The effect of parathyroidectomy on insulin sensitivity in patients with primary hyperparathyroidism - an never ending story?

Previous studies demonstrated insulin resistance and increased prevalence of impaired glucose tolerance and type 2 diabetes mellitus in patients with primary hyperparathyroidism (PHPT). The effect of curative parathyroidectomy on insulin sensitivity was associated with conflicting results depending on which method for measuring the insulin sensitivity has been used. There was no improvement using HOMA and QUICKI while minimal model demonstrated significant improvement in insulin sensitivity. The aim of our study was to evaluate the insulin sensitivity before and after parathyroidectomy in patients with PHPT using a euglycemic clamp. 44 patients with PHPT and 11 age and body mass index matched healthy controls participated in study protocol. Before surgery M values and HOMA IR suggest insulin resistance in patients with PHPT. There was no difference in M index (3.74±1.89 vs. 4.62±2.27, p>0.05), HOMA IR (2.94±1.39 vs. 3.29±0.81, p>0.05), AUC glucose (863.0±261.3 vs. 842.3±165.5, p>0.05), AUC insulin (7068.7±4159.0 vs. 7229.6±2581.7, p>0.05), ISI (4.73±2.77 vs. 4.25±2.94, p>0.05) and AIR (47.89±32.05 vs. 38.96±21.20, p>0.05) between patients with PHPT and HC. There was significant improvement in insulin sensitivity after parathyroidectomy but both preoperative and postoperative M values were not significantly different in comparison to HC. There were no significant changes in HOMA IR, AUC glucose, AUC insulin, ISI and AIR before and after therapy. In conclusion, we observed significant improvement in insulin sensitivity after parathyroidectomy in patients with PHPT. There was no difference in parameters of insulin secretion before and after parathyroidectomy in patients with PHPT.

Genetic detection of Dobrava-Belgrade hantavirus in the edible dormouse (Glis glis) in central Serbia.

Hantaviruses are endemic in the Balkans, particularly in Serbia, where sporadic cases and/or outbreaks of hantaviral human disease have been reported repeatedly, and evidenced serologically. Here, we present genetic detection of Dobrava-Belgrade virus (DOBV) hantaviral sequences in wild rodents trapped in central Serbia. All the animals were pre-screened serologically by indirect immunofluorescence (IF) test and only those with a positive finding of hantaviral antigens were further tested by polymerase chain reaction. Of the total of 104 trapped animals, 20 were found to be IF positive and of those three were positive for hantaviral RNA: one Microtus arvalis for Tula virus, and one each of Apodemus agrarius and Glis glis for DOBV. Phylogenetic analysis of the obtained sequences implies putative DOBV spillover infection of A. agrarius and G. glis from Apodemus flavicollis. However, future investigations should help to identify the most common natural host and geographical distribution of DOBV in its reservoir hosts in Serbia.

[Acute renal insufficiency in hemorrhagic fever with renal syndrome]. / Akutna bubrezna insuficijencija kod hemoragijske groznice sa renalnim sindromom.

In the Clinic for Nephrology of Military Medical Academy, 116 patients with hemorrhagic fever with renal syndrome (HFRS) have been treated in the period from January 1989 to December 1995. The patients were hospitalized with advanced acute renal failure (ARF). The largest number of our patients got ill from HFRS from the middle of March till the end of May and during August when the other frequency elevation was noticed. Most frequently the disease has the course that is followed up by phases. Positive finding of antibodies to HFRS virus was noticed in all 116 patients (Hantaan 45%, Belgrade 35%, Puumala 20%). According to clinical symptoms, signs and syndromes that follow up HFRS, the most of our patients were with more severe disease type. The ARF treatment with dialysis was necessary in 45% our patients. The most severe clinical forms were caused by Belgrade strain. Very favorable effect of "an early dialysis" to the disease course and outcome was observed. By this approach in HFRS therapy, the patient's mortality was decreased to 0.86%. The development of chronic renal failure as HFRS sequela is possible, but not so frequent.

[Serologic diagnosis of Crimean hemorrhagic fever in Kosovo and Metohia]. / Seroloska dijagnostika Krimske hemoragijske groznice na Kosovu i Metohiji.

In the period June-November 1995, 292 sera from 159 patients and 80 healthy persons from Kosovo and Metohia were tested for the presence of antibodies against the causative agents of Crimean hemorrhagic fever (CHF) and hemorrhagic fever with renal syndrome (HFRS). Diffusion precipitation test in agar gel and indirect immunofluorescence assay were used. Specific antibodies against CHF virus were found in 6.9% and against HFRS virus in 15.1 patient's sera. Antibodies against CHF virus were proved in sera of patients on the fifth day from the disease onset at the earliest. No wanted antibodies were found in healthy persons' sera. The results of sera testing on antibodies against CHF virus were analyzed in detail.

