Cytokine responses,microbial aetiology and short‐term outcome in community‐acquired pneumonia

Background

The inflammatory response to community‐acquired pneumonia (CAP) is orchestrated through activation of cytokine networks and the complement system. We examined the association of multiple cytokines and the terminal complement complex (TCC) with microbial aetiology, disease severity and short‐term outcome.

Materials and methods

Plasma levels of 27 cytokines and TCC were analysed in blood samples obtained at hospital admission, clinical stabilization and 6‐week follow‐up from 247 hospitalized adults with CAP. Fourteen mediators were included in final analyses. Adverse short‐term outcome was defined as intensive care unit (ICU) admission and 30‐day mortality.

Results

Cytokine and TCC levels were dynamic in the clinical course of CAP, with highest levels seen at admission for most mediators. Admission levels of cytokines and TCC did not differ between groups of microbial aetiology. High admission levels of IL‐6 (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.18‐1.84, P = .001), IL‐8 (OR 1.79, 95% CI 1.26‐2.55, P = .001) and MIP‐1β (OR 2.28, 95% CI 1.36‐3.81, P = .002) were associated with a CURB‐65 severity score of ≥3, while IL‐6 (OR 1.37, 95% CI 1.07‐1.74, P = .011) and MIP‐1β (OR 1.86, 95% CI 1.03‐3.36, P = .040) were associated with a high risk of an adverse short‐term outcome.

Conclusions

In this CAP cohort, admission levels of IL‐6, IL‐8 and MIP‐1β were associated with disease severity and/or adverse short‐term outcome. Still, for most mediators, only nonsignificant variations in inflammatory responses were observed for groups of microbial aetiology, disease severity and short‐term outcome.     

Long-term results of stereotactic radiosurgery to the pituitary gland in Cushing's disease

Gamma radiation from 60Co delivered with stereotactic technique was given to the pituitary gland in 35 patients, aged 18-65 years, with Cushing's disease. The doses were 70-100 Gy in each single irradiation. The size of the sella turcica was normal in the majority of the patients. The observation time was 3-9 years in 29 patients. Out of them, 14 (48%) obtained clinical remission and normal urinary cortisol after one irradiation. Eight achieved remission after two to four irradiations. In total, 22 out of 29 patients (76%) obtained remission. In 12 of them remission was obtained in 1 year and in another 10 within 3 years. No recurrences were observed. Improvement was seen in 2 patients after one and three irradiations. Bilateral adrenalectomy was performed in 5 patients owing to unsatisfactory effect of irradiation. Pituitary insufficiency with gonadotropin, thyrotropin or corticotropin failure was demonstrated in 12 of 22 patients in remission. This occurred 4 months to 7 years after the first irradiation. Another 6 patients were followed less than 3 years after the first irradiation. Two obtained remission after the first treatment, whereas the other 4 improved. Stereotactic pituitary irradiation is suggested as a non-invasive therapeutic alternative in Cushing's disease for example in patients with considerable surgical risk or as a supplement to pituitary microsurgery.     

