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Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

Mixed acinar neuroendocrine carcinoma of the pancreas (MANEC-P) is an extremely rare malignancy with a poor prognosis. However, epidemiological estimates of MANEC-P remain unknown. This study aimed to estimate and compare the incidence, prevalence, and cancer-specific survival (CSS) of MANEC-P in the United States (US). Patients with MANEC-P were identified through the Surveillance, Epidemiology, and End Results (SEER) and National Program of Cancer Registries databases between 2000-2017. The primary outcomes included age-adjusted incidence rate, limited-duration prevalence, and CSS. A total of 630 patients were identified for the incidence analysis and 149 for the prevalence and CSS analyses. The MANEC-P incidence rate was 0.011 per 100,000 individuals, which was the lowest among pancreatic cancer histologic subtypes. The incidence rate was significantly higher in men and Black races and peaked at 75-79 years of age. The incidence rate was the lowest in the midwestern region (0.009) and the highest in the northeastern US (0.013). The 17-year prevalence was 0.00005%, indicating that 189 patients were alive in the United States at the beginning of 2018. The median CSS of MANEC-P was estimated to be 41 (23, 69) months. In conclusion, MANEC-P is very rare, and its incidence rate has been steady in the US over the last two decades. MANEC-P has a poor prognosis and is the 5th leading cause of pancreatic cancer-related death in the US.

A new technique for 3-D imaging with a row-column array (RCA) configuration has been developed. The technique requires an electrostrictive piezoelectric for the active substrate. While the top set of electrodes is connected to RF transmit and receive channels for conventional diverging wave imaging (DWI), the orthogonal bottom set of electrodes is connected to independently controlled variable dc bias channels. By implementing modulated bias patterns compounded across multiple pulses, fine delay control across the bottom elements can be achieved simultaneously with imaging with the top set of electrodes. This resulted in a high-quality two-way focus in both azimuth and elevation. A 20-MHz electrostrictive composite substrate was fabricated, and 64 top ×64 bottom electrodes were patterned and connected to custom beamforming and biasing electronics. The point spread functions were generated in all dimensions, and the -6 dB resolution was measured to be 93 [Formula: see text] axially, [Formula: see text] in the azimuth, and 328 [Formula: see text] in the elevation dimension. This was in good agreement with the simulated resolutions of 80, 273, and 280 [Formula: see text], respectively.

Cholangiocarcinoma (CCA) is a highly lethal cancer arising from the biliary tract epithelium. The cancer biology of this neoplasm is not well understood. To date, only a few CCA cell lines have been reported, which were mostly developed from Asian patients. In this study, we report and characterize a new intrahepatic CCA cell line, LIV27, derived from a surgically resected tumor in a 67-year-old Caucasian woman with primary sclerosing cholangitis (PSC). LIV27 cells grow well in collagen-coated flasks or plates with a doubling time of 57.8 h at passage 14. LIV27 cells have high tumorigenicity in nude mice and stain positive for CK7 and CK19, markers that differentiate CCA from hepatocellular carcinoma. Karyotype analysis showed that LIV27 is aneuploid. We established a single-locus short tandem repeat profile for the LIV27 cell line. This newly established cell line will be a useful model for studying the molecular pathogenesis of, and developing novel therapies for, cholangiocarcinoma.

A firmware-based high-frequency beam- former implementing both conventional transmit focused B-mode imaging and diverging wave ultrafast (UF) imaging for Doppler overlay was developed. The beamformer can generate one transmit focused frame with four transmit focal zones (FZs), and 68 UF frames with 16 diverging waves each at a 10-Hz frame rate. The beamformer firmware stores the beamforming delays as a single bit, enabling efficient compression within the internal memory. The beamformer was characterized using a 30-MHz 64-element phased array endoscope. The hybrid system generates a 128 line by 768-pixel focused B-mode image spanning 1.2-12.6 mm axially over a ±32° range of steering angles. In addition, the system generates an UF image that is 64 lines by 384-pixels spanning 3.5-10.8 mm axially over a ±16° angle.