[Belgrade and Hantaan hantaviruses--the causative agents of haemorrhagic fever with renal syndrome in children in Serbia]. / Hantavirusi Beograd i Hantan--uzrocnici hemoragijske groznice s bubreznim sindromom kod dece u Srbiji.

During an outbreak of haemorrhagic fever with renal syndrome (HFRS) in 1989, five children (3 girls, 2 boys, aged 6.8-16 years) with severe clinical form of the disease, were treated at the Institute of Mother and Child Health of Serbia; four of them were followed-up 22-28 months thereafter. The main clinical features were: fever, headache, myalgia, abdominal and back pains, and vomiting in all, and haemorrhagic syndrome in three; renal syndrome with severe acute renal failure in all five patients. All the patients recovered. Serological confirmation by an indirect immunofluorescence assay, enzyme immunoassay for IgM antibodies, and by plaque reduction neutralization test revealed that the infection was caused by Belgrade virus in three, and by Hantaan virus in two patients. It was not possible to differentiate these two serogroups on the basis of clinical features. This finding gave further evidence of circulation of different hantaviruses causing severe HFRS in Serbia.

Belgrade and Hantaan hantaviruses--the causative agents of severe haemorrhagic fever with renal syndrome in children in Serbia.

During an outbreak of haemorrhagic fever with renal syndrome (HFRS) in 1989, five children (3 girls, 2 boys, aged 6.8-16 years) with a severe form of the disease were treated; four of these were followed for 22-28 months. The main clinical features in all five patients were: fever, headache, myalgia, abdominal and back pain and vomiting; haemorrhagic syndrome was present in four children. Renal syndrome presented with severe acute renal failure in all five patients. All patients recovered. Serological confirmation by an indirect immunofluorescence assay, by enzyme immunoassay for IgM antibodies and by plaque reduction neutralization test showed infection by Belgrade virus in three and by Hantaan virus in two patients. It was not possible to differentiate these two serogroups on the basis of clinical features. This study provides further information on the circulation of different hantaviruses causing severe HFRS in Serbia.

Isolation of a Puumala-like virus from Mus musculus captured in Yugoslavia and its association with severe hemorrhagic fever with renal syndrome.

An outbreak of severe hemorrhagic fever with renal syndrome (HFRS) occurred in 1988 in Pozarevac, Serbia, Yugoslavia. The disease was diagnosed in 4 children and 1 adult, and 1 of the children died. Rodents were captured from the same area and virus isolation attempted. A hantavirus, POZ-M1, was isolated from lung tissues of hantavirus antigen-positive Mus musculus. Serology and restriction enzyme digestion of polymerase chain reaction-amplified segments from this virus showed that it was a strain of Puumala (PUU) virus, the causative agent of nephropathia epidemica. While Clethrionomys glareolus is the major rodent host for PUU virus, these results suggest that M. musculus may also play an important role in harboring and transmitting PUU-like viruses. The serologic association of this virus with patients with severe HFRS reaffirms that PUU-like viruses may cause severe disease in addition to the generally mild form normally associated with nephropathia epidemica.

Belgrade virus, a cause of hemorrhagic fever with renal syndrome in the Balkans, is closely related to Dobrava virus of field mice.

Belgrade virus is a recently described hantavirus that causes severe hemorrhagic fever with renal syndrome (HFRS) in people living in various parts of the Balkan Peninsula. Nucleotide sequencing of the G2-encoding region in the medium (M) segment of the viral genome, reverse transcribed and amplified by the polymerase chain reaction, revealed the Belgrade virus to be substantially different from Hantaan virus and other major serotypes of hantavirus but identical to Dobrava virus, a virus isolated from a field mouse (Apodemus flavicollis) in Slovenia. Belgrade virus may be an important cause of HFRS in the Balkan Peninsula, extending north toward the Alps. It poses a special danger to humans who have close contact with field rodents.

Hemorrhagic fever with renal syndrome in Yugoslavia: epidemiologic and epizootiologic features of a nationwide outbreak in 1989.

