Francesco Parona (1842-1908) and his contributions to our understanding of surgery through anatomy.

Much of the life of Francesco Parona and many of his contributions to medicine are unknown outside of Europe. Parona made novel contributions to many surgical techniques and medical treatments and was an active member of society and the Italian political regime. Parona's name lives on eponymously by his "space" in the forearm. This paper will discuss the personal life and medical contributions of Francesco Parona.

Fourteen-Day Evolution of COVID-19 Symptoms during the Third Wave in Nonvaccinated Subjects and Effects of Hesperidin Therapy: A Randomized, Double-Blinded, Placebo-Controlled Study.

COVID-19 symptoms can cause substantial disability, yet no therapy can currently reduce their frequency or duration. We conducted a double-blind placebo-controlled trial of hesperidin 1000 mg once daily for 14 days in 216 symptomatic nonvaccinated COVID-19 subjects. Thirteen symptoms were recorded after 3, 7, 10, and 14 days. The primary endpoint was the proportion of subjects with any of four cardinal (group A) symptoms: fever, cough, shortness of breath, or anosmia. At the baseline, symptoms in decreasing frequency were as follows: cough (53.2%), weakness (44.9%), headache (42.6%), pain (35.2%), sore throat (28.7%), runny nose (26.9%), chills (22.7%), shortness of breath (22.2%), anosmia (18.5%), fever (16.2%), diarrhea (6.9%), nausea/vomiting (6.5%), and irritability/confusion (3.2%). Group A symptoms in the placebo vs. hesperidin group were 88.8% vs. 88.5% (day 1) and reduced to 58.5 vs. 49.4% at day 14 (OR 0.69, 95% CI 0.38-1.27, p = 0.23). At day 14, 15 subjects in the placebo group and 28 in the hesperidin group failed to report their symptoms. In an attrition bias analysis imputing "no symptoms" to missing values, the hesperidin group showed reduction of 14.5% of group A symptoms from 50.9% to 36.4% (OR: 0.55, 0.32-0.96, p = 0.03). Anosmia, the most frequent persisting symptom (29.3%), was lowered by 7.3% to 25.3% in the hesperidin group vs. 32.6% in the placebo group (p = 0.29). The mean number of symptoms in the placebo and hesperidin groups was 5.10 (SD 2.26) vs. 5.48 (SD 2.35) (day 1) and 1.40 (SD 1.65) vs. 1.38 (SD 1.76) (day 14) (p = 0.92). In conclusion, most nonvaccinated COVID-19 infected subjects remain symptomatic after 14 days with anosmia being the most frequently persisting symptom. Hesperidin 1 g daily may help reduce group A symptoms. Earlier treatment of longer duration and/or higher dosage should be tested.

Henry Jacob Bigelow (1818-1890): his contributions to anatomy and surgery.

There have been many advances in the medical world over time that have greatly contributed to ameliorating and prolonging human life. The employment of surgical anesthesia is arguably one of the greatest medical discoveries of all time, and has immensely broadened our ability to treat the ill. While Dr. Henry Jacob Bigelow (1818-1890) was not the inventor of anesthesia, he was the first to publish and advocate its use in the 19th century (Bigelow and Bigelow [1894] A Memoir of Henry Jacob Bigelow, Boston: Little, Brown, and Company; Harrington and Mumford [1905] The Harvard Medical School: A History, Narrative and Documentary, Vol 2, New York: Lewis Publishing Company). Bigelow also contributed to revolutionizing the fields of orthopedic and urologic surgery, publishing extensive research on subjects where there was previously very little knowledge, and even developing new techniques. He also impacted the field of neuropsychiatry in his publication regarding Phineas Gage. His contributions to the medical field have set him apart as one of the most influential and famous surgeons of America in the 19th century. Anatomically, he will be remembered eponymously for his iliofemoral ligament and septum in the femur.

Biomechanical assessment of variable instrumentation strategies in adolescent idiopathic scoliosis: preliminary analysis of 3 patients and 6 scenarios.

