic factor (P < 0.02). One year after transplantation, the nutritional status had improved (P < 0.02). Improvements were also noted in walking capacity and for gastrointestinal and urogenital symptoms. The results show that liver transplantation offers an effective means to treat patients with FAP. The procedure should preferably be performed before the nutritional status is poor and advanced organ dysfunction has developed.

The First International Workshop on liver transplantation in patients with familial amyloid polyneuropathy (FAP) was held at Huddinge Hospital in Stockholm, Sweden, September 10–11, 1993. Information was presented on 64 liver transplant recipients treated at 15 centers in 10 countries. Twenty-two patients had a follow-up time of more than 12 months, the longest follow-up was 41 months. Fifty-three patients had survived the procedure, while 11 had died within 8 months after the operation. The 1 and 2 year actuarial patient survival rate was 67 per cent. In most of the 22 patients surviving more than 1 year, the neurological symptoms had stabilized and the beneficial effect was most apparent as regards symptoms from the autonomic nervous system. There was consensus among the participants at the Workshop that liver transplantation for FAP is a worthwhile procedure and that such transplantation activities should continue. Transplantation should preferably be performed before the symptoms become severe and whi...

BACKGROUND: Early insulin treatment is considered more beneficial than anti-diabetic medication with sulphonylureas, because the latter may exert negative effects on beta-cell function, while the former may help preserve it. In a previous study, we found that C-peptide response was increased in the insulin-treated group, whereas it was decreased in the glibenclamide group. However, it was not certain whether the advantage remained in the longer term. AIM: In this study, we tested whether early insulin treatment is more beneficial than glibenclamide against a 6-year follow-up perspective. METHODS: We designed a randomized clinical trial in subjects with newly diagnosed type 2 diabetes. Glucagon stimulatory tests, measuring C-peptide and islet amyloid polypeptide (IAPP), were performed after 2, and 3, days of temporary insulin and glibenclamide withdrawal. RESULTS: 18 subjects initially randomized to glibenclamide, and 16 randomized to two daily injections of insulin, participated in end-of-study investigations. C-peptide response to glucagon deteriorated (p < 0.01 vs. baseline) in initially glibenclamide-treated patients (n = 18), but not in insulin-treated patients (p < 0.05 for difference between groups, after 2 days of treatment withdrawal). The IAPP response to glucagon declined in the glibenclamide group (p < 0.001), but not in insulin-treated subjects (p = 0.05 for difference between groups). CONCLUSIONS: Early insulin treatment preserves beta-cell secretory function better than glibenclamide even in a 6-year perspective.

Familial amyloid polyneuropathy (FAP) is a fatal autosomal dominant disorder. Progressive peripheral and autonomic neuropathy are associated with neural and visceral deposition of amyloid, derived most commonly from the Met-30 variant of the plasma protein transthyretin. We have reported previously that orthotopic liver transplantation causes prompt replacement of variant transthyretin by the donor wild-type in the plasma. We now report clinical outcome 1-2 years after transplantation. Three of the first four patients have improved general wellbeing, walking ability, and bowel function, and one of them has regained normal bladder and bowel function. There has been little objective improvement in peripheral neuropathy. The fourth patient, who had the most severe neurological deficits and a complicated postoperative course, has not improved but there has been no further deterioration in contrast to the inexorable progression before transplantation. Quantitative scintigraphy with radiolabelled serum amyloid P component showed visceral amyloid deposits in all three patients studied; in two who were followed serially the deposits regressed after transplantation in association with the clinical improvement. Another FAP patient who was also monitored prospectively for 2 years but who did not undergo transplantation, showed, as expected, progression of neuropathy and increased visceral amyloid deposition. Liver transplantation does therefore have important benefits in FAP during the first 2 years after surgery. Neurological decline is halted and amyloid deposits can be mobilised. The best timing and long-term results of the procedure must now be established.

The structure of a variant transthyretin has been determined by X-ray crystallography at 2.3 A resolution in order to investigate those changes which lead to amyloid formation. This variant transthyretin, in which the internal valyl residue at position 30 is replaced by methionyl, is associated with the most common form of familial amyloidotic polyneuropathy (FAP). Comparison to the known structure of the normal transthyretin tetramer shows that the bulkier methionine residue 30 which lies between the nearly orthogonal beta sheets of the dimer, results in the sheets being displaced an average of 0.4 A. The internal structure of the sheets and of the monomer-monomer interface is maintained. Such global changes may affect the metabolic properties and the tendency towards polymerization of the mutant protein. These findings may form a basis for understanding other amyloid-deposition diseases.