A forward-looking miniature histotripsy transducer has been developed that incorporates an acoustic lens and dual-frequency stacked transducers. An acoustic lens is used to increase the peak negative pressure through focal gain and the dual-frequency transducers are designed to increase peak negative pressure by summing the pressure generated by each transducer individually. Four lens designs, each with an f -number of approximately 1, were evaluated in a PZT5A composite transducer. The finite-element model (FEM) predicted axial beamwidths of 1.61, 2.40, 2.84, and 2.36 mm for the resin conventional, resin Fresnel, silicone conventional, and silicone Fresnel lenses, respectively; the measured axial beamwidths were 1.30, 2.28, 2.71, and 2.11 mm, respectively. Radial beamwidths from the model were between 0.32 and 0.35 mm, while measurements agreed to within 0.2 mm. The measured peak negative was 0.150, 0.124, 0.160, and 0.160 MPa/V for the resin conventional, resin Fresnel, silicone conventional, and silicone Fresnel lenses, respectively. For the dual-frequency device, the 5-MHz (therapy) transducer had a measured peak negative pressure of 0.136 MPa/V for the PZT5A composite and 0.163 MPa/V for the PMN-PT composite. The 1.2-MHz (pump) transducer had a measured peak negative pressure of 0.028 MPa/V. The pump transducer significantly lowered the cavitation threshold of the therapy transducer. The dual-frequency device was tested on an ex vivo rat brain, ablating tissue at up to 4-mm depth, with lesion sizes as small as [Formula: see text].

Background and Aims: Existing therapeutic approaches to treat cholangiocarcinoma (CCA) have limited effectiveness, prompting further study to develop therapies for CCA. We report a mechanistic role for the heparan sulfate editing enzyme sulfatase 2 (SULF2) in CCA pathogenesis., Approach and Results: In silico analysis revealed elevated SULF2 expression in human CCA samples, occurring partly through gain of SULF2 copy number. We examined the effects of knockdown or overexpression of SULF2 on tumor growth, chemoresistance, and signaling pathway activity in human CCA cell lines in vitro. Up-regulation of SULF2 in CCA leads to increased platelet-derived growth factor receptor beta (PDGFRβ)-Yes-associated protein (YAP) signaling activity, promoting tumor growth and chemotherapy resistance. To explore the utility of targeting SULF2 in the tumor microenvironment for CCA treatment, we tested an anti-SULF2 mouse monoclonal antibody, 5D5, in a mouse CCA xenograft model. Targeting SULF2 by monoclonal antibody 5D5 inhibited PDGFRβ-YAP signaling and tumor growth in the mouse xenograft model., Conclusions: These results suggest that SULF2 monoclonal antibody 5D5 or related agents may be potentially promising therapeutic agents in CCA., (© 2021 by the American Association for the Study of Liver Diseases.)

Sulfatase 2 (SULF2) is a heparan sulfate editing enzyme that regulates the milieu of growth factors and cytokines involved in a variety of cellular processes. We used a murine model of diet-induced steatohepatitis to assess the effect of SULF2 downregulation on the development of nonalcoholic steatohepatitis (NASH) and liver fibrosis. Wild-type B6;129 mice (WT) and Sulf2 -knockout B6;129P2-SULF2 Gt(PST111)Byg mice ( Sulf2- KO) were fed a fast-food diet (FFD) rich in saturated fats, cholesterol, and fructose or a standard chow diet (SC) ad libitum for 9 mo. WT mice on FFD showed a threefold increase in hepatic Sulf2 mRNA expression, and a 2.2-fold increase in hepatic SULF2 protein expression compared with WT mice on SC. Knockout of Sulf2 led to a significant decrease in diet-mediated weight gain and dyslipidemia compared with WT mice on FFD. Knockout of Sulf2 also abrogated diet-induced steatohepatitis and hepatic fibrosis compared with WT mice on FFD. Furthermore, expression levels of the profibrogenic receptors TGFβR2 and PDGFRβ were significantly decreased in Sulf2 -KO mice compared with WT mice on FFD. Together, our data suggest that knockout of Sulf2 significantly downregulates dyslipidemia, steatohepatitis, and hepatic fibrosis in a diet-induced mouse model of NAFLD, suggesting that targeting of SULF2 signaling may be a potential therapeutic mechanism in NASH. NEW & NOTEWORTHY We report for the first time that in wild-type (WT) mice, fast-food diet (FFD) induced a threefold increase in hepatic Sulf2 mRNA and a 2.2-fold increase in sulfatase 2 (SULF2) protein expression compared with WT mice on standard chow diet (SC). We showed that knockout of SULF2 ameliorates FFD-induced obesity, hyperlipidemia, steatohepatitis, and fibrosis. These data, along with work from other laboratories, suggest that SULF2 may be critical to the ability of the liver to progress to nonalcoholic steatohepatitis and fibrosis in conditions of overnutrition.