A nationwide epidemic of hemorrhagic fever with renal syndrome (HFRS) occurred in Yugoslavia in 1989. Sera from 609 hospitalized patients, from all six Republics (Bosnia and Hercegovina, Croatia, Macedonia, Montenegro Serbia, Slovenia) and two Provinces (Kosovo and Vojvodina), who had signs and symptoms suggestive of HFRS, and sera and lung tissues from 544 small mammals belonging to 13 species were studied for evidence of hantavirus infection. Of the 226 patients with serologically confirmed HFRS, 182 resided in Bosnia and Hercegovina or in Serbia. The severity of disease differed from region to region, with an overall fatality of 6.6% (15/226). Patients from southern Yugoslavia tended to have more severe disease and exhibited two types of antibody patterns, while approximately equal numbers of clinically severe and mild cases of HFRS were registered in central Yugoslavia, where four types of antibody patterns were found. Two of these antibody patterns suggested the existence of hantaviruses which are antigenically distinct from those reported to date. Two seasonal peaks of disease, one during the summer and the other in late autumn, were found. Hantaviral antibodies and/or antigens were detected most often in the yellow-necked mouse (Apodemus flavicollis) (88/189), the wood mouse (Apodemus sylvaticus) (28/146), the striped field mouse (Apodemus agrarius) (10/64), the bank vole (Clethrionomys glareolus) (36/63), the house mouse (Mus musculus) (14/29), and the Norway rat (Rattus norvegicus) (14/21). Five other species of rodents and insectivores were infrequently infected.

Characterization of Dobrava virus: a Hantavirus from Slovenia, Yugoslavia.

Small mammals were collected in natural foci of hemorrhagic fever with renal syndrome (HFRS) in Slovenia, Yugoslavia, and a hantavirus was isolated from the lungs of an Apodemus flavicol lis captured in Dobrava village. This new isolate, Dobrava virus, was compared with representative strains of the Hantavirus genus by serological and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. It was found by cross immunofluorescent and enzyme-linked immunosorbent assays that antigenic properties of Dobrava virus were different from those of other hantaviruses. The RNA of this virus was successfully amplified with hantavirus genus reactive primer sets by reverse transcriptase polymerase chain reaction (RT-PCR); however, PCR-RFLP analysis of the amplified product was shown to be unique among those of the known hantaviruses, further indicating that Dobrava virus represents a new hantavirus serotype.

Belgrade virus: a new hantavirus causing severe hemorrhagic fever with renal syndrome in Yugoslavia.

Two biologically and genetically distinct hantaviruses were isolated from blood and urine specimens collected from four Yugoslavian patients with clinically severe hemorrhagic fever with renal syndrome (HFRS). Viral isolates from three patients, designated strains Belgrade 1-3, were distinct from Hantaan, Seoul, Puumala, and Prospect Hill viruses as determined by plaque-reduction neutralization tests and restriction analysis of enzymatically amplified M-segment fragments. The fourth isolate, called Kraljevo, was indistinguishable from Hantaan virus. Strains Belgrade 1 and 2, like the Kraljevo strain, caused a fatal meningoencephalitis in newborn mice inoculated with 100 pfu of virus intracerebrally and intraperitoneally. Strain Belgrade 3 was much less neurovirulent, requiring 30,000 pfu of virus to cause fatal disease in mice. These data indicate that two distinct hantaviruses, one of which constitutes a new serotype, cause clinically severe HFRS in Yugoslavia.

Clinical characteristics of haemorrhagic fever with renal syndrome in children.

From January 1988 to September 1989, seven patients (4 girls and 3 boys, aged 3-12 years) with haemorrhagic fever with renal syndrome (HFRS) were hospitalised at the University Children's Hospital in Belgrade. In four patients the disease appeared as a family outbreak, the others were sporadic cases. In six patients the clinical presentation was suggestive of HFRS, as they had fever with headache, myalgia, sore throat and gastrointestinal illness followed by renal abnormalities. However, severe haemorrhagic syndrome with petechia, haematoma, haematemesis and melaena was present in one patient only. Renal disease presented as nephritic syndrome and/or acute renal failure. Five patients recovered after 2-3 weeks without sequellae, one patient had decreased renal function 17 months after the start of the disease and the remaining patient died. In six patients the diagnosis of HFRS was confirmed serologically by a significant rise in antibody titres against hantaviruses, while in the patient with the fetal and fulminant course of the disease, the diagnosis was established on the basis of epidemiological and autopsy findings. We suggest that children living in endemic areas who develop an ill-defined, febrile and gastrointestinal disease with renal dysfunction should be evaluated for HFRS.

[Epidemiologic characteristics of hemorrhagic fever with renal syndrome in a military population]. / Epidemioloske karakteristike hemoragicne groznice sa bubreznim sindromom u vojnickom kolektivu.

In the period 1952-1990 there have been recorded 84 patients with hemorrhagic fever with renal syndrome (HFRS): 81 soldiers and 3 officers of the Y.P.A. The largest number of cases was recorded in three epidemics, 61 or 72.6%. In 94% of cases the infection occurred during camping of units. The disease appeared in all months, but 57.2% of cases occurred in June and July. The mean lethality was 2.4%, in epidemics 1.6% and as sporadic cases 4.3%. In an army unit staying for six months in HFRS focus, 9.8% of soldiers were infected by the causative agent of this infection and only in one case the clinical picture of HFRS was manifested. Serologic tests (IIF and ELISA) confirmed the diagnosis of HFRS. Virus strains of Hantaan, Puumala and Seoul groups were used as antigens.