Gastrointestinal dysfunction due to autonomous neuropathy is a complication described in various diseases such as diabetes mellitus, multiple sclerosis, and familial amyloidosis with polyneuropathy. We present the results of a prospective investigation of bile acid malabsorption in 17 patients with familial amyloidosis by means of 75Se-labelled homocholic-tauro acid (SeHCAT). The diagnosis was in all cases verified by the DNA test for mutation of transthyretin in position 30. Small-intestinal biopsy specimens were examined for deposits of amyloid, and the presence of gastric retention was evaluated by gastroscopy. In addition, the patients were investigated for bacterial overgrowth by means of the bile acid breath test (BABT). A high frequency of abnormal BABT results (44%) was encountered. However, 65% also had abnormal low SeHCAT values, indicating bile acid malabsorption. Only two patients had abnormal BABT and normal SeHCAT results, indicating bacterial contamination of the small intestine. Bile acid losses increased with the duration of gastrointestinal symptoms. Significantly lower SeHCAT values were encountered in patients with gastric retention, whereas the occurrence of amyloid deposits in small-intestinal biopsy specimens was without effect on SeHCAT retention. Bile acid malabsorption is frequently encountered in familial amyloidosis with polyneuropathy and seems to be more closely associated with gastrointestinal motility dysfunction than with amyloid deposits in the intestinal mucosa.

Objectives: To examine the risk of developing adrenal carcinomas and clinically overt hypersecreting tumours during short-term follow-up in patients with adrenal incidentalomas. Design: 229 (98 males and 131 females) patients with adrenal incidentalomas were investigated in a prospective follow-up study (median time 25 months; range 3–108 months). The patients were registered between January 1996 and July 2001 and followed until December 2004. Twenty-seven Swedish hospitals contributed with follow-up results. Methods: Diagnostic procedures were undertaken according to a protocol including reinvestigation with computed tomography scans after 3–6 months, 15–18 months and 27–30 months, as well as hormonal evaluation at baseline and after 27–30 months of follow-up. Operation was recommended when the incidentaloma size increased or if there was a suspicion of a hypersecreting tumour. Results: The median age at diagnosis of the 229 patients included in the follow-up study was 64 years (range 28–84 years) and the median size of the adrenal incidentalomas when discovered was 2.5 cm (range 1–8 cm). During the follow-up period, an increase in incidentaloma size of ≥0.5 cm was reported in 17 (7.4%) and of ≥1.0 cm was reported in 12 (5.2%) of the 229 patients. A decrease in size was seen in 12 patients (5.2%). A hypersecreting tumour was found in 2% of the hormonally investigated patients: Cushing’s syndrome (n = 2) and phaeochromocytoma (n = 1). Eleven patients underwent adrenalectomy, but no cases of primary adrenal malignancy were observed. Conclusions: Patients with adrenal incidentaloma had a low risk of developing malignancy or hormonal hypersecretion during a short-term follow-up period.

OBJECTIVE—To evaluate whether treatment with insulin in recently diagnosed type 2 diabetes is advantageous compared with glibenclamide treatment. RESEARCH DESIGN AND METHODS—β-Cell function, glycemic control, and quality of life were monitored over 2 years in 39 patients with islet cell antibody-negative type 2 diabetes diagnosed 0–2 years before inclusion in a Swedish multicenter randomized clinical trial. Patients were randomized to either two daily injections of premixed 30% soluble and 70% NPH insulin or glibenclamide (3.5–10.5 mg daily). C-peptide-glucagon tests were performed yearly in duplicate after 2–3 days of temporary withdrawal of treatment. RESULTS—After 1 year the glucagon-stimulated C-peptide response was increased in the insulin-treated group by 0.14 ± 0.08 nmol/l, whereas it was decreased by 0.12 ± 0.08 nmol/l in the glibenclamide group, P < 0.02 for difference between groups. After 2 years, fasting insulin levels were higher after treatment withdrawal in the insulin-treated versus the glibenclamide-treated group (P = 0.02). HbA1c levels decreased significantly during the first year in both groups; however, at the end of the second year, HbA1c had deteriorated in the glibenclamide group (P < 0.01), but not in the insulin-treated group. The difference in evolution of HbA1c during the second year was significant between groups, P < 0.02. A questionnaire indicated no difference in well-being related to treatment. CONCLUSIONS—Early insulin versus glibenclamide treatment in type 2 diabetes temporarily prolongs endogenous insulin secretion and promotes better metabolic control.