Maternal transfer of steroids to eggs can elicit permanent effects on offspring phenotype. Although testosterone was thought to be a key mediator of maternal effects in birds, we now know that vertebrate embryos actively regulate their exposure to maternal testosterone through steroid metabolism, suggesting testosterone metabolites, not testosterone, may elicit the observed phenotypic effects. To address the role steroid metabolism plays in mediating yolk testosterone effects, we used European starling ( Sturnus vulgaris ) eggs to characterize the timing of testosterone metabolism and determine whether etiocholanolone, a prominent metabolite of testosterone in avian embryos, is capable of affecting early embryonic development. Tritiated testosterone was injected into freshly laid eggs to characterize steroid movement and metabolism during early development. Varying levels of etiocholanolone were also injected into eggs, with incubation for either 3 or 5 days, to test whether etiocholanolone influences the early growth of embryonic tissues. The conversion of testosterone to etiocholanolone was initiated within 12 h of injection, but the increase in etiocholanolone was transient, indicating that etiocholanolone is also subject to metabolism, and that exposure to maternal etiocholanolone is limited to a short period during early development. Exogenous etiocholanolone manipulation had no significant effect on the growth rate of the embryos or extra-embryonic membranes early in development. Thus, the conversion of testosterone to etiocholanolone may be an inactivation pathway that buffers the embryo from maternal steroids, with any effects of yolk testosterone resulting from testosterone that escapes metabolism; alternatively, etiocholanolone may influence processes other than growth or take additional time to manifest., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)

Wound assessment is essential to manage wound care. The Wound Trend Scale (WTS) is a paper-and-pen instrument comprised of 14 parameters designed to guide assessment of findings relevant to lower leg ulcer management and includes an infection screen and cues for physician consultation. To determine its clinical utility, predictive value, and reliability, data were retrospectively analyzed from a random sampling of medical records of patients seen at a Foot and Leg Clinic between January 1, 2007 and December 31, 2008. Patients had 1 leg or foot ulcer, 3 consecutive assessments scheduled according to wound status (twice weekly if at high risk for nonhealing or amputation, weekly for moderate risk, or 1 to 2 months if stable), known outcomes, and a maximum treatment period of 3 months. Patient demographics included ulcer etiology, comorbid conditions (diabetes, neuropathy, peripheral arterial disease), and wound outcomes (closed, infection, amputation and surgery). Predictive values, inter- and intrarater reliability (assessed among the authors and 5 additional nurses with expertise using the study instrument), and the impact of WTS education on the wound assessment process were determined using 5 representative cases. Parameters were compared using the t-test. Seventy (70) patient records were examined and subdivided by ulcer site: foot (below ankle, 37) and leg (ankle and above, 33). Of the 13 etiologies, the foot group had 4 and the leg group 10; the foot group had more diabetes (92%), neuropathy (76%), and peripheral arterial disease (95%) than the leg group (52%, 5%, and 70%, respectively). Ulcer duration before referral averaged 16.42 (range 4-144) months. Wound outcomes included closed (57), infection (21), amputation (13), and surgery (3). Healing predictive values were sensitivity (99%), specificity (87%), and positive and negative predictive values and test efficiency (all 96%). Inter- and intrarater reliability were .85 (range .16-.96) and .86 (range .50-1.00), respectively. On admission, leg ulcers had larger surface area (P <0.05), more edema (P <0.01), more granulation (P <0.05), and higher total WTS scores (P <0.05) than foot ulcers, which had more infections (P <0.05). Foot ulcers at the third assessment had decreased tissue depth (P <0.05), increased epithelial tissue (P <0.01), and lower total WTS score (P <0.05). Significant third assessment parameters for leg ulcers were reduced depth (P <0.001), less necrotic tissue (P <0.001), less exudate (P <0.01), improved periwound condition (P <0.05), reduced edema (P <0.001), and increased epithelialization (P <0.01). After exposure to the WTS experience, the number of parameters assessed increased from 2.6 (registered nurses) and 1.5 (student nurses) to both using 15 (P <0.001). Nurses complied 100% with physician consultation for cued risks. Patient outcomes were 81% closure, and 70% had physician consultation for the risks identified. WTS predictive performance was excellent and improved nursing assessment practices. Future research to identify parameter criteria validity is warranted.