[Hemorrhagic fever with renal syndrome in children]. / Hemoragijska groznica s bubreznim sindromom kod dece.

Seven patients, 4 girls and 3 boys, aged 3 to 12 years /X = 7.14/ affected by haemorrhagic fever with renal syndrome /HFRS/., were hospitalized at the University Children's Hospital in Belgrade during the last two years /January 1988-January 1990/. The diagnosis was established on the basis of clinical features, epidemiological data and autopsy findings in one patient while in the others the diagnosis of HFRS was confirmed serologically by indirect immunoflorescence tests on Vero E 6 cells. A significant increase in antibody titre against Hantaan virus was found in all serologically tested patients. Three of them had also significant increase of antibody titre against Soeul and one against Puumale virus. In four patients the disease appeared as family outbreak at the end of January 1988 while the others were sporadical cases. All patients but one mentioned contact with rodents at home or in fields. The predominant slynical symptom were: sudden onset of febrile condition with headache, generalized malaise, myalgia, abdominal pain, vomiting, diarrhoea, oliguria and oedema. All patients had haematuria and only one had other severe haemorrhagic manifestations. Four patients were hypertensive. Two patients had renal insufficiency, but only one required haemodialysis. Five patients recovered after 2 to 8 weeks without sequellae, one patient was still /7 months after the beginning of the disease/ in mild renal insufficiency and one patient died. Autopsy findings showed tubular necrosis in the kidney, myocarditis, massive pneumonia with hydrothorax and jejunal haemorrhagia.

[Hemorrhagic fever with renal syndrome--etiology]. / Hemoragicna groznica sa bubreznim sindromom (HGBS)--etiologija.

HFRS was confirmed serologically in two patients, who were infected in the natural focus near Zupanja. Using the bigger number of virus antigens in indirect immunofluorescent antibody test, afterwards was proved the agent could be classified into the serotype 3 of Hantaviruses, and antigenically is identical with virus NE (strain Hällnäs), respectively Yugoslav isolate "Vranica". Serotype differentiation of the agent in patient who were infected in the area of Igman, near Sarajevo, has not been performed by the same test. There was assumed a possibility for circulation of "new", up to now non-identified, serovariant of Hantaviruses in this natural focus.

Different pathohistological presentations of acute renal involvement in Hantaan virus infection: report of two cases.

We present two patients with Hantaan virus infection, admitted to the Department of Nephrology, Skopje, at the same time, with the same clinical presentation (chills, fever, abdominal pain, hemorrhages, nausea, headache, proteinuria, hematuria, oliguria, acute renal failure) but with different pathohistological findings and different disease courses. In the first case diffuse proliferative glomerulonephritis was found, with a complete recovery of renal function after a month, with a mild proteinuria and erythruria during the second and the third month. In the second case, glomeruli were normal in general, with slight mesangial proliferation found in two out of twenty, but interstitial edema, lymphocyte infiltrations and tubular changes were noted. Complete recovery was not noted after 3 months of follow-up. The patient is now without hemodialysis treatment, with polyuria, in the stable phase of chronic renal failure which is not improving.

[Hemorrhagic fever with renal syndrome in Yugoslavia 1951-1988]. / Hemoragicna groznica sa bubreznim sindromom u SFRJ u periodu od 1951. do 1988.

Data on hemorrhagic fever with renal syndrome (HFRS) incidence in SFRY 1950-1988 were analysed. Information sources were published papers and official reports of Federal and Republic Institutions for Public Health. Indirect immunofluorescence technique was used in testing 1.842 organs of small wild mammals to the presence of HFRS viral antigen. This antigen was found in the lungs of 11 species. Average incidence of the carrier state was 10.4% Registered were 613 cases within the period 1951-1988. Morbidity rate was 0.05-10.6:1.00.000 for years. Disease have been registered during the whole year with maximum incidence rate in summer months. Men most capable of working were the most frequently affected: farmers, wood workers, soldiers. Average lethality was 5.2%.

Evidence for Hantavirus disease in Slovenia, Yugoslavia.

In Slovenia, North-Western part of Yugoslavia, 17 clinically documented Hantavirus disease cases (HVD) were serologically confirmed so far. Previously HVD was reported in the Southern part of Yugoslavia. By the indirect fluorescent antibody test (IFA), the prevalence of IgG class antibodies against different Hantaviral antigens was demonstrated in human sera collected in Slovenia. Three different reactivity patterns were observed. Majority of the IFA-positive human sera were confirmed by the immunoblot method. The distribution of Hantaviral infections was examined in small mammals captured in two natural foci of HVD, where clinical documented cases were reported. Hantaviral antibodies and antigens were demonstrated in C. glareolus, A. flavicollis, A. sylvaticus, and M. musculus.