Congenital cardiac malformations in Iceland from 1990 through 1999

INTRODUCTION AND BACKGROUND: About 1% of live-born children have congenital malformations of the heart. The aim of our study was to investigate the incidence of such defects in children born in Iceland during a period of 10 years, extending from 1990 through 1999. MATERIALS AND METHODS: Information about the patients was obtained from medical records from two hospitals that cover the whole country, a private clinic of pediatric cardiologists, an echocardiography database, autopsy reports, and death certificates. We investigated the distribution of specific malformations, the age at diagnosis, the symptoms leading to the diagnosis, the source of referral, and treatment and quality of life. RESULTS: Between 1990 and 1999, there were 44,013 live births in Iceland, of which 740 patients were diagnosed with congenital cardiac malformations, accounting for 1.7% of the live-born children. The distribution was made up of 338 patients with ventricular septal defect (45.7%), 90 with atrial septal defect (12.2%), 85 with patency of the arterial duct (11.5%), 48 with pulmonary valvar stenosis (6.5%), 38 with a bicuspid aortic valve (5.1%), 28 with aortic coarctation (3.8%), 22 with tetralogy of Fallot (3.0%), 14 with transposed great arteries (1.9%), 11 with aortic stenosis (1.5%), 10 with atrioventricular septal defect and common atrioventricular orifice (1.4%), 9 with mitral valvar regurgitation (1.2%), 7 with sub-aortic stenosis (0.9%), and 5 with hypoplasia of the left heart (0.7%). Extracardiac anomalies were seen in 89 patients (12.0%). Chromosomal defects were seen in 36 patients, of whom 28 had Down's syndrome. DISCUSSION: The annual incidence of diagnosis of patients with congenital cardiac malformations increased during the period of study. This was noted for minor defects, but the incidence of the major anomalies did not alter. Our observed yearly incidence, at 1.7%, was higher than noted in a previous study covering the years 1985 through 1989, and is also higher than in other population-based studies. The most likely explanation is the fact that access to pediatric cardiologists in Iceland is very good. Diagnosis, registration, and follow-up are conducted by only a few cardiologists, and take place at a single center for pediatric cardiology.     

Age-related changes in cortical bone content of insulin-like growth factor binding protein (IGFBP)-3, IGFBP-5, osteoprotegerin,and calcium in postmenopausal osteoporosis: a cross-sectional study

Serum GH and IGF-I levels decline with increasing age, whereas osteoprotegerin (OPG) increases. IGFs as well as OPG are present in bone matrix and mediate the effects of many upstream hormones (e.g. estrogen). To evaluate whether changes in these proteins may to some extent explain the decrease in bone mass in postmenopausal or senile osteoporosis, we measured bone contents of IGF-I, IGF-II, IGF binding protein (IGFBP)-3, IGFBP-5, and OPG in combined extracts obtained after EDTA and guanidine hydrochloride extraction in 60 postmenopausal women aged 47-74 (mean, 63) yr with a previous distal forearm fracture and a hip or spine Z-score less than 0. We found age-related increases in IGFBP-3 (r = 0.35; P < 0.01), IGFBP-5 (r = 0.59; P < 0.001), and OPG (r = 0.36; P < 0.01) in cortical bone, significantly inversely correlated with femoral neck and lumbar spine BMD. A correlation between age and OPG was also detected in trabecular bone (r = 0.27; P < 0.05). A pronounced age-related decrease in cortical calcium contents (r = -0.60; P < 0.001), positively correlated with femoral neck and lumbar spine BMD, was also found. No age-related changes were detected for IGF-I or IGF-II. The present study demonstrates age-related changes in cortical bone contents of IGFBPs, calcium, and OPG, possibly related to the pathophysiology of postmenopausal osteoporosis. As for OPG, our findings probably represent compensatory responses to increased osteoclastic resorption.     

GH/IGF-I and bone resorption in vivo and in vitro

IGF-I may act as one of several coupling agents by activating bone formation and bone resorption. In vivo studies in normal subjects, postmenopausal women and patients with excess or diminished GH production (acromegaly and GHD) indicate that both GH and IGF-I activate osteoclasts, but that GH has a more pronounced effect, independently of IGF-I. In vitro, GH and IGF receptors have been demonstrated on osteoclasts and both GH and IGF-I may directly modify osteoclast function and activity. In addition to direct effects on osteoclasts, GH and IGF-I may affect bone resorption indirectly by stimulating release of paracrine mediators that regulate osteoclastic resorption (cytokines). Critical for the bone resorptive process is the balance between OPG and RANKL, which is regulated by many systemic factors. In vivo and in vitro, GH/IGF-I may modulate this balance but these studies are difficult to interpret, reflecting the complexity of this system. Increased OPG expression may possibly protect against GH/IGF-I-induced bone resorption and potentially be important for the long-term beneficial effects of GH replacement. Further studies investigating the OPG/RANKL ratio and system in experimental and transgenic GH/IGF models may clarify these issues.     