Since the introduction of modern multi-segmental instrumentation systems, disagreement exists about the appropriate instrumentation strategies for the "optimal" correction of scoliotic deformities, and the difference between alternative scenarios is difficult to predict a priori. The purpose of this study is to evaluate the effect of different instrumentation strategies using a computer assisted surgery simulator (S3). We obtained from 32 experienced Fellows of the Scoliosis Research Society and members of the Spinal Deformities Study Group the detailed preoperative planning for three AIS patients with Lenke curve types 1A, 3A and 5C. Their scenarios were individually simulated using a computer model implemented in a spine surgery simulator (S3). The resulting Cobb angles varied for the 3 cases (e.g.: main thoracic: 6-17 degrees; 16-29 degrees; 16-30 degrees). The variability of correction remained important when sub-classifying the results according to the instrumentation strategies: A- "Pedicle Screws Constructs"; B- "Hooks Constructs"; C- "Hybrid Constructs". But overall, the average correction was better in group A (71%) than in groups B (55%) and C (54%). For the first time the effect of various instrumentation strategies can be assessed preoperatively thanks to S3. A large variability of instrumentation strategies exist within experienced surgeons and these produce rather different results. This study also questions the criteria for optimal configuration and standards to objectively design the best surgical construct.

Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog.

In vivo bioconjugation to the free thiol on Cys34 of serum albumin by a strategically placed reactive group on a bioactive peptide is a useful tool to extend plasma half-life. Three maleimido derivates of human GH-releasing factor (hGRF)(1-29) were synthesized and bioconjugated to human serum albumin ex vivo. All three human serum albumin conjugates showed enhanced in vitro stability against dipeptidylpeptidase-IV and were bioactive in a GH secretion assay in cultured rat anterior pituitary cells. When the maleimido derivatives were individually administered sc to normal male Sprague Dawley rats, an acute secretion of GH was measured in plasma. The best compound, CJC-1295, showed a 4-fold increase in GH area under the curve over a 2-h period compared with hGRF(1-29). CJC-1295, a tetrasubstituted form of hGRF(1-29) with an added N epsilon-3-maleimidopropionamide derivative of lysine at the C terminus, was selected for further pharmacokinetic evaluation, where it was found to be present in plasma beyond 72 h. A Western blot analysis of the plasma of a rat injected with CJC-1295 showed the presence of a CJC-1295 immunoreactive species on the band corresponding to serum albumin, appearing after 15 min and remaining in circulation beyond 24 h. These results led to the identification of CJC-1295 as a stable and active hGRF(1-29) analog with an extended plasma half-life.

Development and characterization of a glucagon-like peptide 1-albumin conjugate: the ability to activate the glucagon-like peptide 1 receptor in vivo.

The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has fostered new approaches for generation of degradation-resistant GLP-1 analogues. We examined the biological activity of CJC-1131, a DPP-IV-resistant drug affinity complex (DAC) GLP-1 compound that conjugates to albumin in vivo. The CJC-1131 albumin conjugate bound to the GLP-1 receptor (GLP-1R) and activated cAMP formation in heterologous fibroblasts expressing a GLP-1R. CJC-1131 lowered glucose in wild-type mice, but not in GLP-1R-/- mice. Basal glucose and glycemic excursion following glucose challenge remained significantly reduced 10-12 h following a single injection of CJC-1131. Twice daily administration of CJC-1131 to db/db mice significantly reduced glycemic excursion following oral and IP glucose challenge (P < 0.01 to 0.05) but did not significantly lower body weight during the 4-week study period. Levels of random fed glucose were significantly lower in CJC-1131-treated +/+ and db/db mice and remained significantly lower even 1 week following discontinuation of CJC-1131 administration. CJC-1131 increased levels of pancreatic proinsulin mRNA transcripts, percent islet area, and the number of bromodeoxyuridine-positive islet cells. These findings demonstrate that an albumin-conjugated DAC:GLP-1 mimics the action of native GLP-1 and represents a new approach for prolonged activation of GLP-1R signaling.

Effects of alternative instrumentation strategies in adolescent idiopathic scoliosis: a biomechanical analysis.

