Weak elastic energy of irregular curves.

A weak notion of elastic energy for (not necessarily regular) rectifiable curves in any space dimension is proposed. Our [Formula: see text]-energy is defined through a relaxation process, where a suitable [Formula: see text]-rotation of inscribed polygons is adopted. The discrete [Formula: see text]-rotation we choose has a geometric flavour: a polygon is viewed as an approximation to a smooth curve, and hence its discrete curvature is spread out into a smooth density. For any exponent [Formula: see text] greater than 1, the [Formula: see text]-energy is finite if and only if the arc-length parametrization of the curve has a second-order summability with the same growth exponent. In that case, moreover, the energy agrees with the natural extension of the integral of the [Formula: see text]th power of the scalar curvature. Finally, a comparison with other definitions of discrete curvature is provided. This article is part of the theme issue 'Foundational issues, analysis and geometry in continuum mechanics'.

Prognostic role of serum thymidine kinase 1 kinetics during neoadjuvant chemotherapy for early breast cancer.

BACKGROUND: Emerging data support the use of thymidine kinase 1 (TK1) activity as a prognostic marker and for monitoring of response in breast cancer (BC). The long-term prognostic value of TK1 kinetics during neoadjuvant chemotherapy is unclear, which this study aimed to elucidate. METHODS: Material from patients enrolled to the single-arm prospective PROMIX trial of neoadjuvant epirubicin, docetaxel and bevacizumab for early BC was used. Ki67 in baseline biopsies was assessed both centrally and by automated digital imaging analysis. TK1 activity was measured from blood samples obtained at baseline and following two cycles of chemotherapy. The associations of TK1 and its kinetics as well as Ki67 with event-free survival and overall survival (OS) were evaluated using multivariable Cox regression models. RESULTS: Central Ki67 counting had excellent correlation with the results of digital image analysis (r = 0.814), but not with the diagnostic samples (r = 0.234), while it was independently prognostic for worse OS [adjusted hazard ratio (HRadj) = 2.72, 95% confidence interval (CI) 1.19-6.21, P = 0.02]. Greater increase in TK1 activity after two cycles of chemotherapy resulted in improved event-free survival (HRadj = 0.50, 95% CI 0.26-0.97, P = 0.04) and OS (HRadj = 0.46, 95% CI 0.95, P = 0.04). There was significant interaction between the prognostic value of TK1 kinetics and Ki67 (pinteraction 0.04). CONCLUSION: Serial measurement of serum TK1 activity during neoadjuvant chemotherapy provides long-term prognostic information in BC patients. The ease of obtaining serial samples for TK1 assessment motivates further evaluation in larger studies.

Bolus compared with continuous infusion of microbubble contrast agent using real-time contrast harmonic imaging ultrasound in breast tumors.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) has gained interest because of its ability to gather vascular information in various organs. There is still a matter of debate concerning its value in breast lesions. The method of choice on how to administer the contrast agent varies depending on the organ to be studied. Infusion of microbubbles is used in echocardiography, while bolus administration is the preferred technique for abdominal organs. PURPOSE: To compare-in equal doses-bolus versus continuous infusion of microbubbles, using real-time contrast harmonic imaging in breast tumors. MATERIAL AND METHODS: A total of 29 female patients (mean age 54 years) with either clear malignant or benign findings in the breast or axilla were included. Contrast harmonic imaging (CHI US) was performed with a Philips iU22 using an L9-3 MHz linear probe, especially designed for this purpose. A low mechanical index (0.06-0.07) was used to avoid massive destruction of the microbubbles. A dose of 2.4 ml of Sono Vue was first infused intravenously over 1 min with an infusion pump. After 10 min, the same dose was injected as a bolus over 2 s, followed by a flush of 10 ml of saline solution. Contrast uptakes by the tumors were recorded 2 min from the moment of injection, with both methods for each patient. RESULTS: Bolus administration of contrast agent provided a sharply demarcated enhancement and wash-out pattern for all lesions. The continuous infusion of the same contrast agent failed to show any wash-in/wash-out or time-to-peak/peak intensity phenomena in all cases. CONCLUSION: CEUS using real-time harmonic imaging in order to evaluate breast tumors should be performed with bolus administration of contrast agent in order to achieve better intensity/time curve outcomes.