In Sweden, hospital stays, deaths, sick‐ listings and censuses have long been stored on electronic media. The purpose of the study was to apply post‐hospital survival measures to hospitals having differing degrees of specialization by linking existing data in censuses and in‐patient registers. In‐patient records totaling 3.6 million were collected. They were linked to the 1985 and 1990 censuses regarding patients’ background data, and the national insurance register. Results found that the survival was longer and the return to work quicker when hospitals were well staffed, had competent personnel and many specialties. In general, small hospitals were worse off in all aspects. Concludes that small hospitals should be given better support.

Liver transplantation is the only effective treatment of familial amyloidotic polyneuropathy type I (FAP). The aim of the present investigation was to identify factors at the time of submission for transplantation that had impact on survival, with special reference to gastrointestinal disturbances. All 28 liver-transplanted FAP patients evaluated at Umea University Hospital were included in the study. A modified body mass index was used to assess nutritional status. Intestinal examinations were performed to diagnose bile acid malabsorption, gastric retention, and bacterial contamination of the small bowel. A significantly improved survival rate was found for patients in a good nutritional state (P = 0.002). Peripheral neurological symptoms were unrelated to survival, whereas increased mortality was found for patients with bile acid malabsorption (P < 0.05). Bacterial contamination and gastric retention were common complications of the disease. In conclusion, malabsorption and malnutrition have a profound impact on the outcome of liver transplantation for familial amyloidotic polyneuropathy.

Objectives. To describe the evolution of nutritional and neurological complications in a Swedish population of patients with familial amyloidotic polyneuropathy, and to identify prognostic factors and useful tests for monitoring the progress of the disease. Design. Prospective and retrospective study of patients with familial amyloidotic polyneuropathy. Setting. Tertiary referral centre. Subjects. Twenty-seven patients with familial amyloidotic polyneuropathy, and a symptomatic onset before the age of 50. Main outcome measures. Age at onset, duration of disease before death, serum albumin, body mass index (BMI), duration and grade of peripheral neuropathy and gastrointestinal disturbances. Faecal fat, xylose test and 75selenohomocholic acid-taurine (SeHCAT) test were used for assessment of malabsorption. Results. Thirteen patients died during the study period after a disease duration of between 9 and 18 years (mean 13). A short time interval between the onset of neurological and of gastrointestinal symptoms had greater impact on survival than age at onset in this selected group of patients (r = 0.65; P = 0.017). Malnutrition was evaluated by multiplying the [body weight (kg)/height2 (m)] with the serum albumin to compensate for oedema. This modified body mass index (mBMI) was significantly correlated to the number of years before death (r = 0.89; P < 0.0005) and to the duration of gastrointestinal symptoms (r = —0.66; P < 0.0005), but not to duration of disease (r = —0.2; P = 0.20). Polyneuropathy was graded according to functional capacity from I to IV (PND score) and was correlated to the number of years before death and mBMI, but not to serum albumin. The SeHCAT test for bile acid malabsorption was significantly correlated to the duration of gastrointestinal symptoms and to mBMI (r = —0.67; P = 0.0003 and r = —0.62; P = 0.003, respectively). Conclusion. The investigation disclosed that a short time interval between the onset of neurological and of gastrointestinal symptoms is associated with a decreased survival time. The mBMI was closely related to time before death, duration of gastrointestinal disturbances, malabsorption and functional capacity. The mBMI appears to be well suited to monitoring disease progress and gives prognostic information.

Patients who suffer from familial amyloidotic polyneuropathy frequently complain of mouth dryness and an increased need for dental treatment. The aim of the present investigation was to study saliva secretion rate and composition and other factors related to the risk of dental caries in patients with familial amyloidotic polyneuropathy. Thirty patients with familial amyloidotic polyneuropathy volunteered for the study and were compared with a matched control group. Samples of unstimulated and stimulated whole saliva were collected in a standardized manner. The secretion rates were calculated, and the concentrations of electrolytes, glycoprotein markers, and proteins with antibacterial properties were analyzed. Dental caries and variables related to the risk of dental caries were also scored. The results show that familial amyloidotic polyneuropathy patients frequently have a decreased rate of saliva secretion and that the degree of salivary hypofunction is positively correlated to the progress of familial amyloidotic polyneuropathy. Forty-three percent of the familial amyloidotic polyneuropathy patients in this study had no detectable secretion of unstimulated saliva. A low secretion rate of stimulated saliva (0.7 ml/min) was found in 33% of the patients. The concentrations of salivary protein, amylase, lysozyme, salivary peroxidase, secretory IgA, hexosamines, sialic acid, fucose, phosphate, potassium, and the degree of protein glycosylation were higher in the familial amyloidotic polyneuropathy patients than in the control patients. We conclude that patients with familial amyloidotic polyneuropathy have a reduced saliva secretion and are subsequently at risk for increased development of dental caries.

