[Treatment of polyneuropathy: autonomic symptoms and pain]. / Therapie der Polyneuropathie ­ autonome Symptome und Schmerzen.

BACKGROUND: The treatment of polyneuropathy includes symptomatic therapy of sensory, motor and autonomic dysfunctions. AIM: This article provides an overview of the current treatment recommendations for polyneuropathy, focusing on pain. METHODS: Current treatment guidelines will be discussed based on a literature research. RESULTS: Calcium-channel anticonvulsants gabapentin/pregabalin as well as antidepressants duloxetine and amitriptyline are recommended as first line therapeutics. Alternatively, topical therapeutics can be used in the case of localized disorders. In individual cases, opioids or other antidepressants/anticonvulsants may be effective. Pharmacological treatment is often limited due to adverse events, which affect the central nervous system in particular. DISCUSSION: In general, treatment for polyneuropathy should follow a multimodal concept and include the treatment of other symptoms. When choosing pain medication, comorbidities, patient's age and adverse events need to be taken into consideration. Phenotype-based stratification may support specialized pain therapy and achieve the best medical treatment.

Effects of flexible scheduling and virtual visits on burnout for clinicians.

OBJECTIVE: Burnout is a healthcare quality problem, linked to negative impacts in patient care and healthcare providers. The pandemic prompted clinicians to adapt virtual practices and adopt more flexible, autonomous schedules. However, the impact of flexible scheduling and autonomy on provider burnout is unknown. The study aim was to evaluate the effect of flexible schedules versus standard schedules, and the amount of digital care, on burnout. METHODS: This was a prospective survey study at two time points 6 months apart. Providers from Rheumatology, Neurology, and Pediatrics completed surveys at baseline, between 6/22/2020-9/8/2020, and six months later, between 12/20/20-3/12/21. The primary outcome was the Mini-Z work life survey which measured burnout in 2 different groups: flexible schedules (FS) and standard schedules (SS) during the height of the pandemic. RESULTS: The study included 149 providers, 47 with FS and 102 with SS, who completed the survey at baseline and 6 months later. At baseline providers reported high job satisfaction (85.9%) and low burnout (29.7%), which remained consistent at 6 months. Compared to those with SS, clinicians with FS participated in a greater number of telemedicine activities at baseline, but did not differ significantly in degree of burnout (25.5% FS, 31.7% SS, p=0.45). Participants in the FS group were significantly more likely to indicate improvement in control over workload and experience reduced work-related stress compared to those in the SS group. There was no association between amount of telemedicine visits and burnout. Predictors of burnout at 6 months included Rheumatology providers and those in the 20-39 year old age group. DISCUSSION: Schedule flexibility does not appear to influence overall burnout; however it does impact variables associated with burnout such as control over workload and perceived job stress. CONCLUSIONS: Participants reported overall job satisfaction, and FS did not impact overall burnout. FS was more likely to indicate improvement in control over workload and experienced reduced work-related stress compared to SS. In addition, burnout was more likely in the 20-39 year old age group, suggesting that special focus should be paid to this age group.

The non-specific lipid transfer protein, Ara h 9, is an important allergen in peanut.

BACKGROUND: Plant food allergy in the Mediterranean area is mainly caused by non-specific lipid transfer proteins (nsLTP). The aim of this study was to characterize peanut nsLTP in comparison with peach nsLTP, Pru p 3, and assess its importance in peanut allergy. METHODS: Peanut-allergic patients from Spain (n=32) were included on the basis of a positive case history and either a positive skin prick test or specific IgE to peanut. For comparison, sera of 41 peanut-allergic subjects from outside the Mediterranean area were used. Natural Ara h 9 and two isoforms of recombinant Ara h 9, expressed in Pichia pastoris, were purified using a two-step chromatographic procedure. Allergen characterization was carried out by N-terminal sequencing, circular dichroism (CD) spectroscopy, immunoblotting, IgE inhibition tests and basophil histamine release assays. RESULTS: Compared with natural peanut nsLTP, the recombinant proteins could be purified in high amounts from yeast supernatant (> or =45 mg/L). The identity of the proteins was verified by N-terminal amino acid sequencing and with rabbit nsLTP-specific antibodies. CD spectroscopy revealed similar secondary structures for all preparations and Pru p 3. The Ara h 9 isoforms showed 62-68% amino acid sequence identity with Pru p 3. IgE antibody reactivity to rAra h 9 was present in 29/32 Spanish and 6/41 non-Mediterranean subjects. Recombinant Ara h 9 showed strong cross-reactivity to nPru p 3 and similar IgE-binding capacity as nAra h 9. The two Ara h 9 isoforms displayed similar IgE reactivity. In peanut-allergic patients with concomitant peach allergy, Ara h 9 showed a weaker allergenic potency than Pru p 3 in histamine release assays. CONCLUSIONS: Ara h 9 is a major allergen in peanut-allergic patients from the Mediterranean area. Ara h 9 is capable of inducing histamine release from basophils, but to a lesser extent than Pru p 3.