Adjunctive diagnostic value of targeted electrical impedance imaging to conventional methods in the evaluation of breast lesions.

PURPOSE: To determine the diagnostic accuracy of targeted electrical impedance imaging in characterizing breast lesions, and to evaluate whether lesion size, depth and histopathology affect the diagnosis. MATERIAL AND METHODS: A total of 137 women with 145 lesions (79 malignant and 66 benign) found by palpation or mammography were prospectively enrolled in this study. The patients were examined by means of clinical breast examination, mammography, ultrasonography, and electrical impedance imaging with TransScan TS2000. A level of suspicion (LOS) post-processing algorithm (v2.67) was used for TS2000 lesion assessment. Imaging findings were correlated with cytologic (n=54) and histologic diagnoses (n=91). Patients with benign lesions were followed up for a mean of 36 months. RESULTS: TS2000 showed a high sensitivity (86%) which did not differ significantly from that of mammography (87%) and ultrasonography (US) (75%). The specificity of TS2000 (49%) was significantly lower compared to mammography (97%, P<0.0001) and US (100%, P<0.0001). The additive use of TS2000 to mammography and US yielded no significant increase in sensitivity (97%), but the decrease in specificity was significant (46%, P<0.0001). Diagnostic effectiveness of TS2000 (Az=0.68), as measured by the area under the ROC curve, was significantly lower than for mammography (Az=0.93, P<0.0001) and for US (Az=0.91, P<0.0001). When using TS2000 in addition to mammography and US (Az=0.86), a significant impairment was found (P=0.0003). CONCLUSION: The role of targeted electrical impedance imaging as an adjunct to mammography and ultrasonography in the diagnosis of breast lesions is not justified by the result of this study.

Implementation of an Italian multicentric care network for early HIV infection diagnosis: 1999-2001 report.

BACKGROUND: Diagnosis of a new HIV infection during the primary phase (PHI) is sometimes misleading in a primary care setting. Since 1999 the Italian network for the study of acute HIV infection (ISAI) has been operative. At the time of PHI diagnosis the case is reported to the coordinating centre and enrolled in the National Register which records all epidemiological, demographic and clinical information. PATIENTS AND METHODS: From 1999 to September 2001, 51 symptomatic or asymptomatic patients with diagnosis of primary HIV infection were signalled to the coordinating centre. At screening, assessments were: interview to collect demographic and epidemiological data, clinical history (regarding PHI signs and symptoms) and, if available, relevant index case information; physical examination; routine hematology and chemistry; lymphocyte count; plasma HIV-RNA. In a subset of patients PBMC HIV-DNA, HIV-RNA, resistance genotyping and HIV subtype characterization were assessed. RESULTS: 74.5% of patients were males and all but four were Italian. Hetero and homosexual contacts were the prevalent route of HIV transmission. Forty-five patients (89%) were symptomatic and the most frequent signs and symptoms were: fever, lymphadenopathy, malaise and pharyngodinia. Baseline reverse-transcriptase (RT) and protease (PR) genotyping analysis was available for 29 patients. Only one of 29 patients harbored a virus with a resistance-associated mutation in the RT region (215Y); NNRTI mutations were identified in 3 of 29 patients. In the remaining 20 (69%) patients no mutations were found in the RT region. Sequence data from PR region were successfully obtained in 21 patients. Only one of these had a high-level resistance mutation (46L); in an additional 10 cases 1 or more secondary mutations were identified. The remaining 10 patients harbored a PR region wild type virus. One patient presenting two secondary mutations in the PR region, even if highly adherent and tolerant to drug regimen, showed a slow viral load decrease. CONCLUSIONS: Our cohort confirms the uptrend of new infections through unsafe sexual contacts involving both homosexual and heterosexual couples. Genotype sequencing for antiretroviral resistant viral variants describes a low prevalence of RT resistance-associated mutations, as well as primary mutations in the PR region. On the contrary, a higher prevalence of PR gene polymorphisms and mutations is not known with any certainty to confer resistance to NRTI and NNRTI. The identification of antiretroviral drug resistant HIV strains is strategic for clinical and therapeutical intervention, even though from a public health point of view cost-efficacy must be considered.