Intestinal parasitic infection and other sexually transmitted diseases in asymptomatic homosexual men

76/133 (57%) asymptomatic homosexual men harboured intestinal parasites. Of these, 40 had Entamoeba histolytica or Giardia lamblia, or both. In a control group of heterosexual men, no pathogenic protozoa were found. Stool specimen cultures for Salmonella, Shigella, and Campylobacter were negative. 7% of the homosexual men were infected with Neisseria gonorrhoeae in the pharynx or rectum, or both, and 5% with Chlamydia trachomatis in the urethra or rectum. Serological evidence of syphilis was detected in 18 men (13.5%) of whom 2 were untreated. Serological markers of hepatitis A were found in 20% and of hepatitis B in 48%. The prevalence of antibodies to cytomegalovirus was higher in homosexual than in heterosexual men (88% versus 59%).     

Glioblastoma and malignant melanoma: Serendipitous or anticipated association?

We describe a patient who had primary glioblastoma (GB) and malignant melanoma (MM). A 78‐year‐old man presented with several weeks to months of history of gait disturbance, confusion, memory disturbance, and worsening speech. Imaging studies performed on admission revealed a large frontotemporal lobe mass associated with the surrounding zone of vasogenic edema. Given the patient's medical history of incomplete biopsy of a midback tumor performed three weeks before, the presumptive clinical diagnosis was metastatic MM. Pathological examination of frozen sections of fragmented specimens obtained at stereotactic biopsy performed on admission revealed a high‐grade malignant neoplasm characterized by discohesive cells in a blue myxoid background and abundant foci of tumor necrosis. Given these features, in conjunction with the abovementioned pathological report, the frozen section diagnosis by the neuropathologist was “neoplasm identified, favor melanoma.” Due to the paucity of lesional tissue, a limited immunohistochemistry performed on the permanent sections revealed positive staining of lesional cells for Sox10 alone using a multiplex MART1/Sox10 immunostain and S‐100 protein, an immunohistochemical profile supporting the presumptive frozen section diagnosis. A tumor debulk procedure, performed two weeks later, revealed histopathologic features most compatible with GB, IDH wild‐type. Thus, additional immunohistochemistry on the permanent sections revealed positive staining of glial fibrillary acidic protein (GFAP), Sox10, and S‐100 protein as well as negative staining of gp100, a complex carbohydrate matrix protein in embryonic melanosomes, using a specific antibody HMB45. The concomitant occurrence of MM and GB in our patient underscores the association between these two entities. Our literature review suggests that the sporadic co‐occurrence of these two conditions is likely not serendipitous.     

Mediation Analysis of Aortic Stiffness and Renal Microvascular Function

Aortic stiffening, assessed by carotid-femoral pulse wave velocity, is associated with CKD. Transmission of excessive flow pulsatility into the low-impedance renal microvasculature may mediate this association. However, direct analyses of macrovascular–microvascular relations in the kidney are limited. Using arterial tonometry, iohexol clearance, and magnetic resonance imaging, we related arterial stiffness, GFR, urinary albumin excretion, and potential mediators, including renal artery pulsatility index, renal vascular resistance, and arterial volume in the cortex, in 367 older adults (ages 72–92 years) participating in the Age, Gene/Environment Susceptibility-Reykjavik Study. In a model adjusted for age, sex, heart rate, and body size, aortic stiffness was related to GFR (Slope of regression B=−2.28±0.85 ml/min per SD, P=0.008) but not urine albumin (P=0.09). After accounting for pulsatility index, the relation between aortic stiffness and GFR was no longer significant (P=0.10). Mediation analysis showed that 34% of the relation between aortic stiffness and GFR was mediated by pulsatility index (95% confidence interval of indirect effect, −1.35 to −0.29). An additional 20% or 36% of the relation was mediated by lower arterial volume in the cortex or higher renal vascular resistance, respectively, when offered as mediators downstream from higher pulsatility index (95% confidence interval of indirect effect including arterial volume in the cortex, −2.22 to −0.40; 95% confidence interval of indirect effect including renal vascular resistance, −2.51 to −0.76). These analyses provide the first evidence that aortic stiffness may contribute to lower GFR by transferring excessive flow pulsatility into the susceptible renal microvasculature, leading to dynamic constriction or vessel loss.