Outcomes with daptomycin versus standard therapy for osteoarticular infections associated with Staphylococcus aureus bacteraemia.

OBJECTIVES: To evaluate the clinical characteristics, treatment and outcomes of patients with osteoarticular infections (OAIs) associated with Staphylococcus aureus bacteraemia (SAB). METHODS: The clinical characteristics and outcomes for patients with OAI were described using a post hoc analysis of an open label, randomized trial comparing daptomycin with standard therapy (vancomycin or anti-staphylococcal penicillin with initial gentamicin) for the treatment of SAB. RESULTS: OAI occurred in 32 of 121 patients (21 daptomycin and 11 standard therapy) with complicated SAB (18 septic arthritis, 9 vertebral osteomyelitis and 7 others). Two patients had osteomyelitis in more than one site. Success rates seen in two groups were as follows: vertebral osteomyelitis [3/5 (60%) daptomycin versus 0/2 (0%) comparator], septic arthritis [7/11 (64%) versus 3/5 (60%)], sternal osteomyelitis [3/3 (100%) versus 1/2 (50%)] and long bone osteomyelitis [0/1 (0%) versus 1/1 (100%)]. Success rates in both treatment groups improved with surgical therapy. Creatine phosphokinase elevations to >500 IU/L occurred in one patient on daptomycin who discontinued therapy, whereas renal impairment developed in three patients on standard therapy, two of whom discontinued therapy. Two patients treated with daptomycin and one patient on vancomycin had increases in S. aureus MICs to daptomycin and vancomycin, respectively. Three patients treated with daptomycin died following completion of therapy, with mortality attributed to multiple co-morbid conditions and inadequate debridement of OAIs in these patients. No deaths were reported in the standard therapy group. CONCLUSIONS: Daptomycin may be considered an alternative to standard therapy in the treatment of patients with complicated SAB and OAI.

Early bacterial clearance from murine lungs. Species-dependent phagocyte response.

Two sets of phagocytic cells are available to defend the lung against inhaled bacteria. Both resident alveolar macrophages and granulocytes from the circulation have been observed in pulmonary air spaces after the deposition of bacteria; their functional roles, however, have been defined. We rendered mice selectively granulocytopenic with heterologous antiserum in order to ascertain the relative contributions of these two groups of cells in intrapulmonary bacterial killing. The clearance of Staphylococcus aureus was unimpaired in granulocytopenic animals, confirming the primary role of the alveolar macrophages in the killing of these organisms. In contrast, granulocytopenic animals cleared only 10.0+/-7.0% of an inoculum of Klebsiella pneumoniae compared with 33.0+/-4.0% clearance in normal animals (P < 0.02), and Pseudomonas aeruginosa proliferated to 513% of baseline levels in granulocytopenic animals, whereas normal mice cleared 26.8+/-10.6% of the inoculum. These findings indicate that circulating granulocytes play a major role in the clearance of the latter two organisms. This variation in cellular response to different bacterial species suggests that the defense of the lung against pathogenic bacteria is more complex than has been previously assumed.

The effect of complement depletion on lung clearance of bacteria.