The molecular structure of the Met-30 variant of human serum prealbumin (transthyretin) has been determined by x-ray crystallography to 2.3 A resolution. Refinement using XPLOR and the Konnert-Hendrickson constrained least-squares programs has now reached the crystallographic residual R = 23%. All 127 residues of both independent protein molecules are present, including low density for residues 1-9 and 124-127, which were not found by Blake, et al. in the structure of normal human prealbumin. At the present stage of refinement the two protein molecules in the crystallographic asymmetric unit are still constrained to obey a local 2-fold rotation axis. The mutated residue (30) is securely positioned in the interior of the molecule. In the vicinity of residue 30, the beta sheets have been shifted from 0.5 to 1.0 Angstroms in comparison to the structure of normal prealbumin and the size of the thyroxine binding site has been increased by about 0.8 A.

A mutant variant of the serum protein transthyretin (TTR-met30) appears to be a necessary but not sufficient condition for the development of familial amyloidotic polyneuropathy (FAP). We have studied a number of serum protein markers (alpha 1-antitrypsin, properdin factor B, C3, C4A, C4B, haptoglobin, transferrin and group-specific component) in FAP patients and healthy controls in an attempt to identify additional pathogenic factors which may influence the risk for developing FAP in male and female patients as well as the age of onset of the disease. Statistically significant associations were found in the complement systems C3 and C4A. The C3F variant was significantly increased in all FAP patients with a relative risk (RR) of 2.0, more pronounced in female patients (RR = 2.6) and patients with an early onset of the disease (RR = 4.5). In the FAP patients only the variants A3 and A4 were found in the C4A system. C4A3 was found in all patients, which was significantly higher than in the controls. The remaining serum protein systems showed no statistically significant associations with FAP. The results suggest that genetic variants of complement factors C3 and C4A may interact with the mutant TTR-met30 by modifying the expression and onset of FAP.

Thirty patients with mild to moderate essential hypertension entered a randomised double-blind parallel group study for 6 months to compare the effects of the new calcium channel blocker nicardipine 90 mg/day and propranolol 240 mg/day. Both drugs reduced systolic and diastolic blood pressures significantly in the supine and in standing positions. After 6 months of treatment, nicardipine had reduced the supine systolic and diastolic blood pressures by 16 and 17 mm Hg, respectively, and propranolol by 15 and 12 mm Hg. While propranolol treatment led to a marked decline in heart rate, nicardipine caused a small but statistically significant increase in heart rate throughout the study. Both drugs reduced blood pressure during maximal exercise, but propranolol had a greater effect. During exercise nicardipine did not affect the heart rate, whereas propranolol dramatically reduced it. Nicardipine did not produce any ECG changes at rest or during exercise. The side-effects for nicardipine were mild and were related to the vasodilatation induced by the drug. No abnormalities in routine blood chemical tests were found for either of the drugs. Nicardipine appears to be an effective single drug treatment for mild to moderate hypertension.

• Amyloid deposits of the vitreous are usually associated with familial amyloidotic polyneuropathy (FAP). Various mutated forms of transthyretin (prealbumin) seem to form the main amyloid fibril component. Five Swedish patients, all with vitreous amyloidosis but no systemic symptoms or family history of amyloidosis, were examined using restriction fragment length polymorphism analysis. Genomic DNA was tested with a transthyretin complementary DNA probe. After cleavage with Nsi1, two restriction fragment length polymorphism markers of 5.1 and 1.5 kilobase were detected in the patients but not in the control subjects. These observations indicate the same methionine for valine substitution at position 30 of the transthyretin molecule in patients with vitreous amyloidosis as seen in Swedish patients with FAP as well as in patients with FAP from Japan and Portugal, and patients of Swedish descent with FAP from the United States.