Neurological symptoms during primary human immunodeficiency virus (HIV) infection correlate with high levels of HIV RNA in cerebrospinal fluid.

This analysis involves 22 patients with diagnosed symptomatic human immunodeficiency virus (HIV) infection. Neurologic symptoms were present in 11 patients, ranging from severe and persistent headache to clinical signs suggestive of meningitis. A strong correlation between neurological symptoms and cerebrospinal fluid (CSF) viral load was found. The mean CSF HIV ribonucleic acid (RNA) level was 4. 12 log for patients with neurological symptoms and 2.58 log for patients without neurological symptoms (P<.00001). Plasma viral load alone does not correlate or predict central nervous system (CNS) involvement. In our sample of patients, HIV RNA levels could be detected in most patients regardless of the presence of neurological symptoms. Moreover, early treatment including drugs with high levels of penetration in the CNS must be considered for patients with primary HIV infection.

Anti-CD4 antibodies in exposed seronegative adults and in newborns of HIV type 1-seropositive mothers: a follow-up study.

In this work, an ELISA for the quantitative determination of IgG anti-CD4 autoantibodies was validated and utilized in the follow-up of two cohorts of HIV-1-exposed seronegative subjects. A serum with an arbitrarily assigned concentration of 100,000 units/ml was used as a reference, and the detection limit, inter- and intraassay variability, and analytical recovery were calculated. The study subjects included adults sexually exposed to HIV-1-infected partners and the newborns of HIV-1+ mothers who seroreverted by 18 months of age. Some of these individuals were studied over an 18- to 24-month period. The detection limit of the assay was 2000 AU/ml. Intra- and interassay variability was, respectively, 3.92 and 3.90%. Analytical recovery in an assay in which a fixed amount of anti-CD4 antibodies was added to different samples was 98%. A proportion of adults (16 of 47, 34.0%) and babies (12 of 27, 44.4%) had significantly higher concentrations of anti-CD4 antibodies. Among them, 8 adults maintained the same concentration as that found in the first determination; on the other hand, 12 babies born to seronegative mothers showed a significant increase in the concentration of anti-CD4 antibodies during their first months of life. In conclusion, anti-CD4 antibodies can be measured using a validated ELISA. They represent a serologic trait that is quantitatively conserved in HIV-1-exposed seronegative adult individuals and is actively acquired by newborns to HIV+ mothers.

Idiopathic chronic fatigue and chronic fatigue syndrome: a comparison of two case-definitions.

The aim of the study was to compare the signs and symptoms of individuals meeting two different definitions of chronic fatigue syndrome (CFS). Ninety-four patients fitting the eligibility criteria for idiopathic fatigue were enrolled into the study. Of the 94 patients, 48 met the 1988 definition of CFS, 20 the 1994 (but not the 1988) definition of CFS, and 26 met neither definition. The 1994 defined cases were more likely than 1988 defined cases, and non-syndromal individuals to be male, married, and high school educated. The 1994 cases were less likely than 1988 cases to present acute onset, self reported sore throat, mild fever lymphadenopathy, pharyngitis. In conclusion, the 1994 criteria increased the number of patients classified as CFS; however, those who fit only the 1994 criteria were less likely to have an acute symptomatic onset and signs and symptoms suggestive of an infectious process.

Monitoring antiretroviral activity using ICDp24 and CD4 counts in HIV infection.