We have investigated the effect of hypocomplementemia on early pulmonary clearance of four species of bacteria. The experiments were performed in an inbred animal model to minimize immunologic variability. Complement was depleted by cobra venom factor, and activity in serum was monitored with a phagocytic assay. Bacterial specific antibodies were examined by an indirect radioimmunoassay, and animals with high levels of activity were excluded from anaysis. 4 h after aerosolization with Streptococcus pneumoniae, complement-depleted animals had cleared only 75% of the initial number of organisms, whereas saline-treated controls cleared 91% (P less than 0.01). Aerosolization with Pseudomonas aeruginosa was followed at 4 h by a twofold greater growth of organisms in the complement-depleted animals (446% of original deposition) as compared to the saline-treated controls (211% of original deposition) (P less than 0.02). Clearance of Klebsiella pneumoniae and Staphylococcus aureus were similar in complement-depleted animals and saline-treated controls. These experiments suggest that hypocomplementemia predisposes to bacterial pneumonia and may explain the high incidence of pulmonary infections in patients having impaired complement activity. Our results further indicate that varying defense mechanisms may be involved with clearing the lung of differing bacterial species.

Propionibacterium acnes endocarditis: a case series.

OBJECTIVES: Propionibacterium acnes remains a rare cause of infective endocarditis (IE). It is challenging to diagnose due to the organism's fastidious nature and the indolent presentation of the disease. The purpose of this study was to describe the clinical presentation and management of P. acnes IE with an emphasis on the methods of diagnosis. METHODS: We identified patients from the Cleveland Clinic Infective Endocarditis Registry who were admitted from 2007 to 2015 with definite IE by Duke Criteria. Propionibacterium acnes was defined as the causative pathogen if it was identified in at least two culture specimens, or identified with at least two different modalities: blood culture, valve culture, valve sequencing or histopathological demonstration of microorganisms. RESULTS: We identified 24 cases of P. acnes IE, 23 (96%) of which were either prosthetic valve endocarditis or IE on an annuloplasty ring. Invasive disease (71%) and embolic complications (29%) were common. All but one patient underwent surgery. Propionibacterium acnes was identified in 12.5% of routine blood cultures, 75% of blood cultures with extended incubation, 55% of valve cultures, and 95% of valve sequencing specimens. In 11 of 24 patients (46%), no causative pathogen would have been identified without valve sequencing. CONCLUSIONS: Propionibacterium acnes almost exclusively causes prosthetic valve endocarditis and patients often present with advanced disease. The organism may not be readily cultured, and extended cultures appear to be necessary. In patients who have undergone surgery, valve sequencing is most reliable in establishing the diagnosis.

Spontaneous ovarian tumors in Han:NMRI mice: histologic classification, incidence, and influence of food restriction.

In a life-span study with female Han:NMRI virgin mice (300 of a fat subline, 300 of a lean subline, and 300 controls), a total of 424 mice developed 673 ovarian tumors. Half of the mice in each group were fed ad libitum, and for the other half food was restricted. Most prevalent were tubular adenomas followed by granulosa and Sertoli cell tumors. Altogether, 42 neoplasms were classified as tubular adenocarcinomas, and 21, as luteomas . The general incidence of tumors increased sharply beyond the 18th month of age. Granulosa cell tumors arose relatively early, and tubular adenocarcinomas occurred very late in life. The occurrence of ovarian tumors depended mainly on life expectancy. All animals subjected to food restriction lived longer and developed more ovarian neoplasms than those fed ad libitum.

Biochemical characterization of endogenous carbohydrate-binding proteins from spontaneous murine rhabdomyosarcoma, mammary adenocarcinoma, and ovarian teratoma.

Three entirely different tumor types were investigated biochemically for the presence and characteristics of endogenous carbohydrate-binding proteins in an inbred Brown Norway rat, an outbred Sprague-Dawley rat, and an outbred Han:NMRI mouse. The patterns under investigation included specificities for alpha- and beta-galactosyl, alpha-mannosyl, and alpha-fucosyl moieties, respectively, and specificities for heparin, analyzed by affinity chromatography on resins with immobilized sugars or glycoproteins and polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The patterns were divided into categories according to dependence of the binding activity on the presence of Ca2+ and dependence on extraction conditions. Rhabdomyosarcoma revealed only Ca2+-independent activities, i.e., activities with specificity for beta-galactosides at a molecular weight of 12,000, with specificity for alpha-galactosides at molecular weights of 29,000, 43,000, and 45,000, with specificity for heparin at molecular weights of 13,000 and 16,000, and with specificities for mannose and fucose at molecular weights ranging from 62,000 to 70,000. For the spontaneous mammary adenocarcinoma the pattern was entirely different and more diverse, including species with the Ca2+ requirement. Extracts with the use of 0.2 M NaCl (salt) and 2% Triton X-100 (detergent) from teratoma contained at least nine different carbohydrate-binding proteins. The only similarities between the pattern of endogenous carbohydrate-binding proteins from teratoma and from mammary adenocarcinoma were beta-galactoside-binding proteins, one with a Ca2+ requirement and one without a Ca2+ requirement, and the heparin-binding proteins. These heparin-binding proteins were the only types of carbohydrate-binding proteins common to all three tumor types. The analysis indicates that certain bands represented newly identified proteins capable of binding to galactose-, mannose- or fucose-containing glycoconjugates, respectively. When assayed with rabbit erythrocytes, the different fractions showed agglutination activity. They can thus be termed "endogenous lectins." The use of endogenous lectin patterns as potential diagnostic markers in addition to the corresponding changes in the glycoconjugate composition is proposed.