In the present investigation 11 females of normal constitution were subjected to a standardized fasting diet for 8 days. Three subjects dropped out early during the experimental period. Saliva and blood samples were collected before, during and after the fasting period. Serum analyses were made of some parameters often studied during undernutrition. As expected, values for creatinine and uric acid were increased. Secretion rate, pH, buffer capacity, electrolytes, total protein, carbohydrates, some antibacterial substances, the amount of Streptococcus mutans, total streptococci, and lactobacilli were determined in the saliva samples. The rate of plaque formation was also estimated. The effect of fasting on the measured parameters varied greatly among the individuals. Fasting caused a significant decrease in secretion rate, concentration of phosphate and sialic acid in stimulated whole saliva. There was no significant increase in concentration of any substance measured. The decrease of the ratio of sialic acid to protein indicates a disturbance of glycoprotein synthesis. In resting saliva the activity of a bacteria-aggregating glycoprotein appeared to be unchanged, whereas the decreases in thiocyanate concentration and lysozyme activity were statistically significant. Lactoperoxidase activities did not change significantly. The amount of IgA, IgG, IgM as well as the microbial counts showed no changes. The rate of plaque formation increased during fasting.

Genomic DNA from 17 Swedish patients with familial amyloidotic polyneuropathy (FAP), and 50 healthy controls were tested with a cDNA transthyretin probe. In seven of the patients, FAP was not reported in either of their parents. All 50 controls showed restriction fragments of 6.6 kb and 3.2 kb after cleavage with Nsil, while the 17 FAP patients showed RFLP markers of 5.1 and 1.5 kb. These observations indicate the same methionine for valine substitution at position 30 in Swedish patients with FAP as seen in patients with FAP from Japan, Portugal and FAP-patients of Swedish descent from USA. However, the mean onset of FAP symptoms for the 17 Swedish patients was found to be significantly later than for the patients from Japan, Portugal and USA.

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder. Recent biochemical studies have revealed that amyloid protein in FAP of Japanese, Swedish and Portuguese origin mainly consists of a variant transthyretin (TTR) (formerly called prealbumin) with one amino acid substitution of methionine for valine at position 30. In a 56-year-old man with typical polyneuropathy, gastrointestinal problems and vitreous amyloid, we diagnosed homozygosity for the TTR-met30-gene using RFLP analysis. In a family study, a sister presented the same homozygous RFLP pattern; however, in a careful clinical investigation we were not able to demonstrate any of the typical symptoms of FAP, nor could we demonstrate amyloid deposits in a biopsy skin specimen. This is the first report of homozygosity for the TTR-met30-gene, and it shows that the mutation of the protein involved in amyloid formation may be necessary but is clearly not sufficient for the clinical symptoms.

The renal function is assumed to be normal in most patients with familial amyloidosis with polyneuropathy (FAP) type 1. In the present study of 24 patients with FAP type 1, estimation of the urinary concentrating capacity and 51Cr-EDTA clearance demonstrated that the glomerular clearance and the concentrating capacity were imparied in most patients. The concentrating capacity was significantly correlated with the clearance values. Urine electrophoresis indicated a glomerular cause for the proteinuria. It is suggested that the renal dysfunction should be attributed to deposition of amyloid substance in the glomeruli.

A radiological study of the feet was performed in 162 unselected diabetic patients with gangrene. They were compared with 59 diabetic patients without gangrene, 45 patients with familial amyloidosis and polyneuropathy and 30 healthy controls. The patients with familial amyloidosis had severe distal neuropathy but normal oral glucose tolerance test curves. Radiographic findings, e.g. skeletal destructions (diabetic osteopathy) and arterial calcification of the medial type were classified without knowledge of the clinical findings. Osteopathy was more common in diabetic patients with gangrene than in the other groups of patients. Medial arterial calcification was more common among diabetics with gangrene compared to patients with amyloidosis and to controls. There were no differences between diabetics without gangrene and patients with amyloidosis, but both of these groups had more calcifications than the controls. Our study suggests that diabetic osteopathy is not caused by peripheral neuropathy per se. The skeletal and skin lesions in diabetic patients are probably equivalent lesions localized to different tissues in the feet. It has been suggested that medial degeneration in the arterial wall is due to neuropathy. In agreement with this suggestion, the patients with familial amyloidosis and neuropathy had medial calcification. However, in diabetic patients this does not exclude other etiological agents.