The fluctuations of HIV-1 p24 antigen concentration have been monitored in the follow-up of 118 subjects in different clinical stages and compared to their CD4 cell count; 104 patients received antiretroviral therapy. Persistent (65%) or sporadic (28%) antigenaemia has been detected in most patients in different clinical stages. The variations of the p24 Ag level are significantly correlated with the CD4 cell count and therapy administration (P = 0.0001). In patients with relatively conserved immune function (CDC II and III), antiretroviral therapy shows the best efficacy and can be efficiently monitored by p24 and CD4 surrogate markers. The data here suggest that although the informative value of p24 Ag is not representative of an AIDS-defining event, it can be used as a short-term and relatively inexpensive virological marker of antiviral activity in vivo, to support the routine management of patients.

Epidemic HIV-related Kaposi's sarcoma: a retrospective analysis and validation of TIS staging. GICAT. Gruppo Italiano Collaborativo AIDS e Tumori.

BACKGROUND: We wished to assess the clinical value in terms of treatment choice and establishment of the prognosis of the ACTG classification modified (TNM-TIS) according to the recent guidelines of CDC for the classification of the HIV infection in patients with HIV-related epidemic Kaposi's sarcoma (EKS). PATIENTS: We retrospectively studied 296 HIV-positive individuals with EKS. Patients were initially classified according to the NYU system and then reclassified according to the TNM-TIS proposal which considers three major parameters: T, anatomical extent of the lesion; I, immune system status; S, HIV-related systemic illness. METHODS: Survival analyses according to patient characteristics and the different TNM-TIS classification stages were performed; curves were compared using the Kaplan-Meyer method, and predictive factors for survival using the Cox model. RESULTS: Of the parameters considered in the TNM-TIS staging system, the T variable was not predictive of survival. Conversely, I and S variables revealed predictive value in the survival analyses, when considered separately and together. CONCLUSIONS: The extent of cutaneous or mucosal lesions of Kaposi's sarcoma did not correlate with prognosis. However, both CD4+ cell count and history of systemic illness were predictive of survival. Indicators of HIV infection must be included in the clinical evaluation of EKS patients and taken into account when choosing optimal treatment.

Antiretroviral treatment of men infected with human immunodeficiency virus type 1 reduces the incidence of heterosexual transmission. Italian Study Group on HIV Heterosexual Transmission.

OBJECTIVE: To determine the incidence of heterosexual human immunodeficiency virus type 1 disease transmission and the effect of zidovudine therapy on this risk of transmission. DESIGN: A cohort of 436 monogamous seronegative female sexual partners of human immunodeficiency virus type 1-infected males was followed up for 740 person-years with regular structured interviews and laboratory tests. PATIENTS: At enrollment of the women, 50% of their infected partners had one or more signs of disease progression (symptoms of acquired immunodeficiency syndrome, p24 antigen positivity, or CD4+ cell counts lower than 0.4 x 10(9)/L) and 15% were treated with zidovudine. MAIN OUTCOME MEASURE: Incidence rates of seroconversion were calculated and relative risks were estimated as incidence rate ratios. RESULTS: Twenty-seven women seroconverted during follow-up, and the incidence of seroconversion was 3.7 per 100 person-years. Seroconversion was about six times more frequent (relative risk, 5.8; 95% confidence interval, 2.2 to 15.3) in couples not using condoms. Men with signs of disease progression transmitted infection to their partners more frequently and were more frequently treated with zidovudine. When the risk of transmission was estimated accounting for disease progression, the rate of transmission in zidovudine-treated men was lower than in untreated men (relative risk, 0.5; 95% confidence interval, 0.1 to 0.9). CONCLUSION: Treatment of human immunodeficiency virus type-1 infected men with zidovudine reduces, but does not eliminate, heterosexual transmission of infection. Behavioral counseling that encourages sexual practices with a lower risk of transmission remains the most important method of prevention.

Risk factors for woman-to-man sexual transmission of the human immunodeficiency virus. Italian Study Group on HIV Heterosexual Transmission.