Spontaneous urinary bladder tumors in DA/Han rats: a feasible model of human bladder cancer.

In a life-span study of virgin DA/Han inbred rats, 53.9% of the males and 14.4% of the females developed spontaneous urinary bladder tumors. A peak incidence was noted between the ages of 25 and 30 months. With the exception of 1 leiomyosarcoma, all neoplasms were of epithelial origin. After the papilloma, the majority of tumors were classified as transitional cell carcinoma of the papillary, solid, or mixed type. Less frequent were unclassified microcarcinoma, squamous cell, adenoid, and undifferentiated carcinomas. A sexual difference was found for almost every tumor type. Of the rats bearing tumors, 3.5% of the males and 64.4% of the females also were affected with urinary bladder stones. Squamous cell and glandular metaplasias of the tumors commonly were observed, and invasive growth into the bladder wall occurred frequently in less-differentiated tumors. Metastases were rare. The DA/Han rat strain is discussed as a suitable animal model for human urinary bladder cancer.

Inflammatory, proliferative, and neoplastic lesions at the site of metallic identification ear tags in Wistar [Crl:(WI)BR] rats.

During a 2-yr study of carcinogenesis by CdCl2 in male Wistar [Crl:(WI)BR] rats, weekly clinical observations during the last 6 mo of the study revealed many cases of persistent tumor-like masses at the site of the metal identification tags in the ears of the animals. A total of 14 tumors (mostly compound osteosarcomas) was diagnosed in 168 rats. Histologically, almost 90% of the rats in this study (henceforth referred to as Study I) showed some significant lesion at the tag site including various degrees of chronic inflammation, chondrous hyperplasia, and osseous metaplasia of the pinnal cartilage. In marked contrast, only two tumors were detected in 193 animals in a second study (Study II) in the same strain of rats, and only 56% of the rats had lesions at the tag site. A high incidence (greater than 25%) of clinically severe inflammation at the tag site was seen early in Study I and persisted during the first 6 mo of the study, while the incidence of such reactions in Study II was never more than 1%. Elemental analysis of the tags provided no explanation for the differences between the two studies, as tags used in both studies were of the same composition, predominantly nickel and copper. Metallic internal prostheses have induced local malignancies in humans and animals, and the present observations provide further evidence of the hazard posed by such devices at the site of prolonged contact with tissues. These findings suggest that a persistent tissue reaction may be an important factor in tumor development.

Transplacental carcinogenicity of cisplatin: initiation of skin tumors and induction of other preneoplastic and neoplastic lesions in SENCAR mice.

cis-Dichlorodiammineplatinum (cis-DDP), an anticancer agent sometimes used in pregnant women for the treatment of malignant ovarian and uterine tumors, was tested for transplacental carcinogenic and/or tumor-initiating effects in SENCAR mice. Pregnant mice were given a single i.p. injection of either cis-DDP (7.5 mg/kg body weight) in 2.5% NaCl or the same weight-adjusted volume of NaCl (5 ml/kg body weight) on day 17 of gestation. Offspring were delivered and raised by their natural mothers until weaning at 3 weeks of age. Starting at week 4, offspring in experimental groups received topical applications of 2 micrograms 12-O-tetradecanoylphorbol-13-acetate (TPA) in acetone twice a week for 20 weeks while those in control groups received only acetone (0.2 ml/application) for the same duration. The experiment was terminated at 25 weeks of age. A high incidence (18 of 37; 48.7%) of papillomas was observed in offspring exposed transplacentally to cis-DDP and postnatally to TPA, while only 10% (4 of 40) of offspring exposed to TPA alone developed such tumors (P < 0.0002). Although no skin tumors were observed without TPA promotion, transplacental administration of cis-DDP resulted in development of thymic lymphomas, lung tumors, and proliferative kidney lesions in offspring. These results provide the first evidence that cis-DDP can initiate and/or induce preneoplastic and neoplastic lesions in multiple tissues transplacentally.