Offloading heel ulcers is a challenging task because strategies deemed to be most optimal from a medical perspective may be unacceptable to patients. Observed adverse dressing events and problems with offloading devices led to a pilot study and subsequent change in practice at the authors' Foot and Leg Ulcer Clinic. Starting in 2004, patients requiring offloading received a nonremovable padded heel dressing (PHD) that was changed twice a week by the visiting nurse. A retrospective quality improvement review was conducted to compare outcomes, nursing visits, and nursing visit costs for 40 consecutive patients with heel ulcers treated at this clinic with a nonremovable PHD (n = 20) or without a PHD (n = 20) between January 20, 2001 and December 31, 2006. Patient demographic data, relevant comorbidities, wound depth, weeks of care, adverse events, and treatment-related narrative comments were abstracted from patient records. Relevant comorbidities were similar in both groups. The PHD group was younger (average age of 74.6 [range 35-91] years) compared to PHD nonuse group (average age 79.5 [range 25-95] years; P less than 0.04). The PHD group required fewer total weeks of care compared to the nonuse group (368 versus 527 weeks, respectively; P less than 0.001), and average duration of clinic treatment in the PHD group was 18.40 (range 5-51) weeks versus 40.54 (range 6-88) weeks in the nonuse group. The PHD group had fewer total nursing visits (736 versus 1,581, P less than 0.001); the average number of nursing visits for the PHD was 36.80 (range 10-102) compared to 121.61 (range 18-264) for the nonuse group. Nursing visit costs were lower for PHD users ($114,080 versus $245,055, P less than 0.001), and the cost-efficiency ratio was less than one third (1:3.3) of PHD nonuse for the average heel ulcer. All 20 patients in the PHD use group had wound closure compared with the PHD nonuse group, in which 13 out of 20 wounds closed, 3 amputations were performed, and 4 patients were lost to review (P less than 0.000). No adverse events were reported in the records of the PHD use group; the PHD nonuse group reported periwound maceration, skin stripping, pressure injury, and sensitivity. Patient and nurse feedback identified pain relief, improved mobility, easy technique, low cost, and reduced workload as benefits of PHD. The results of this quality improvement review warrant a prospective clinical study to examine the efficacy, effectiveness, and cost-effectiveness of PHD for the care of patients with heel ulcers.

Background: A shift towards partial nephrectomy (PN) in the management of small renal cell carcinoma (RCC) in recent years has prompted a parallel change in the management of rare cases of transplant allograft RCC. There are currently no guidelines on the management of allograft RCC. We present our center experience and review the latest evidence for management of RCC in renal transplant allografts., Methods: We performed a retrospective review of the transplant patient registry of a kidney-pancreas transplant center between 1984 and 2012. All confirmed allograft kidney RCC cases were included in this series. MEDLINE search of current literature on renal allograft RCC and selection of appropriate studies were conducted., Results: A total of 1,241 patients had received either a living, cadaveric, or combined kidney-pancreas transplant at our center, and four cases of allograft RCC were identified. The first case underwent a radical nephrectomy given the central location of the tumor and his young age. The second case underwent an open PN in the setting of a central tumor with minimal morbidity. The third case involved multiple renal lesions that were subsequently treated with radiofrequency ablation (RFA). The fourth case underwent a non-ischemic open PN in the setting of a midpole tumor with minimal morbidity. There have been no cases of local recurrence or metastatic progression at median 21.5 months' follow-up., Conclusion: We have shown the safety and efficacy of minimally invasive techniques such as PN and RFA in a variety of tumors. We consider PN as an appropriate therapy for localized, clinical T1 allograft RCC tumors.

Background: There is little published data regarding the caseloads of general surgeons working in rural Australia conducting outreach services as part of their practice. It remains difficult to attract and retain surgeons in rural Australia. This study aims to describe the workload of surgeons working in a rural centre with outreach practices in order to determine the required skills mix for prospective surgeons., Methods: A retrospective review of surgical procedures carried out by two surgeons over 5 years working from a base in Wangaratta, Victoria, with outreach services to Benalla, Bright and Mansfield was undertaken. Data were extracted from surgeon records using Medicare Benefits Schedule item numbers., Results: A total of 18 029 procedures were performed over 5 years, with 15% of these performed in peripheral hospitals as part of an outreach service. A full range of general surgical procedures were undertaken, with endoscopies accounting for 32% of procedures. In addition, vascular procedures and emergency craniotomies were also performed. The majority of procedures undertaken at peripheral centres were minor procedures, with only two laparotomies performed at these centres over 5 years., Conclusion: General surgeons working in rural centres are required to have broad skills and be able to undertake a large number of procedures. Trainees should be encouraged to consider rural practice, and those who are interested should consider the needs of the community in which they intend to practice. Outreach work to surrounding communities can be rewarding for both the surgeon and the community., (© 2012 The Authors. ANZ Journal of Surgery © 2012 Royal Australasian College of Surgeons.)