The recent advent of modern instrumentation systems has improved the correction of scoliosis, but complicated the surgical decision-making process, especially with the introduction of diverse spinal fixation devices, new preoperative corrective maneuvers, and the reevaluation of many rules concerning the selection of fusion levels and other guidelines for surgical correction. Our objective was to assess the biomechanical effects of different instrumentation strategies for the same scoliotic cases. Several instrumentation strategies suggested by a group of 32 experienced senior surgeons for five cases were individually simulated using a validated computer model implemented in a spine surgery simulator. The resulting geometric indices varied among the five cases (e.g., range of main thoracic Cobb angles: 5-17 degrees , 16-29 degrees , 25-44 degrees , 15-34 degrees , 16-32 degrees ; kyphosis: 22-33 degrees , 20-54 degrees , 33-55 degrees , 24-49 degrees , 29-46 degrees ; and lordosis: 10-52 degrees , 24-38 degrees , 26-54 degrees , 8-28 degrees , 34-53 degrees ). The average correction was better with pedicle screws (71%) than with hooks (51%) and hybrid constructs (67%). For the first time, to our knowledge, the effect of different instrumentation strategies was compared on the same patients, which is possible only with a surgery simulator. A large variability of instrumentation strategies existed among experienced surgeons and produced rather different results. This study questions the criteria for optimal configuration and standards to design the best surgical construct.

Albumin-conjugated C34 peptide HIV-1 fusion inhibitor: equipotent to C34 and T-20 in vitro with sustained activity in SCID-hu Thy/Liv mice.

Entry inhibitors of human immunodeficiency virus, type 1 (HIV-1) have been the focus of much recent research. C34, a potent fusion inhibitor derived from the HR2 region of gp41, was engineered into a 1:1 human serum albumin conjugate through stable covalent attachment of a maleimido-C34 analog onto cysteine 34 of albumin. This bioconjugate, PC-1505, was designed to require less frequent dosing and less peptide than T-20 and was assessed for its antifusogenic activity both in vitro and in vivo in the SCID-hu Thy/Liv mouse model. PC-1505 was essentially equipotent to the original C34 peptide and to T-20 in vitro. In HIV-1-infected SCID-hu Thy/Liv mice, T-20 lost activity with infrequent dosing, whereas the antiviral potency of PC-1505 was sustained, and PC-1505 was active against T-20-resistant ("DIV") virus with a G36D substitution in gp41. The in vivo results are the direct result of a significantly improved pharmacokinetic profile for the C34 peptide following albumin conjugation. Contrary to previous reports that the gp41 NHR trimer is poorly accessible to C34 fused to protein cargoes of increasing size (Hamburger, A. E., Kim, S., Welch, B. D., and Kay, M. S. (2005) J. Biol. Chem. 280, 12567-12572), these results are the first demonstration of the capacity for a large, endogenous serum protein to gain unobstructed access to the transient gp41 intermediates that exist during the HIV fusion process, and it supports further development of albumin conjugation as a promising approach to inhibit HIV-1 entry.

Scoliosis correction objectives in adolescent idiopathic scoliosis.

BACKGROUND: A recent study revealed large variability among a group of 32 spine surgeons in the preoperative instrumentation strategies for the same 5 adolescent idiopathic scoliosis (AIS) patients. The surgical plans were determined to be surgeon and curve-type dependent. It is hypothesized that this variability may be attributed to different objectives for correction. This study is presented to document and analyze 3-dimensional (3-D) surgical correction goals for AIS as determined by a sample of experienced spine surgeons. METHODS: Fifty surgeons from the Spinal Deformity Study Group were surveyed and asked to rank 20 parameters of scoliosis correction and to provide weights for correction in the coronal, sagittal, and transverse planes and for mobility (number of unfused vertebrae) according to their importance for an optimal 3-D correction. Responders were also asked to complete a more detailed survey where the correction objectives were assessed for each of the 6 Lenke curve types. Importance and variability of the correction parameters were evaluated using median (M) and interquartile range (IQR) of the rank (1-20). Intraobserver reliability was assessed by means of intraclass correlation coefficients. RESULTS: Twenty-five surgeons completed the first questionnaire. There was overall agreement that sagittal (M, 1; IQR, 1) and coronal (M, 2; IQR, 0.5) balance were the most important parameters for an optimal correction. Apical vertebral rotation was the least important. All other parameters were highly variable. The Cobb angles were moderately important, with ranks between 8 and 11 (IQR, 3-5.75). Lumbar lordosis (M, 6.5; IQR, 6.5) had a better rank and consensus than thoracic kyphosis (M, 13; IQR, 10). Results for individual parameters were in agreement with the weights given for an optimal 3-D correction in the coronal (36%) and sagittal (34%) planes. A subgroup of 10 surgeons completed the second survey. Mobility was more important for Lenke curve types 3 to 6 than for types 1 and 2 (P < 0.032). The coronal plane was more important for curve types 2 and 4 than for the other types (P < 0.032). The intraobserver reliability for determining the different parameters of scoliosis correction was poor to moderate. CONCLUSIONS: There is a large variability in scoliosis correction objectives. The variability is both surgeon and curve-type dependent. The variability in instrumentation goals may explain the documented variability of spine instrumentation strategies among surgeons. Aside from achieving sagittal and coronal balance, the goals of surgical correction in AIS remain to be further determined and agreed upon by a consensus of spine deformity surgeons. LEVEL OF EVIDENCE: Level V.