Cadmium carcinogenesis in male Wistar [Crl:(WI)BR] rats: dose-response analysis of tumor induction in the prostate and testes and at the injection site.

Carcinogenic dose-response effects of CdCl2 in male Wistar [Crl:(WI)BR] rats were studied over a 2-year period. Groups of rats received a single s.c. injection of CdCl2 at doses of 0, 1.0, 2.5, 5.0, 10.0, 20.0, or 40.0 mumol/kg in the dorsal thoracic midline. Other groups received either four separate s.c. doses of 5 mumol Cd/kg each (at 0, 48, 96, and 168 h), or low dose cadmium (5.0 mumol/kg, s.c., at 0 h) followed by a higher dose (10.0 or 20.0 mumol/kg, s.c., at 48 h). The cadmium treatments resulted in appearance of tumors at the injection site, in the testes, and in the ventral prostate. Injection site tumors (mostly sarcomas) appeared to be strictly related to accumulated dose of cadmium and approached a 45% incidence at the highest cadmium dose (40 mumol/kg). Testicular tumors (mostly Leydig cell adenomas) were found to be highly dependent on testicular degeneration caused by cadmium. The highest Leydig cell tumor incidence occurred in the 40 mumol/kg (83%) and 20 mumol/kg (72%) dosage groups. Low dose pretreatment (5.0 mumol/kg) reduced or prevented the testicular degeneration and tumor formation that would otherwise result from a subsequent higher dose of CdCl2 (20 mumol/kg). Prostatic tumors (mostly adenomas of the ventral lobe) were also found to be associated with cadmium treatment, but in a non-dose related fashion. Prostatic tumor incidence was significantly elevated at the 2.5 mumol/kg dose of CdCl2 (eight tumors/26 rats; 31%) and showed a strong positive correlation between 0.0 and 2.5 mumol/kg in both tumor incidence and multiplicity. At higher doses, including those that caused marked testicular degeneration and induced prostatic atrophy, an elevated incidence of tumors did not occur. The occurrence of hyperplastic foci of the prostate, however, showed a strong positive correlation with increasing dose after single injections of cadmium up to and including 20.0 mumol/kg. Results indicate that CdCl2 can induce preneoplastic lesions of the prostate that appear to develop into tumors only at doses well below those causing marked degeneration of the testes and atrophy of the prostate.

Mouse papillary lung tumors transplacentally induced by N-nitrosoethylurea: evidence for alveolar type II cell origin by comparative light microscopic, ultrastructural, and immunohistochemical studies.

A histogenetic study was designed to evaluate controversial findings on the cell of origin of tubular/papillary lung tumors in mice, i.e., bronchiolar Clara cell versus alveolar type II cell. N-Nitrosoethylurea (0.5 mmol or 0.74 mmol/kg) was given to pregnant C3H (C3H/HeNCr MTV-) and Swiss Webster [Tac:(SW)fBR] mice as a single i.p. injection on Day 14, 15, 16, or 18 of gestation. The offspring were studied at various ages ranging from 7 days to 52 wk. Serial sections of the whole lung (100 to 200 sections per mouse) showed that solid/alveolar and papillary tumors arose from the pulmonary acinus, invading the bronchioles only as the tumors grew. Furthermore, a mixture of solid and papillary patterns within a single module did not represent a merging of two tumors but a progression from the solid to the papillary form. By use of two rabbit antisera against mouse lung surfactant apoproteins found in normal alveolar type II cells, it was shown by the avidin-biotin peroxidase complex procedure, by the peroxidase-antiperoxidase technique, and by indirect immunofluorescence that both solid and papillary tumors contained these proteins that are specific markers for alveolar type II cells. With a rabbit anti-rat Clara cell antiserum, none of the tumors studied was immunoreactive while normal Clara cells were reactive. The nitroblue tetrazolium formazan stain for dehydrogenase enzymes, found particularly in Clara cells, did not reveal these enzymes in any lung tumors from either strain. Ultrastructurally, no typical features of the mature Clara cell were detected in papillary or other pulmonary neoplasms. However, all tumors showed characteristic alveolar type II cell structures such as various stages of lamellar body formation, although these features were less well differentiated in the papillary tumors. Argentaffin dense bodies, representing lysosomes and immature forms of lamellar bodies, were commonly observed in papillary tumors. Some features of the papillary tumors such as cell shape, high glycogen content, and primary cilia were equivalent to those seen in pulmonary epithelial precursor cells during fetal development. With age, the papillary tumors became invasive, accumulated neutral lipids, and developed bizarre cleaved nuclei and lamellated nuclear pseudoinclusions. In conclusion, the papillary lung tumors of the mouse, at least those induced transplacentally by N-nitrosoethylurea, constitute less well-differentiated or poorly differentiated alveolar type II cell adenomas or carcinomas with fetal morphological and biochemical properties.