Purpose: There is a paucity of information on the clinical efficacy and safety of the photoselective vaporization (PVP) of the prostate using the 180W lithium triborate (LBO) laser. We report on initial outcomes of PVP with the 180W laser, comparing the first 50 cases with the last 50 cases performed with the 120W LBO laser., Methods: All cases performed by a single surgeon (HHW) have been prospectively maintained. The last 50 cases treated with the 120W LBO laser (December 2009 to August 2010) were compared with the first 50 cases treated with the 180W LBO (July 2010 to June 2011). Patient variables were recorded preoperatively and at 3 months postoperatively. Perioperative data was also recorded., Results: The 180W cases had a larger median transrectal ultrasound prostate volume (68 mL vs. 51 mL, P<0.05). For the 180W and 120W LBO lasers, total operating time was 64.2 and 72.5 minutes (not significant [NS] at P=0.22), lasering time 49.6 and 54.6 minutes (NS, P=0.30) and energy utilisation 477.6 kJ and 377.9 kJ (P<0.05) respectively. When compared per gram of prostate tissue lasered, the 180W is quicker at 0.67 min/g vs. 1.0 min/g for the 120W laser. Complications using the Clavien-Dindo classification included 5 grade 1 complications and 3 grade 3b (bladder neck contractures) with the 180W LBO laser. The 120 W LBO laser had 4 grade 1 complications and 1 grade 2., Conclusions: There is little change in clinical outcomes with the transition from 120W to 180W LBO PVP with an already experienced PVP surgeon. The 180W LBO laser appears to have impacted upon patient selection with significantly increased prostate size and associated with increased energy utilisation. There appears to be a trend toward shorter laser times.

Background: There is a lack of published data on the range of procedures currently carried out by rural general surgeons. The aim of this study is to demonstrate the diversity of conditions encountered and managed by rural general surgeons, in order to determine the scope of training necessary to adequately equip trainees for rural practice., Methods: An audit of surgical procedures completed by two surgeons over 5 years from June 2004 to June 2009 in a rural Victorian hospital was carried out. Operations were further categorized into specialty groups., Results: A total of 8336 operations were completed over 5 years, by two surgeons servicing a catchment population of 54 000 people. Traditional general surgical procedures accounted for 44.3% with endoscopies accounting for a further 27.4% of cases. The remainder was accounted for by 11.8% orthopaedics, 4.5% urology, 4.4% vascular (including pacemaker insertion), 3.4% ear, nose and throat, 2.7% neurosurgery, 0.88% obstetrics and 0.42% thoracics. There was a need to be able to perform procedures well outside the field of traditional general surgery, including multisystem trauma, vascular emergencies, caesarean sections and post-partum hysterectomy., Conclusion: General surgeons servicing small rural communities are required to carry out a variety of procedures outside the realms of traditional general surgery. Trainees need to acquire a broad skill base, and should be competent managing surgical emergencies across all specialties. A supportive team of medical, nursing and paramedical staff are required for achieving the best outcome for patients.

The human immunodeficiency virus type 1 (HIV-1) matrix (MA) domain is involved in both early and late events of the viral life cycle. Simultaneous mutation of critical serine residues in MA has been shown previously to dramatically reduce phosphorylation of MA. However, the role of phosphorylation in viral replication remains unclear. Viruses harboring serine to alanine substitutions at positions 9, 67, 72, and 77 are severely impaired in their ability to infect target cells. In addition, the serine mutant viruses are defective in their ability to fuse with target cell membranes. Interestingly, both the fusion defect and the infectivity defect can be rescued by truncation of the long cytoplasmic tail of gp41 envelope protein (gp41CT). Sucrose density gradient analysis also reveals that these mutant viruses have reduced levels of gp120 envelope protein incorporated into the virions as compared to wild type virus. Truncation of the gp41CT rescues the envelope incorporation defect. Here we propose a model in which mutation of specific serine residues prevents MA interaction with lipid rafts during HIV-1 assembly and thereby impairs recruitment of envelope to the sites of viral budding.