A cross-sectional study of stable monogamous couples, recruited from 16 clinical and surveillance centers in Italy between 1987 and 1992, was carried out to investigate the risk factors of woman-to-man sexual transmission of human immunodeficiency virus (HIV). The male partners of all HIV-infected women attending the centers were invited to participate in the study. Of the 275 male partners who were tested for HIV and interviewed with use of a structured questionnaire, 51 were excluded because they had other possible risk factor for HIV infection, no established risk factor was found in the index case, or they had stopped engaging in sexual intercourse. Fourteen of the 224 men (6.3%) were seropositive for HIV. At logistic regression, the highest risks of transmission were for men practicing peno-anal intercourse [odds ratio (OR), 4.6; 95% confidence interval (CI), 1.0-22.2] and for men whose partner had acquired immune deficiency syndrome (AIDS) or a CD4+ lymphocyte count of < or = 400/mm3. No seropositive men were observed among those who were aware of the woman's HIV seropositivity since the beginning of the relationship or were partners of a zidovudine-treated woman. The results suggest that the risk factors described in man-to-woman and man-to-man HIV sexual transmission also operate in woman-to-man transmission.

Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men.

To study incidence and risk factors of heterosexually transmitted HIV infection, we followed a cohort of 343 seronegative women, stable, monogamous partners of infected men whose only risk of acquiring HIV was sexual exposure to the infected partner. Nineteen seroconversions occurred in 529.6 person years (py) of observation, yielding an incidence rate of 3.6 per 100 py. The incidence rate was 7.2 per 100 py among women who did not always use or never used condoms and 1.1 among those who always used them [relative risk (RR) 6.6, 95% confidence interval (CI) 1.9-21.9]. Anal sex was associated with a risk increase in only those women not always using condoms (RR 1.4, 95% CI 0.4-4.8). No seroconversions were observed among 22 women using oral contraceptives. One of the women using intrauterine devices seroconverted. In couples who did not always use condoms, seroconversions occurred more frequently in partners of men with symptomatic diseases, with a low CD4+ cell number (< 400 per mm3) or with a detectable p24 antigen. In couples not always using condoms and where the man had a low CD4+ cell count, the joint presence of blood viral antigens and AIDS symptoms conditioned a fivefold increased risk of seroconversion of the woman (RR 5.4, CI 1.4-20.3). At multivariate analysis, women with longer relationships (> or = 1 year) showed a lower risk of seroconversion (RR 0.3, CI 0.1-0.8), and those partners of men positive for p24 antigen in serum had an increased risk of seroconversion (RR = 4.0, CI 0.1-0.8).

Incidence and prevalence trends of HIV infection in intravenous drug users attending treatment centers in Milan and northern Italy, 1986-1990.

To assess the incidence and time trends of human immunodeficiency virus (HIV) infection among intravenous drug users (IVDUs) and to evaluate the opportunities for prevention, we studied IVDUs recruited from 23 drug dependence treatment centers in Milan and Northern Italy. Participants were screened for HIV antibodies, and seronegative subjects were enrolled. A preventive intervention, based on counseling and HIV antibody testing, was done, and participants were invited to the centers for follow-up visits. We enrolled 1,532 subjects between 1 January 1987 and 31 October 1990, and we observed 901 subjects for an average of 15.9 months. Forty-one cases of HIV infection occurred, giving a seroconversion rate of 6.1% in 1987, 4.1% in 1988, 2.2% in 1989, and 1.6% in 1990. HIV prevalence decreased from 54% in 1986 to 49% in 1989. Incidence rates were higher in areas with high prevalence. During follow-up, 35 to 55% of the subjects stopped injecting heroin intravenously altogether, and those who did not stop decreased the frequency of syringe sharing. This is probably the reason for the decline in seroconversion rates, while the apparent decline in prevalence may be due to the entry of new seronegative individuals and/or to differential withdrawal of HIV-positive individuals from the IVDU population to the heterosexual (non-IVDU) population.