Cadmium carcinogenesis in male Wistar [Crl:(WI)BR] rats: dose-response analysis of effects of zinc on tumor induction in the prostate, in the testes, and at the injection site.

The ability of zinc acetate to modify the carcinogenic effects of CdCl2 in male Wistar [Crl:(WI)BR] rats was studied over a 2-year period. Groups of rats received a single s.c. injection of Cd (30.0 mumol/kg) in the dorsal thoracic midline or i.m. in the right thigh at time 0. Zinc was given in three separate s.c. doses of 0.1, 0.3, or 1.0 mmol/kg (at -6, 0, and +18 h relative to cadmium) in the lumbosacral area or p.o. at 100 ppm in the drinking water (-2 to +100 weeks). Cadmium treatments (s.c.) resulted in the appearance of tumors at the injection site and in the testes. The incidence of s.c. injection site tumors (mostly mixed sarcomas) was markedly reduced by high dose (1.0 mmol/kg) s.c. zinc (50% reduction) and was almost abolished by p.o. zinc (92% reduction). Testicular tumors (mostly Leydig cell adenomas) induced by s.c. cadmium were reduced in a dose-related fashion by zinc and were found to be highly dependent on the ability of zinc to prevent the chronic degenerative effects of cadmium in the testes. Oral zinc had no effect on s.c. cadmium-induced testicular tumors, while i.m. cadmium alone did not induce these tumors. In rats in which s.c. cadmium-induced testicular tumors and chronic degenerative effects were prevented by zinc (1.0 mmol/kg, s.c.), a marked elevation in prostatic tumors (exclusively adenomas) occurred (control, 9.6%; cadmium plus high zinc 29.6%). Cadmium given i.m., which did not result in testicular tumors or degeneration, also induced an elevated incidence (42.3%) of prostatic tumors, again indicating a dependence on testicular function. Prostatic tumor incidence was also significantly elevated (25.0%) in rats receiving 1.0 mmol/kg zinc, s.c., in combination with i.m. cadmium. These results indicate that zinc inhibition of cadmium carcinogenesis is a complex phenomenon, depending not only on dose and route but also on the target site in question.

The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting.

NIH sponsored a meeting of medical and veterinary pathologists with mammary gland expertise in Annapolis in March 1999. Rapid development of mouse mammary models has accentuated the need for definitions of the mammary lesions in genetically engineered mice (GEM) and to assess their usefulness as models of human breast disease. The panel of nine pathologists independently reviewed material representing over 90% of the published systems. The GEM tumors were found to have: (1) phenotypes similar to those of non-GEM; (2) signature phenotypes specific to the transgene; and (3) some morphological similarities to the human disease. The current mouse mammary and human breast tumor classifications describe the majority of GEM lesions but unique morphologic lesions are found in many GEM. Since little information is available on the natural history of GEM lesions, a simple morphologic nomenclature is proposed that allows direct comparisons between models. Future progress requires rigorous application of guidelines covering pathologic examination of the mammary gland and the whole animal. Since the phenotype of the lesions is an essential component of their molecular pathology, funding agencies should adopt policies ensuring careful morphological evaluation of any funded research involving animal models. A pathologist should be part of each research team.