Inflammatory activation of microglia in response to neurodegenerative changes in diseases such as Alzheimer's disease (AD) and Parkinson's disease has been extensively described. These observations have suggested that inflammation could be contributing to disease progression. In this paper, the potential role of CD200 and CD200 receptor (CD200R), whose known functions are to activate anti-inflammatory pathways and induce immune tolerance through binding of CD200 to CD200 receptor (CD200R), was studied in AD. Quantitative studies showed a significant decrease in CD200 protein and mRNA in AD hippocampus and inferior temporal gyrus, but not cerebellum. Immunohistochemistry of brain tissue sections of hippocampus, superior frontal gyrus, inferior temporal gyrus and cerebellum from AD and non-demented cases demonstrated a predominant, though heterogeneous, neuronal localization for CD200. Decreased neuronal expression was apparent in brain regions affected by AD pathology. There was also a significant decrease in CD200R mRNA expression in AD hippocampus and inferior temporal gyrus, but not cerebellum. Low expression of CD200R by microglia was confirmed at the mRNA and protein level using cultured human microglia compared to blood-derived macrophages. Treatment of microglia and macrophages with interleukin-4 and interleukin-13 significantly increased expression of CD200R. Expression of these cytokines was not generally detectable in brain. These data indicate that the anti-inflammatory CD200/CD200R system may be deficient in AD brains. Mechanisms aimed at increasing levels of CD200 and CD200R could have therapeutic potential for controlling inflammation in human neurodegenerative diseases.

We report on two cases of small bowel obstruction in the setting of a previous laparoscopic adjustable gastric band insertion. In both cases, a closed loop obstruction was created by the band and delayed diagnosis resulted in significant morbidity. Early recognition with deflation of the adjustable gastric band and nasogastric tube insertion is paramount to managing these patients.

Solitary fibrous tumours of the pleura are rare tumours originating from the mesenchymal cells of the submesothelial tissue of the pleura. The tumours may present in a variety of ways, ranging from no symptoms, to local symptoms such as dyspnoea, cough and chest pain, through to systemic symptoms such as clubbing and hypoglycaemia. We present a case of a solitary fibrous tumour, which presented with clubbing.

Physicians are not only called upon to deal with biological, but also with psychosocial issues and concerns in the treatment of the terminally ill. Their training, however, usually does not prepare them to value palliative care, or help them cope with personal feelings about death and possible grief over a patient's loss. The authors describe what one medical school is doing regarding the challenge of preparing medical students to deal more competently and confidently with end-of-life scenarios they will encounter as primary care practitioners in underserved areas of a rural state.

The activation of CD8(+) T cells by normal intestinal epithelial cells in antigen-specific or allogeneic mixed cell culture systems has significant implications for the modulation of mucosal immune responses due to the fact that these T cells appear to have regulatory rather than cytolytic activity. A 180-kDa glycoprotein (gp180) has been identified and shown to be important in CD8(+) T cell activation by intestinal epithelial cells. In this study, we examine, in further detail, the role that the CD8 molecule plays in this interaction. It has been previously shown that monoclonal antibodies against gp180 inhibited the activation of CD8-associated p56(lck) in T cells. Although indirectly suggested by these data, there was no evidence that the activation of this protein tyrosine kinase was a direct result of gp180 interacting with the CD8 molecule. In this study, we document that soluble gp180 is able to bind to CD8-Fc fusion proteins and is absorbed by human CD8 alpha but not CD4 transfected murine T cells and that this interaction is dependent upon carbohydrate on the gp180 molecule. Furthermore, the sites used for binding by gp180 are distinct from those used by the conventional CD8 ligand, class I MHC. Thus, gp180 appears to be a novel CD8 ligand that plays an important role in the activation of CD8-associated kinases and of CD8(+) T cells.

In the spring of 1999 in rural Newfoundland, abortions in goats were associated with illness in goat workers. An epidemiologic investigation and a serologic survey were conducted in April 1999 to determine the number of infections, nature of illness, and risk factors for infection. Thirty-seven percent of the outbreak cohort had antibody titers to phase II Coxiella burnetii antigen >1:64, suggesting recent infection. The predominant clinical manifestation of Q fever was an acute febrile illness. Independent risk factors for infection included contact with goat placenta, smoking tobacco, and eating cheese made from pasteurized goat milk. This outbreak raises questions about management of such outbreaks, interprovincial sale and movement of domestic ungulates, and the need for discussion between public health practitioners and the dairy industry on control of this highly infectious organism.