A covalent inhibitor targeting an intermediate conformation of the fusogenic subunit of the HIV-1 envelope complex.

Peptide inhibitors corresponding to sequences in the six helix bundle structure of the fusogenic portion (gp41) of the HIV envelope glycoprotein have been successfully implemented in preventing HIV entry. These peptides bind to regions in HIV gp41 transiently exposed during the fusion reaction. In an effort to improve upon these entry inhibitors, we have successfully designed and tested peptide analogs composed of chemical spacers and reactive moieties positioned strategically to facilitate covalent attachment. Using a temperature-arrested state prime wash in vitro assay we show evidence for the trapping of a pre-six helix bundle fusion intermediate by a covalent reaction with the specific anti-HIV-1 peptide. This is the first demonstration of the trapping of an intermediate conformation of a viral envelope glycoprotein during the fusion process that occurs in live cells. The permanent specific attachment of the covalent inhibitor is projected to improve the pharmacokinetics of administration in vivo and thereby improve the long-term sustainability of peptide entry inhibitor therapy and help to expand its applicability beyond salvage therapy.

Synthesis and evaluation of insulin-human serum albumin conjugates.

A series of human insulin maleimido derivatives with short and long linkers was synthesized by exploiting the variations in the pK(a) values and environment of the three amino groups present in the protein. The syntheses were accomplished in organic solvent because of maleimide's instability in basic aqueous media. The derivatives thus obtained were conjugated to the free thiol on Cys34 of human serum albumin (HSA) and purified. A structure-activity relationship based on in vitro receptor binding and activation results for this series of insulin-HSA conjugates showed that the best compounds were attached at the B1 position of insulin with either short or long linkers. Two conjugates were administered subcutaneously to streptozotocin-induced diabetic rats and found to possess blood glucose normalizing activity up to 8 h post-administration. The return to diabetic plasma glucose levels was not observed within the time frame of the experiment (48 h). In comparison, the insulin-treated group's normalization activity lasted 2 h and returned to a diabetic level at 8 h. The onset of the conjugate activities were delayed by 1 h when compared to the activity of human insulin. The study results led to the identification of CJC-1575 as a potent and long lasting human insulin analogue.

Identification of CJC-1131-albumin bioconjugate as a stable and bioactive GLP-1(7-36) analog.

A series of analogs of GLP-1(7-36) amide containing a Nepsilon-(2-[2-[2-(3-maleimidopropylamido)ethoxy]ethoxy]acetyl)lysine has been synthesized and the resulting derivatives were bioconjugated to Cys34 of human serum albumin (HSA). The GLP-1-HSA bioconjugates were analyzed in vitro to assess the stabilizing effect of bioconjugation in the presence of DPP-IV as well as GLP-1 receptor binding and activation. Compound 9 (CJC-1131) having the point of attachment to albumin at the C-terminal of GLP-1 and a D-alanine substitution at position 8 was identified as having the best combination of stability and bioactivity.

Design, synthesis, and characterization of peptide nanostructures having ion channel activity.

We report the synthesis and the functional studies of multiple crown alpha-helical peptides designed to form artificial ion channels. The approach combines the versatility of solid phase peptide synthesis, the conformational predictability of peptidic molecules, and the solution synthesis of crown ethers with engineerable ion-binding abilities. Several biophysical methods were employed to characterize the activity and the mode of action of these crown peptide nanostructures. The 21 residue peptides bearing six 21-EC-7 turned out to facilitate the translocation of ions in a similar fashion to natural ion channels.

Synthesis and in vitro analysis of atrial natriuretic peptide-albumin conjugates.

Atrial natriuretic peptide (ANP) is a clinically useful anti-hypertensive hormone. Maleimide derivatives of ANP have been synthesized and conjugated to cysteine-34 of human serum albumin. The conjugates were analyzed to assess their stability, receptor binding affinity and ability to stimulate guanylyl-cyclase activity in rat lung fibroblasts.