Vertebral osteomyelitis presenting as spinal compression fracture. Six patients with underlying osteoporosis.

Six patients with osteoporosis had vertebral osteomyelitis (VO) with infection of a single vertebra that presented with a collapsed vertebral body, thought to be a simple compression fracture. The resulting delay in correctly diagnosing VO was associated with disabling sequelae in a high proportion of cases. This distinctive presentation accounted for 13% of all hospitalized patients with VO and 2.4% of inpatients with osteoporotic compression fractures during the last five years; it may be more common than suggested by the paucity of published cases. In patients with osteoporosis and vertebral compression fractures, osteomyelitis should be considered when there is severe back pain, persistent unexplained fever, unexplained elevation of the erythrocyte sedimentation rate, or bacteremia without an obvious extravertebral focus of infection, particularly if the patient is immunocompromised. Early biopsy and culture of the collapsed vertebral body will facilitate diagnosis and therapy.

Cytopathologic and neurochemical correlates of progression to motor/cognitive impairment in SIV-infected rhesus monkeys.

Neurochemical, pathologic, virologic, and histochemical correlates of simian immunodeficiency virus (SIV)-associated central nervous system (CNS) dysfunction were assessed serially or at necropsy in rhesus monkeys that exhibited motor and cognitive deficits after SIV infection. Some infected monkeys presented with signs of acquired immunodeficiency disease (AIDS) at the time of sacrifice. Seven of eight animals exhibited motor skill impairment which was associated with elevated quinolinic acid in cerebrospinal fluid (CSF). Examination of the brains revealed diffuse increases in glial fibrillary acidic protein immunoreactivity in cerebral cortex in all animals, regardless of evidence of immunodeficiency disease. Reactive astrogliosis preceded or was coincident with the onset of neuropsychological impairments. Virus rescue from CSF of six of eight infected animals showed that one of three animals with AIDS and none of three animals without AIDS at necropsy had virus rescue-positive CSF. Multinucleated giant cells were seen in the brain of only one animal with end-stage AIDS and high systemic virus burden at death. Neither systemic nor CNS virus burden was associated with the onset of CNS dysfunction. SIV-associated motor/cognitive impairment is associated with subtle, widespread changes in CNS cytology and neurochemistry, rather than with large increases in brain virus burden or widespread virus-associated brain lesions.

Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats.

Idoxifene, a novel selective estrogen receptor modulator, was tested for its effects on bone loss, serum cholesterol, and uterine wet weight and histology in the ovariectomized (Ovx) rat. Idoxifene (0.5 mg/kg x day) completely prevented loss of both lumbar and proximal tibial bone mineral density (BMD). In an intervention study, idoxifene (0.5 and 2.5 mg/kg x day) completely prevented further loss of both lumbar and proximal tibial BMD during a 2-month treatment period commencing 1 month after surgery, when significant loss of BMD had occurred in the Ovx control group. Idoxifene reduced total serum cholesterol, which was maximal at 0.5 mg/kg x day. Idoxifene alone displayed minimal uterotrophic activity in Ovx rats and inhibited the agonist activity of estrogen in intact rats. Histologically, myometrial and endometrial atrophy were observed in both idoxifene and vehicle-treated Ovx rats. In this report, we also provide molecular-based evidence to support the observations in vivo of a novel selective estrogen receptor modulator (SERM) mechanism of action in bone and endometrial cells. Idoxifene is an agonist through the estrogen response element (ERE) and exhibits similar postreceptor effects to estrogen in bone-forming osteoblasts. Idoxifene also stimulates osteoclast apoptosis, and these pleiotropic effects ultimately could contribute to the maintenance of bone homeostasis. However, idoxifene differs from estrogen in a tissue-specific manner. In human endometrial cells, where estrogen is a potent agonist through the ERE, idoxifene has negligible agonist activity. Moreover, idoxifene was able to block estrogen induced gene expression in endometrial cells, which is in agreement with the observation in the intact rat study. In the uterus, idoxifene has a pharmacologically favorable profile, lacking agonist and therefore growth-promoting activity. Together with its cholesterol lowering effect and lack of uterotrophic activity, these data suggest that idoxifene may be effective in the prevention of osteoporosis and other postmenopausal diseases without producing unwanted estrogenic effects on the endometrium.